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Mehrani Y, Morovati S, Keivan F, Sarmadi S, Shojaei S, Forouzanpour D, Bridle BW, Karimi K. Dendritic Cell-Based Cancer Vaccines: The Impact of Modulating Innate Lymphoid Cells on Anti-Tumor Efficacy. Cells 2025; 14:812. [PMID: 40497988 PMCID: PMC12155103 DOI: 10.3390/cells14110812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2025] [Revised: 05/15/2025] [Accepted: 05/28/2025] [Indexed: 06/19/2025] Open
Abstract
Dendritic cell (DC) vaccines stimulate the immune system to target cancer antigens, representing a promising option for immunotherapy. However, clinical trials have demonstrated limited effectiveness, emphasizing the need for enhanced immune responses. Improving the production of DC vaccines, assessing their impact on immune components, and observing responses could improve the results of DC-based therapies. Innate lymphoid cells (ILCs) represent a heterogeneous population of innate immune components that generate cytokines and modulate the immune system, potentially enhancing immunotherapies. Recent research highlights the different functions of ILCs in cancer, demonstrating their dual capabilities to promote tumors and exhibit anti-tumor actions. DCs and ILCs actively communicate under physiological and pathological conditions, and the activation of ILCs by DCs or DC vaccines has been shown to influence ILC cytokine production and function. Gaining insights into the interaction between DC-activated ILCs and tumors is essential for creating exciting new therapeutic strategies. These strategies aim to boost anti-tumor immunity while reducing the support that tumors receive. This review examines the effect of DC vaccination on host ILCs, illustrating the complex relationship between DC-based vaccines and ILCs. Furthermore, it explores some exciting strategies to enhance DC vaccines, aiming to boost anti-tumor immune responses by fostering better engagement with ILCs.
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Affiliation(s)
- Yeganeh Mehrani
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada;
| | - Solmaz Morovati
- Division of Biotechnology, Department of Pathobiology, School of Veterinary Medicine, Shiraz University, Shiraz 71557-13876, Iran;
| | - Fatemeh Keivan
- Department of Microbiology and Immunology, School of Veterinary Medicine, University of Tehran, Tehran 14179-35840, Iran; (F.K.); (S.S.); (S.S.); (D.F.)
| | - Soroush Sarmadi
- Department of Microbiology and Immunology, School of Veterinary Medicine, University of Tehran, Tehran 14179-35840, Iran; (F.K.); (S.S.); (S.S.); (D.F.)
| | - Sina Shojaei
- Department of Microbiology and Immunology, School of Veterinary Medicine, University of Tehran, Tehran 14179-35840, Iran; (F.K.); (S.S.); (S.S.); (D.F.)
| | - Diba Forouzanpour
- Department of Microbiology and Immunology, School of Veterinary Medicine, University of Tehran, Tehran 14179-35840, Iran; (F.K.); (S.S.); (S.S.); (D.F.)
| | - Byram W. Bridle
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada;
| | - Khalil Karimi
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada;
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2
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von Renesse J, Lin MC, Ho PC. Tumor-draining lymph nodes - friend or foe during immune checkpoint therapy? Trends Cancer 2025:S2405-8033(25)00104-9. [PMID: 40348668 DOI: 10.1016/j.trecan.2025.04.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2025] [Revised: 04/20/2025] [Accepted: 04/21/2025] [Indexed: 05/14/2025]
Abstract
The pivotal role of tumor-draining lymph nodes (TDLNs) in supporting antitumor immunity and serving as sites for cancer metastasis presents a clinical challenge: eliminate tumors while preserving antitumor immune responses. In this article, we explore the initiation of tumor-specific immune responses within lymph nodes (LNs), the immunocompromised microenvironment induced by tumors within LNs, and the crucial involvement of TDLNs in immunotherapy. Additionally, we examine the clinical prospects of modifying surgical procedures or therapy sequences to enhance the efficacy of cancer treatment.
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Affiliation(s)
- Janusz von Renesse
- Department of Oncology, University of Lausanne, Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland
| | - Mei-Chun Lin
- Department of Oncology, University of Lausanne, Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland; Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan.
| | - Ping-Chih Ho
- Department of Oncology, University of Lausanne, Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland.
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3
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Qin S, Na J, Yang Q, Tang J, Deng Y, Zhong L. Advances in dendritic cell-based therapeutic tumor vaccines. Mol Immunol 2025; 181:113-128. [PMID: 40120558 DOI: 10.1016/j.molimm.2025.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 02/09/2025] [Accepted: 03/11/2025] [Indexed: 03/25/2025]
Abstract
Dendritic cell-based therapeutic tumor vaccines are an active immunotherapy that has been commonly tried in the clinic,traditional treatment modalities for malignant tumors, such as surgery, radiotherapy and chemotherapy, have the disadvantages of high recurrence rates and side effects. The dendritic cell vaccination destroys cells from tumors by means of the patient's own system of immunity, a very promising treatment. However, due to the suppression of the tumor immune microenvironment, the difficulty of screening for optimal specific antigens, and the high technical difficulty of vaccine production. Most tumor vaccines currently available in the clinic have failed to produce significant clinical therapeutic effects. In this review, the fundamentals of therapeutic dendritic cells vaccine therapy are briefly outlined, with a focus on the progress of therapeutic Dendritic cells vaccine research in the clinic and the initiatives undertaken to enhance dendritic cell vaccinations' anti-tumor effectiveness. It is believed that through the continuous exploration of novel therapeutic strategies, therapeutic dendritic cells vaccines can play a greater role in improving tumor treatment for tumor patients.
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Affiliation(s)
- Simin Qin
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-targeting Therangstics, Guangxi Key Laboratory of Bio-targeting Therangstics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Major New Drugs Innovation and Development, Guangxi Medical University, Nanning 530021, China.
| | - Jintong Na
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-targeting Therangstics, Guangxi Key Laboratory of Bio-targeting Therangstics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Major New Drugs Innovation and Development, Guangxi Medical University, Nanning 530021, China.
| | - Qun Yang
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-targeting Therangstics, Guangxi Key Laboratory of Bio-targeting Therangstics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Major New Drugs Innovation and Development, Guangxi Medical University, Nanning 530021, China.
| | - Jing Tang
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-targeting Therangstics, Guangxi Key Laboratory of Bio-targeting Therangstics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Major New Drugs Innovation and Development, Guangxi Medical University, Nanning 530021, China.
| | - Yamin Deng
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-targeting Therangstics, Guangxi Key Laboratory of Bio-targeting Therangstics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Major New Drugs Innovation and Development, Guangxi Medical University, Nanning 530021, China.
| | - Liping Zhong
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-targeting Therangstics, Guangxi Key Laboratory of Bio-targeting Therangstics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Major New Drugs Innovation and Development, Guangxi Medical University, Nanning 530021, China; Pharmaceutical College, Guangxi Medical University, Nanning, Guangxi 530021, China.
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4
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Giudice GC, Sonpavde GP. Vaccine approaches to treat urothelial cancer. Hum Vaccin Immunother 2024; 20:2379086. [PMID: 39043175 PMCID: PMC11268260 DOI: 10.1080/21645515.2024.2379086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 07/08/2024] [Indexed: 07/25/2024] Open
Abstract
Bladder cancer (BC) accounts for about 4% of all malignancies. Non-muscle-invasive BC, 75% of cases, is treated with transurethral resection and adjuvant intravesical instillation, while muscle-invasive BC warrants cisplatin-based perioperative chemotherapy. Although immune-checkpoint inhibitors, antibody drug conjugates and targeted agents have provided dramatic advances, metastatic BC remains a generally incurable disease and clinical trials continue to vigorously evaluate novel molecules. Cancer vaccines aim at activating the patient's immune system against tumor cells. Several means of delivering neoantigens have been developed, including peptides, antigen-presenting cells, virus, or nucleic acids. Various improvements are constantly being explored, such as adjuvants use and combination strategies. Nucleic acids-based vaccines are increasingly gaining attention in recent years, with promising results in other malignancies. However, despite the recent advantages, numerous obstacles persist. This review is aimed at describing the different types of cancer vaccines, their evaluations in UC patients and the more recent innovations in this field.
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Affiliation(s)
- Giulia Claire Giudice
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Guru P. Sonpavde
- AdventHealth Cancer Institute, University of Central Florida, Orlando, FL, USA
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Gautam N, Ramamoorthi G, Champion N, Han HS, Czerniecki BJ. Reviewing the significance of dendritic cell vaccines in interrupting breast cancer development. Mol Aspects Med 2024; 95:101239. [PMID: 38150884 DOI: 10.1016/j.mam.2023.101239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 12/06/2023] [Accepted: 12/12/2023] [Indexed: 12/29/2023]
Abstract
Breast cancer is a heterogeneous disease and is the most prevalent cancer in women. According to the U.S breast cancer statistics, about 1 in every 8 women develop an invasive form of breast cancer during their lifetime. Immunotherapy has been a significant advancement in the treatment of cancer with multiple studies reporting favourable patient outcomes by modulating the immune response to cancer cells. Here, we review the significance of dendritic cell vaccines in treating breast cancer patients. We discuss the involvement of dendritic cells and oncodrivers in breast tumorigenesis, highlighting the rationale for targeting oncodrivers and neoantigens using dendritic cell vaccine therapy. We review different dendritic cell subsets and maturation states previously used to develop vaccines and suggest the use of DC vaccines for breast cancer prevention. Further, we highlight that the intratumoral delivery of type 1 dendritic cell vaccines in breast cancer patients activates tumor antigen-specific CD4+ T helper cell type 1 (Th1) cells, promoting an anti-tumorigenic immune response while concurrently blocking pro-tumorigenic responses. In summary, this review provides an overview of the current state of dendritic cell vaccines in breast cancer highlighting the challenges and considerations necessary for an efficient dendritic cell vaccine design in interrupting breast cancer development.
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Affiliation(s)
- Namrata Gautam
- Clinical Science & Immunology Program, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - Ganesan Ramamoorthi
- Clinical Science & Immunology Program, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - Nicholas Champion
- Department of Breast Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - Hyo S Han
- Department of Breast Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - Brian J Czerniecki
- Clinical Science & Immunology Program, H. Lee Moffitt Cancer Center, Tampa, FL, USA; Department of Breast Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
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6
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Mishra R, Sukhbaatar A, Mori S, Kodama T. Metastatic lymph node targeted CTLA4 blockade: a potent intervention for local and distant metastases with minimal ICI-induced pneumonia. J Exp Clin Cancer Res 2023; 42:132. [PMID: 37259163 DOI: 10.1186/s13046-023-02645-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 03/14/2023] [Indexed: 06/02/2023] Open
Abstract
BACKGROUND Immune checkpoint blockade (ICB) elicits a strong and durable therapeutic response, but its application is limited by disparate responses and its associated immune-related adverse events (irAEs). Previously, in a murine model of lymph node (LN) metastasis, we showed that intranodal administration of chemotherapeutic agents using a lymphatic drug delivery system (LDDS) elicits stronger therapeutic responses in comparison to systemic drug delivery approaches, while minimizing systemic toxicity, due to its improved pharmacokinetic profile at the intended site. Importantly, the LN is a reservoir of immunotherapeutic targets. We therefore hypothesized that metastatic LN-targeted ICB can amplify anti-tumor response and uncouple it from ICB-induced irAEs. METHODS To test our hypothesis, models of LN and distant metastases were established with luciferase expressing LM8 cells in MXH10/Mo-lpr/lpr mice, a recombinant inbred strain of mice capable of recapitulating ICB-induced interstitial pneumonia. This model was used to interrogate ICB-associated therapeutic response and immune related adverse events (irAEs) by in vivo imaging, high-frequency ultrasound imaging and histopathology. qPCR and flowcytometry were utilized to uncover the mediators of anti-tumor immunity. RESULTS Tumor-bearing LN (tbLN)-directed CTLA4 blockade generated robust anti-tumor response against local and systemic metastases, thereby improving survival. The anti-tumor effects were accompanied by an upregulation of effector CD8T cells in the tumor-microenvironment and periphery. In comparison, non-specific CTLA4 blockade was found to elicit weaker anti-tumor effect and exacerbated ICI-induced irAEs, especially interstitial pneumonia. Together these data highlight the importance of tbLN-targeted checkpoint blockade for efficacious response. CONCLUSIONS Intranodal delivery of immune checkpoint inhibitors to metastatic LN can potentiate therapeutic response while minimizing irAEs stemming from systemic lowering of immune activation threshold.
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Affiliation(s)
- Radhika Mishra
- Laboratory of Biomedical Engineering for Cancer, Graduate School of Biomedical Engineering, Tohoku University, 4-1 Seiryo, Aoba, Sendai, Miyagi, 980-8575, Japan
| | - Ariunbuyan Sukhbaatar
- Laboratory of Biomedical Engineering for Cancer, Graduate School of Biomedical Engineering, Tohoku University, 4-1 Seiryo, Aoba, Sendai, Miyagi, 980-8575, Japan
- Biomedical Engineering Cancer Research Center, Graduate School of Biomedical Engineering, Tohoku University, 4-1 Seiryo, Aoba, Sendai, Miyagi, 980-8575, Japan
- Division of Oral and Maxillofacial Oncology and Surgical Sciences, Graduate School of Dentistry, Tohoku University, 4-1 Seiryo, Aoba, Sendai, Miyagi, 980-8575, Japan
| | - Shiro Mori
- Laboratory of Biomedical Engineering for Cancer, Graduate School of Biomedical Engineering, Tohoku University, 4-1 Seiryo, Aoba, Sendai, Miyagi, 980-8575, Japan
- Biomedical Engineering Cancer Research Center, Graduate School of Biomedical Engineering, Tohoku University, 4-1 Seiryo, Aoba, Sendai, Miyagi, 980-8575, Japan
- Division of Oral and Maxillofacial Oncology and Surgical Sciences, Graduate School of Dentistry, Tohoku University, 4-1 Seiryo, Aoba, Sendai, Miyagi, 980-8575, Japan
| | - Tetsuya Kodama
- Laboratory of Biomedical Engineering for Cancer, Graduate School of Biomedical Engineering, Tohoku University, 4-1 Seiryo, Aoba, Sendai, Miyagi, 980-8575, Japan.
- Biomedical Engineering Cancer Research Center, Graduate School of Biomedical Engineering, Tohoku University, 4-1 Seiryo, Aoba, Sendai, Miyagi, 980-8575, Japan.
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7
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Mattathil JG, Volz A, Onabajo OO, Maynard S, Bixler SL, Shen XX, Vargas-Inchaustegui D, Robert-Guroff M, Lebranche C, Tomaras G, Montefiori D, Sutter G, Mattapallil JJ. Direct intranodal tonsil vaccination with modified vaccinia Ankara vaccine protects macaques from highly pathogenic SIVmac251. Nat Commun 2023; 14:1264. [PMID: 36882405 PMCID: PMC9990026 DOI: 10.1038/s41467-023-36907-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 02/23/2023] [Indexed: 03/09/2023] Open
Abstract
Human immunodeficiency virus (HIV) is a mucosally transmitted virus that causes immunodeficiency and AIDS. Developing efficacious vaccines to prevent infection is essential to control the epidemic. Protecting the vaginal and rectal mucosa, the primary routes of HIV entry has been a challenge given the significant compartmentalization between the mucosal and peripheral immune systems. We hypothesized that direct intranodal vaccination of mucosa associated lymphoid tissue (MALT) such as the readily accessible palatine tonsils could overcome this compartmentalization. Here we show that rhesus macaques primed with plasmid DNA encoding SIVmac251-env and gag genes followed by an intranodal tonsil MALT boost with MVA encoding the same genes protects from a repeated low dose intrarectal challenge with highly pathogenic SIVmac251; 43% (3/7) of vaccinated macaques remained uninfected after 9 challenges as compared to the unvaccinated control (0/6) animals. One vaccinated animal remained free of infection even after 22 challenges. Vaccination was associated with a ~2 log decrease in acute viremia that inversely correlated with anamnestic immune responses. Our results suggest that a combination of systemic and intranodal tonsil MALT vaccination could induce robust adaptive and innate immune responses leading to protection from mucosal infection with highly pathogenic HIV and rapidly control viral breakthroughs.
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Affiliation(s)
- Jeffy G Mattathil
- Henry M. Jackson Foundation for Military Medicine, Bethesda, MD, USA
| | - Asisa Volz
- Institute of Virology, University of Veterinary Medicine Hannover, Hanover, Germany
| | | | - Sean Maynard
- Henry M. Jackson Foundation for Military Medicine, Bethesda, MD, USA
| | - Sandra L Bixler
- Henry M. Jackson Foundation for Military Medicine, Bethesda, MD, USA
| | | | | | | | | | | | | | - Gerd Sutter
- Division of Virology, Department of Veterinary Sciences, LMU, Munich, Germany
| | - Joseph J Mattapallil
- Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD, USA.
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Morisaki T, Morisaki T, Kubo M, Morisaki S, Nakamura Y, Onishi H. Lymph Nodes as Anti-Tumor Immunotherapeutic Tools: Intranodal-Tumor-Specific Antigen-Pulsed Dendritic Cell Vaccine Immunotherapy. Cancers (Basel) 2022; 14:cancers14102438. [PMID: 35626042 PMCID: PMC9140043 DOI: 10.3390/cancers14102438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 05/06/2022] [Accepted: 05/13/2022] [Indexed: 02/01/2023] Open
Abstract
Simple Summary In the field of cancer therapy, lymph nodes are important not only as targets for metastases resection but also as prudent target organs for cancer immunotherapy. Lymph nodes comprise a complete structure for the accumulation of a large number of T cells and their distribution throughout the body after antigen presentation and activation of dendritic cells. This review highlights current topics on the importance of lymph node structure in antitumor immunotherapy and intranodal-antigen-presenting mature dendritic cell vaccine therapy. We also discuss the rationale behind intranodal injection methods and their applications in neoantigen vaccine therapy, a new cancer immunotherapy. Abstract Hundreds of lymph nodes (LNs) are scattered throughout the body. Although each LN is small, it represents a complete immune organ that contains almost all types of immunocompetent and stromal cells functioning as scaffolds. In this review, we highlight the importance of LNs in cancer immunotherapy. First, we review recent reports on structural and functional properties of LNs as sites for antitumor immunity and discuss their therapeutic utility in tumor immunotherapy. Second, we discuss the rationale and background of ultrasound (US)-guided intranodal injection methods. In addition, we review intranodal administration therapy of tumor-specific-antigen-pulsed matured dendritic cells (DCs), including neoantigen-pulsed vaccines.
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Affiliation(s)
- Takashi Morisaki
- Fukuoka General Cancer Clinic, Fukuoka 812-0018, Japan;
- Correspondence: ; Tel.: +81-922827696; Fax: +81-924056376
| | - Takafumi Morisaki
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; (T.M.); (M.K.)
| | - Makoto Kubo
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; (T.M.); (M.K.)
| | - Shinji Morisaki
- Fukuoka General Cancer Clinic, Fukuoka 812-0018, Japan;
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University; Fukuoka 812-8582, Japan;
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Yusuke Nakamura
- Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan;
| | - Hideya Onishi
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University; Fukuoka 812-8582, Japan;
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Yu J, Sun H, Cao W, Song Y, Jiang Z. Research progress on dendritic cell vaccines in cancer immunotherapy. Exp Hematol Oncol 2022; 11:3. [PMID: 35074008 PMCID: PMC8784280 DOI: 10.1186/s40164-022-00257-2] [Citation(s) in RCA: 99] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 01/16/2022] [Indexed: 12/13/2022] Open
Abstract
Dendritic cell (DC) vaccines induce specific immune responses that can selectively eliminate target cells. In recent years, many studies have been conducted to explore DC vaccination in the treatment of hematological malignancies, including acute myeloid leukemia and myelodysplastic syndromes, as well as other nonleukemia malignancies. There are at least two different strategies that use DCs to promote antitumor immunity: in situ vaccination and canonical vaccination. Monocyte-derived DCs (mo-DCs) and leukemia-derived DCs (DCleu) are the main types of DCs used in vaccines for AML and MDS thus far. Different cancer-related molecules such as peptides, recombinant proteins, apoptotic leukemic cells, whole tumor cells or lysates and DCs/DCleu containing a vaster antigenic repertoire with RNA electroporation, have been used as antigen sources to load DCs. To enhance DC vaccine efficacy, new strategies, such as combination with conventional chemotherapy, monospecific/bispecific antibodies and immune checkpoint-targeting therapies, have been explored. After a decade of trials and tribulations, much progress has been made and much promise has emerged in the field. In this review we summarize the recent advances in DC vaccine immunotherapy for AML/MDS as well as other nonleukemia malignancies.
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Affiliation(s)
- Jifeng Yu
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
- Henan International Joint Laboratory of Nuclear Protein Gene Regulation, Henan University College of Medicine, Kaifeng, 475004, Henan, China
| | - Hao Sun
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Weijie Cao
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Yongping Song
- Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, 450008, Henan, China.
| | - Zhongxing Jiang
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
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10
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Leal L, Couto E, Sánchez-Palomino S, Climent N, Fernández I, Miralles L, Romero Y, González T, Maleno MJ, Paño B, Pich J, Nicolau C, Gatell JM, Plana M, García F. Effect of Intranodally Administered Dendritic Cell-Based HIV Vaccine in Combination With Pegylated Interferon α-2a on Viral Control Following ART Discontinuation: A Phase 2A Randomized Clinical Trial. Front Immunol 2021; 12:767370. [PMID: 34858423 PMCID: PMC8632026 DOI: 10.3389/fimmu.2021.767370] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 10/06/2021] [Indexed: 12/19/2022] Open
Abstract
Introduction Functional cure has been proposed as an alternative to lifelong antiretroviral therapy and therapeutic vaccines represent one of the most promising approaches. Materials and Methods We conducted a double-blind randomized placebo-controlled clinical trial to evaluate the safety, immunogenicity, and effect on viral dynamics of a therapeutic vaccine produced with monocyte-derived dendritic cells (MD-DC) loaded with a high dose of heat-inactivated autologous (HIA) HIV-1 in combination with pegylated interferon alpha 2a (IFNα-2a) in people with chronic HIV-1. Results Twenty-nine male individuals on successful ART and with CD4+ ≥450 cells/mm3 were randomized 1:1:1:1 to receive three ultrasound-guided inguinal intranodal immunizations, one every 2 weeks: (1) vaccine ~107 MD-DC pulsed with HIA-HIV-1 (1010 HIV RNA copies) (n = 8); (2) vaccine plus three doses of 180 mcg IFNα-2a at weeks 4-6 (n = 6); (3) placebo = saline (n = 7); and (4) placebo plus three doses of 180 mcg IFNα-2a (n = 8). Thereafter, treatment was interrupted (ATI). Vaccines, IFNα-2a, and the administration procedures were safe and well tolerated. All patients' viral load rebounded during the 12-week ATI period. According to groups, changes in viral set-point between pre-ART and during ATI were not significant. When comparing all groups, there was a tendency in changes in viral set-point between the vaccine group vs. vaccine + IFNα-2a group (>0.5log10 p = 0.05). HIV-1-specific T-cell responses (IFN-ƴ Elispot) were higher at baseline in placebo than in the vaccine group (2,259 ± 535 vs. 900 ± 200 SFC/106 PBMC, p = 0.028). A significant difference in the change of specific T-cell responses was only observed at week 4 between vaccine and placebo groups (694 ± 327 vs. 1,718 ± 282 SFC/106 PBMC, p = 0.04). No effect on T-cell responses or changes in viral reservoir were observed after INFα-2a administration. Discussion Results from this study show that intranodally administered DC therapeutic vaccine in combination with IFNα-2a was safe and well-tolerated but had a minimal impact on viral dynamics in HIV-1 chronic infected participants. Clinical Trial Registration (www.ClinicalTrials.gov), identifier NCT02767193.
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Affiliation(s)
- Lorna Leal
- Infectious Diseases Department-HIV Unit, Hospital Clínic Barcelona, Barcelona, Spain.,AIDS and HIV Infection Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Faculty of Medicine, Universitat de Barcelona, Barcelona, Spain
| | - Elvira Couto
- Infectious Diseases Department-HIV Unit, Hospital Clínic Barcelona, Barcelona, Spain.,AIDS and HIV Infection Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Sonsoles Sánchez-Palomino
- AIDS and HIV Infection Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Núria Climent
- AIDS and HIV Infection Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Irene Fernández
- Infectious Diseases Department-HIV Unit, Hospital Clínic Barcelona, Barcelona, Spain.,AIDS and HIV Infection Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Laia Miralles
- AIDS and HIV Infection Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Yolanda Romero
- Infectious Diseases Department-HIV Unit, Hospital Clínic Barcelona, Barcelona, Spain.,AIDS and HIV Infection Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Tania González
- AIDS and HIV Infection Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Maria José Maleno
- AIDS and HIV Infection Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Blanca Paño
- Diagnostic Imaging Center (CDI), Hospital Clínic Barcelona, Barcelona, Spain
| | - Judit Pich
- Clinical Trials Unit (CTU), Hospital Clínic Barcelona, Barcelona, Spain
| | - Carlos Nicolau
- Faculty of Medicine, Universitat de Barcelona, Barcelona, Spain.,Diagnostic Imaging Center (CDI), Hospital Clínic Barcelona, Barcelona, Spain
| | - José Maria Gatell
- Infectious Diseases Department-HIV Unit, Hospital Clínic Barcelona, Barcelona, Spain.,AIDS and HIV Infection Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Faculty of Medicine, Universitat de Barcelona, Barcelona, Spain.,ViiV Healthcare, Barcelona, Spain
| | - Montserrat Plana
- AIDS and HIV Infection Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Faculty of Medicine, Universitat de Barcelona, Barcelona, Spain
| | - Felipe García
- Infectious Diseases Department-HIV Unit, Hospital Clínic Barcelona, Barcelona, Spain.,AIDS and HIV Infection Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Faculty of Medicine, Universitat de Barcelona, Barcelona, Spain
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11
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Sanz-Ortega L, Rojas JM, Barber DF. Improving Tumor Retention of Effector Cells in Adoptive Cell Transfer Therapies by Magnetic Targeting. Pharmaceutics 2020; 12:E812. [PMID: 32867162 PMCID: PMC7557387 DOI: 10.3390/pharmaceutics12090812] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 08/19/2020] [Accepted: 08/24/2020] [Indexed: 02/07/2023] Open
Abstract
Adoptive cell transfer therapy is a promising anti-tumor immunotherapy in which effector immune cells are transferred to patients to treat tumors. However, one of its main limitations is the inefficient trafficking of inoculated effector cells to the tumor site and the small percentage of effector cells that remain activated when reaching the tumor. Multiple strategies have been attempted to improve the entry of effector cells into the tumor environment, often based on tumor types. It would be, however, interesting to develop a more general approach, to improve and facilitate the migration of specific activated effector lymphoid cells to any tumor type. We and others have recently demonstrated the potential for adoptive cell transfer therapy of the combined use of magnetic nanoparticle-loaded lymphoid effector cells together with the application of an external magnetic field to promote the accumulation and retention of lymphoid cells in specific body locations. The aim of this review is to summarize and highlight the recent findings in the field of magnetic accumulation and retention of effector cells in tumors after adoptive transfer, and to discuss the possibility of using this approach for tumor targeting with chimeric antigen receptor (CAR) T-cells.
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Affiliation(s)
- Laura Sanz-Ortega
- Center for Hematology and Regenerative Medicine (HERM), Department of Medicine, Karolinska Institute, 14183 Stockholm, Sweden;
| | - José Manuel Rojas
- Animal Health Research Centre (CISA)-INIA, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, 28130 Madrid, Spain;
| | - Domingo F. Barber
- Department of Immunology and Oncology, and NanoBiomedicine Initiative, Centro Nacional de Biotecnología (CNB)-CSIC, 28049 Madrid, Spain
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12
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Morisaki T, Hikichi T, Onishi H, Morisaki T, Kubo M, Hirano T, Yoshimura S, Kiyotani K, Nakamura Y. Intranodal Administration of Neoantigen Peptide-loaded Dendritic Cell Vaccine Elicits Epitope-specific T Cell Responses and Clinical Effects in a Patient with Chemorefractory Ovarian Cancer with Malignant Ascites. Immunol Invest 2020; 50:562-579. [PMID: 32660279 DOI: 10.1080/08820139.2020.1778721] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Chemorefractory ovarian cancer has limited therapeutic options. Hence, new types of treatment including neoantigen-specific immunotherapy need to be investigated. Neoantigens represent promising targets for personalized cancer immunotherapy. We here describe the clinical and immunological effects of a neoantigen peptide-loaded DC-based immunotherapy in a patient with recurrent and chemoresistant ovarian cancer. A 71-year-old female patient with chemorefractory ovarian cancer and malignant ascites received intranodal vaccination of DCs loaded with four neoantigen peptides that were predicted by our immunogenomic pipeline. Following four rounds of vaccinations with this therapy, CA-125 levels were remarkably declined and tumor cells in the ascites were also decreased. Concordantly, the tumor-related symptoms such as respiratory discomfort improved without any adverse reactions. The reactivity against one HLA-A2402-restricted neoantigen peptide derived from a mutated PPM1 F protein was detected in lymphocytes from peripheral blood by IFN-γ ELISPOT assay. Furthermore, the neoantigen (PPM1 F mutant)-specific TCRs were detected in the tumor-infiltrating T lymphocytes post-vaccination. Our results showed that vaccination with intranodal injection of neoantigen peptide-loaded DCs may have clinical and immunological impacts on cancer treatment.
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Affiliation(s)
- Takashi Morisaki
- Department of Cancer Immunotherapy, Fukuoka General Cancer Clinic, Fukuoka, Japan
| | - Tetsuro Hikichi
- R & D Department, Cancer Precision Medicine Inc, Kawasaki, Kanagawa, Japan
| | - Hideya Onishi
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takafumi Morisaki
- Department of Cancer Immunotherapy, Fukuoka General Cancer Clinic, Fukuoka, Japan.,Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Makoto Kubo
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | | | - Sachiko Yoshimura
- R & D Department, Cancer Precision Medicine Inc, Kawasaki, Kanagawa, Japan
| | - Kazuma Kiyotani
- Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yusuke Nakamura
- Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan
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13
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Audsley KM, McDonnell AM, Waithman J. Cross-Presenting XCR1 + Dendritic Cells as Targets for Cancer Immunotherapy. Cells 2020; 9:cells9030565. [PMID: 32121071 PMCID: PMC7140519 DOI: 10.3390/cells9030565] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 02/14/2020] [Accepted: 02/25/2020] [Indexed: 12/11/2022] Open
Abstract
The use of dendritic cells (DCs) to generate effective anti-tumor T cell immunity has garnered much attention over the last thirty-plus years. Despite this, limited clinical benefit has been demonstrated thus far. There has been a revival of interest in DC-based treatment strategies following the remarkable patient responses observed with novel checkpoint blockade therapies, due to the potential for synergistic treatment. Cross-presenting DCs are recognized for their ability to prime CD8+ T cell responses to directly induce tumor death. Consequently, they are an attractive target for next-generation DC-based strategies. In this review, we define the universal classification system for cross-presenting DCs, and the vital role of this subset in mediating anti-tumor immunity. Furthermore, we will detail methods of targeting these DCs both ex vivo and in vivo to boost their function and drive effective anti-tumor responses.
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Affiliation(s)
- Katherine M. Audsley
- Telethon Kids Institute, University of Western Australia, Perth Children’s Hospital, Nedlands, WA 6009, Australia
- School of Biomedical Sciences, The University of Western Australia, Crawley, WA 6009, Australia
- Correspondence: (K.M.A.); (A.M.M.); (J.W.); Tel.: +61-08-6319-1198 (K.M.A); +61-08-6319-1744 (J.W.)
| | - Alison M. McDonnell
- Telethon Kids Institute, University of Western Australia, Perth Children’s Hospital, Nedlands, WA 6009, Australia
- National Centre for Asbestos Related Diseases, The University of Western Australia, QEII Medical Centre, Nedlands, WA 6009, Australia
- Correspondence: (K.M.A.); (A.M.M.); (J.W.); Tel.: +61-08-6319-1198 (K.M.A); +61-08-6319-1744 (J.W.)
| | - Jason Waithman
- Telethon Kids Institute, University of Western Australia, Perth Children’s Hospital, Nedlands, WA 6009, Australia
- Correspondence: (K.M.A.); (A.M.M.); (J.W.); Tel.: +61-08-6319-1198 (K.M.A); +61-08-6319-1744 (J.W.)
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14
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Li C, Liu T, Zhou B, Zhou Y, Yu H, Sun Y. Efficacy and safety analysis on dendritic cell-based vaccine-treated high-grade glioma patients: a systematic review and meta-analysis. Onco Targets Ther 2018; 11:7277-7293. [PMID: 30425519 PMCID: PMC6204866 DOI: 10.2147/ott.s177768] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background Dendritic cell (DC)-based vaccine is a promising therapy for high-grade gliomas (HGGs); however, its actual effectiveness still remains controversial. This meta-analysis aims to extensively evaluate the efficacy and safety of DC vaccine for HGG patients. Methods We systematically searched PubMed, the Cochrane Library, EMBASE, Medline, and Web of Science for relevant parallel randomized controlled trials (RCTs) and properly controlled non-randomized studies (NRS) published in English. Two investigators reviewed all the texts and extracted information regarding overall survival (OS), progression-free survival (PFS), and adverse events (AEs) from eligible studies. Sensitivity analyses and subgroup analyses were also conducted. Results Of 353 suitable studies, 13 studies (three RCTs and ten NRS) involving 944 patients were finally included. Compared to the control therapy group (CT group), the DC group showed better OS and PFS without serious AEs. Subgroup analysis showed that trials designed as NRS obtained better results in the DC group in this study; however, no specific subgroup regarding dosages, cycles or injection routes was found to be superior in the DC group compared to the CT group. Conclusion DC vaccine can significantly improve OS and PFS, with acceptable toxicity, of HGG patients. Nevertheless, further studies are needed to verify this conclusion.
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Affiliation(s)
- Changling Li
- Department of Experimental Medicine, Northern Hospital, Shenyang 110016, China,
| | - Ting Liu
- Department of General Practice, The Second Hospital of Dalian Medical University, Dalian 116023, China,
| | - Bo Zhou
- Department of Clinical Epidemiology and Evidence-based Medicine, The First Affiliated Hospital, China Medical University, Shenyang 110001, China
| | - Yubin Zhou
- Department of Oncology, The People's Hospital of China Medical University, Shenyang 110015, China
| | - Huiying Yu
- Department of Experimental Medicine, Northern Hospital, Shenyang 110016, China,
| | - Yun Sun
- Department of General Practice, The Second Hospital of Dalian Medical University, Dalian 116023, China,
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15
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16
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Obermajer N, Urban J, Wieckowski E, Muthuswamy R, Ravindranathan R, Bartlett DL, Kalinski P. Promoting the accumulation of tumor-specific T cells in tumor tissues by dendritic cell vaccines and chemokine-modulating agents. Nat Protoc 2018; 13:335-357. [PMID: 29345636 DOI: 10.1038/nprot.2017.130] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
This protocol describes how to induce large numbers of tumor-specific cytotoxic T cells (CTLs) in the spleens and lymph nodes of mice receiving dendritic cell (DC) vaccines and how to modulate tumor microenvironments (TMEs) to ensure effective homing of the vaccination-induced CTLs to tumor tissues. We also describe how to evaluate the numbers of tumor-specific CTLs within tumors. The protocol contains detailed information describing how to generate a specialized DC vaccine with augmented ability to induce tumor-specific CTLs. We also describe methods to modulate the production of chemokines in the TME and show how to quantify tumor-specific CTLs in the lymphoid organs and tumor tissues of mice receiving different treatments. The combined experimental procedure, including tumor implantation, DC vaccine generation, chemokine-modulating (CKM) approaches, and the analyses of tumor-specific systemic and intratumoral immunity is performed over 30-40 d. The presented ELISpot-based ex vivo CTL assay takes 6 h to set up and 5 h to develop. In contrast to other methods of evaluating tumor-specific immunity in tumor tissues, our approach allows detection of intratumoral T-cell responses to nonmanipulated weakly immunogenic cancers. This detection method can be performed using basic laboratory skills, and facilitates the development and preclinical evaluation of new immunotherapies.
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Affiliation(s)
- Nataša Obermajer
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Julie Urban
- Immunotransplantation Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Eva Wieckowski
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Immunotransplantation Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | | | | | - David L Bartlett
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Pawel Kalinski
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Immunotransplantation Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- University of Pittsburgh Cancer Institute, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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17
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Hodgson Reyes L, Olarte Carrillo I, Ramos Peñafiel C, Martínez Tovar A, Gallardo E, Castellanos Sinco H, Collazo Jaloma J. Expression of cancer testis antigens in patients with Hodgkin's lymphoma and their clinical correlation. REVISTA MÉDICA DEL HOSPITAL GENERAL DE MÉXICO 2018. [DOI: 10.1016/j.hgmx.2016.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
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18
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Advances in immunotherapeutic research for glioma therapy. J Neurol 2017; 265:741-756. [PMID: 29209782 DOI: 10.1007/s00415-017-8695-5] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Revised: 11/28/2017] [Accepted: 11/29/2017] [Indexed: 01/29/2023]
Abstract
Gliomas are primary malignancies of the brain. Tumors are staged based on malignancy, nuclear atypia, and infiltration of the surrounding brain parenchyma. Tumors are often diagnosed once patients become symptomatic, at which time the lesion is sizable. Glioblastoma (grade IV glioma) is highly aggressive and difficult to treat. Most tumors are diagnosed de novo. The gold standard of therapy, implemented over a decade ago, consists of fractionated radiotherapy and temozolomide, but unfortunately, chemotherapeutic resistance arises. Recurrence is common after initial therapy. The tumor microenvironment plays a large role in cancer progression and its manipulation can repress progression. The advent and implementation of immunotherapy, via manipulation and activation of cytotoxic T cells, have had an outstanding impact on reducing morbidity and mortality associated with peripheral cancers under certain clinical circumstances. An arsenal of immunotherapeutics is currently under clinical investigation for safety and efficacy in the treatment of newly diagnosed and recurrent high grade gliomas. These immunotherapeutics encompass antibody-drug conjugates, autologous infusions of modified chimeric antigen receptor expressing T cells, peptide vaccines, autologous dendritic cell vaccines, immunostimulatory viruses, oncolytic viruses, checkpoint blockade inhibitors, and drugs which alter the behavior of innate immune cells. Effort is focusing on determining which patient populations will benefit the most from these treatments and why. Research addressing synergism between treatment options is gaining attention. While advances in the treatment of glioma stagnated in the past, we may see a considerable evolution in the management of the disease in the upcoming years.
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19
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Murthy V, Minehart J, Sterman DH. Local Immunotherapy of Cancer: Innovative Approaches to Harnessing Tumor-Specific Immune Responses. J Natl Cancer Inst 2017; 109:4085220. [DOI: 10.1093/jnci/djx097] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Accepted: 04/24/2017] [Indexed: 12/12/2022] Open
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20
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Aznar MA, Tinari N, Rullán AJ, Sánchez-Paulete AR, Rodriguez-Ruiz ME, Melero I. Intratumoral Delivery of Immunotherapy-Act Locally, Think Globally. THE JOURNAL OF IMMUNOLOGY 2017; 198:31-39. [PMID: 27994166 DOI: 10.4049/jimmunol.1601145] [Citation(s) in RCA: 165] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 08/31/2016] [Indexed: 12/16/2022]
Abstract
Immune mechanisms have evolved to cope with local entry of microbes acting in a confined fashion but eventually inducing systemic immune memory. Indeed, in situ delivery of a number of agents into tumors can mimic in the malignant tissue the phenomena that control intracellular infection leading to the killing of infected cells. Vascular endothelium activation and lymphocyte attraction, together with dendritic cell-mediated cross-priming, are the key elements. Intratumoral therapy with pathogen-associated molecular patterns or recombinant viruses is being tested in the clinic. Cell therapies can be also delivered intratumorally, including infusion of autologous dendritic cells and even tumor-reactive T lymphocytes. Intralesional virotherapy with an HSV vector expressing GM-CSF has been recently approved by the Food and Drug Administration for the treatment of unresectable melanoma. Immunomodulatory monoclonal Abs have also been successfully applied intratumorally in animal models. Local delivery means less systemic toxicity while focusing the immune response on the malignancy and the affected draining lymph nodes.
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Affiliation(s)
- M Angela Aznar
- Division of Immunology and Immunotherapy, Center for Applied Medical Research, University of Navarra, Pamplona 31008, Spain
| | - Nicola Tinari
- Department of Experimental and Clinical Sciences, G. D'Annunzio University and Foundation, Chieti 66100, Italy
| | - Antonio J Rullán
- Department of Medical Oncology, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona 08908, Spain; and
| | - Alfonso R Sánchez-Paulete
- Division of Immunology and Immunotherapy, Center for Applied Medical Research, University of Navarra, Pamplona 31008, Spain
| | - María E Rodriguez-Ruiz
- Division of Immunology and Immunotherapy, Center for Applied Medical Research, University of Navarra, Pamplona 31008, Spain.,University Clinic, University of Navarra and Health Research Institute of Navarra, 31008 Pamplona, Spain
| | - Ignacio Melero
- Division of Immunology and Immunotherapy, Center for Applied Medical Research, University of Navarra, Pamplona 31008, Spain; .,University Clinic, University of Navarra and Health Research Institute of Navarra, 31008 Pamplona, Spain
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21
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Tao Z, Li S, Ichim TE, Yang J, Riordan N, Yenugonda V, Babic I, Kesari S. Cellular immunotherapy of cancer: an overview and future directions. Immunotherapy 2017; 9:589-606. [DOI: 10.2217/imt-2016-0086] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The clinical success of checkpoint inhibitors has led to a renaissance of interest in cancer immunotherapies. In particular, the possibility of ex vivo expanding autologous lymphocytes that specifically recognize tumor cells has attracted much research and clinical trial interest. In this review, we discuss the historical background of tumor immunotherapy using cell-based approaches, and provide some rationale for overcoming current barriers to success of autologous immunotherapy. An overview of adoptive transfer of lymphocytes, tumor infiltrating lymphocytes and dendritic cell therapies is provided. We conclude with discussing the possibility of gene-manipulating immune cells in order to augment therapeutic activity, including silencing of the immune-suppressive zinc finger orphan nuclear receptor, NR2F6, as an attractive means of overcoming tumor-associated immune suppression.
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Affiliation(s)
- Ziqi Tao
- The Affiliated XuZhou Center Hospital of Nanjing University of Chinese Medicine, The Affiliated XuZhou Hospital of Medical College of Southeast University, Jiangsu, China
| | - Shuang Li
- Department of Endocrinology, the Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | | | - Junbao Yang
- Department of Translational Neurosciences and Neurotherapeutics, Pacific Neuroscience Institute, John Wayne Cancer Institute, Providence Saint John’s Health Center, Santa Monica, CA 90404, USA
| | - Neil Riordan
- Medistem Panama, Inc., City of Knowledge, Clayton, Republic of Panama
| | - Venkata Yenugonda
- Department of Translational Neurosciences and Neurotherapeutics, Pacific Neuroscience Institute, John Wayne Cancer Institute, Providence Saint John’s Health Center, Santa Monica, CA 90404, USA
| | - Ivan Babic
- Department of Translational Neurosciences and Neurotherapeutics, Pacific Neuroscience Institute, John Wayne Cancer Institute, Providence Saint John’s Health Center, Santa Monica, CA 90404, USA
| | - Santosh Kesari
- Department of Translational Neurosciences and Neurotherapeutics, Pacific Neuroscience Institute, John Wayne Cancer Institute, Providence Saint John’s Health Center, Santa Monica, CA 90404, USA
- John Wayne Cancer Institute, 2200 Santa Monica Blvd, Santa Monica, CA 90404, USA
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22
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Combinational Immunotherapy with Allo-DRibble Vaccines and Anti-OX40 Co-Stimulation Leads to Generation of Cross-Reactive Effector T Cells and Tumor Regression. Sci Rep 2016; 6:37558. [PMID: 27874054 PMCID: PMC5118714 DOI: 10.1038/srep37558] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Accepted: 11/01/2016] [Indexed: 11/13/2022] Open
Abstract
It is well-known that vaccines comprising of irradiated whole tumor cells or tumor-derived heat shock proteins can generate tumor-specific immune responses. In contrast, we showed recently that vaccines composed of autophagosomes (DRibbles) derived from syngeneic sarcomas could induce cross-reactive T-cell responses and cross-protection against the tumor. This unusual property of DRibbles was related to the selective recruitment of defective ribosomal products (DRiPs) and other short-lived proteins (SLiPs) into autophagosomes via sequestosome (SQSTM1, p62) mediated association of ubiquitinated SLiPs to the autophagy gene product LC3. Here, we extend our observations to mammary carcinomas from mice of different genetic background. We demonstrated that combined of intranodal administration of autologous or allogeneic DRibbles together with anti-OX40 antibody led to robust proliferation, expansion, and differentiation of memory and effector T cells. We also showed that SLiPs is an excellent source of antigen for cross-priming of CD8+ T-cells that recognize shared tumor antigens in the context of host MHC class I molecules. Thus, our results provide a strong basis for novel clinical trials that combine allogeneic “off-the-shelf” DRibble vaccines together with antibodies against co-stimulatory molecules.
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23
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Kyte JA, Aamdal S, Dueland S, Sæbøe-Larsen S, Inderberg EM, Madsbu UE, Skovlund E, Gaudernack G, Kvalheim G. Immune response and long-term clinical outcome in advanced melanoma patients vaccinated with tumor-mRNA-transfected dendritic cells. Oncoimmunology 2016; 5:e1232237. [PMID: 27999747 DOI: 10.1080/2162402x.2016.1232237] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Revised: 08/30/2016] [Accepted: 08/31/2016] [Indexed: 01/18/2023] Open
Abstract
The most effective anticancer immune responses are probably directed against patient-specific neoantigens. We have developed a melanoma vaccine targeting this individual mutanome based on dendritic cells (DCs) loaded with autologous tumor-mRNA. Here, we report a phase I/II trial evaluating toxicity, immune response and clinical outcome in 31 metastatic melanoma patients. The first cohort (n = 22) received the vaccine without any adjuvant; the next cohort (n = 9) received adjuvant IL2. Each subject received four weekly intranodal or intradermal injections, followed by optional monthly vaccines. Immune response was evaluated by delayed-type hypersensitivity (DTH), T cell proliferation and cytokine assays. Data were collected for 10 y after inclusion of the last patient. No serious adverse events were detected. In the intention-to-treat-cohort, we demonstrated significantly superior survival compared to matched controls from a benchmark meta-analysis (1 y survival 43% vs. 24%, 2 y 23% vs. 6.6%). A tumor-specific immune response was demonstrated in 16/31 patients. The response rate was higher after intradermal than intranodal vaccination (80% vs. 38%). Immune responders had improved survival compared to non-responders (median 14 mo vs. 6 mo; p = 0.030), and all eight patients surviving >20 mo were immune responders. In addition to the tumor-specific response, most patients developed a response against autologous DC antigens. The cytokine profile was polyfunctional and did not follow a Th1/Th2 dichotomy. We conclude that the favorable safety profile and evidence of a possible survival benefit warrant further studies of the RNA/DC vaccine. The vaccine appears insufficient as monotherapy, but there is a strong rationale for combination with checkpoint modulators.
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Affiliation(s)
- Jon Amund Kyte
- Department for Cell Therapy, Radiumhospitalet, Oslo University Hospital, Oslo, Norway; The Clinical Trial Unit, Radiumhospitalet, Oslo University Hospital, Oslo, Norway; Department of Immunology, Radiumhospitalet, Oslo University Hospital, Oslo, Norway
| | - Steinar Aamdal
- The Clinical Trial Unit, Radiumhospitalet, Oslo University Hospital , Oslo, Norway
| | - Svein Dueland
- The Clinical Trial Unit, Radiumhospitalet, Oslo University Hospital , Oslo, Norway
| | - Stein Sæbøe-Larsen
- Department for Cell Therapy, Radiumhospitalet, Oslo University Hospital , Oslo, Norway
| | - Else Marit Inderberg
- Department for Cell Therapy, Radiumhospitalet, Oslo University Hospital , Oslo, Norway
| | - Ulf Erik Madsbu
- Department for Radiology, Radiumhospitalet, Oslo University Hospital , Oslo, Norway
| | - Eva Skovlund
- Department of Public Health and General Practice, NTNU , Trondheim, Norway
| | - Gustav Gaudernack
- Department of Immunology, Radiumhospitalet, Oslo University Hospital , Oslo, Norway
| | - Gunnar Kvalheim
- Department for Cell Therapy, Radiumhospitalet, Oslo University Hospital , Oslo, Norway
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24
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Seyfizadeh N, Muthuswamy R, Mitchell DA, Nierkens S, Seyfizadeh N. Migration of dendritic cells to the lymph nodes and its enhancement to drive anti-tumor responses. Crit Rev Oncol Hematol 2016; 107:100-110. [PMID: 27823637 DOI: 10.1016/j.critrevonc.2016.09.002] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2016] [Revised: 09/02/2016] [Accepted: 09/06/2016] [Indexed: 12/29/2022] Open
Abstract
Better prognoses associated with increased T cell infiltration of tumors, as seen with chimeric antigen receptor (CAR) T cell therapies and immune checkpoint inhibitors, portray the importance and potential of the immune system in controlling tumors. This has rejuvenated the field of cancer immunotherapy leading to an increasing number of immunotherapies developed for cancer patients. Dendritic Cells (DCs) vaccines represent an appealing option for cancer immunotherapy since DCs have the ability to circumvent tolerance to tumors by its adjuvant properties and to induce memory T cells that can become persistent after initial tumor clearance to engage potential metastatic tumors. In the past, DC-based cancer vaccines have elicited only poor clinical response in cancer patients, which can be attributed to complex and a multitude of issues associated with generation, implementing, delivery of DC vaccine and their potential interaction with effector cells. The current review mainly focuses on migration/trafficking of DCs, as one of the key issues that affect the success of DC-based cancer vaccines, and discusses strategies to enhance it for cancer immunotherapy. Additionally, impact of maturation, route of DC delivery and negative effects of tumor microenvironment (TME) on DC homing to LN are reviewed. Moreover, strategies to increase the expression of genes involved in Lymph node homing, preconditioning of the vaccination site, enhancing lymph node ability to attract and receive DCs, while limiting negative impact of TME on DC migration are discussed.
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Affiliation(s)
- Narges Seyfizadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | | | - Duane A Mitchell
- Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC 27710, USA
| | - Stefan Nierkens
- Laboratory of Translational Immunology, U-DAIR, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Nayer Seyfizadeh
- Umbilical Cord Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Clinical Biochemistry and Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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Lowenfeld L, Zaheer S, Oechsle C, Fracol M, Datta J, Xu S, Fitzpatrick E, Roses RE, Fisher CS, McDonald ES, Zhang PJ, DeMichele A, Mick R, Koski GK, Czerniecki BJ. Addition of anti-estrogen therapy to anti-HER2 dendritic cell vaccination improves regional nodal immune response and pathologic complete response rate in patients with ER pos/HER2 pos early breast cancer. Oncoimmunology 2016; 6:e1207032. [PMID: 28932627 PMCID: PMC5599079 DOI: 10.1080/2162402x.2016.1207032] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Accepted: 06/23/2016] [Indexed: 10/21/2022] Open
Abstract
HER2-directed therapies are less effective in patients with ERpos compared to ERneg breast cancer, possibly reflecting bidirectional activation between HER2 and estrogen signaling pathways. We investigated dual blockade using anti-HER2 vaccination and anti-estrogen therapy in HER2pos/ERpos early breast cancer patients. In pre-clinical studies of HER2pos breast cancer cell lines, ERpos cells were partially resistant to CD4+ Th1 cytokine-induced metabolic suppression compared with ERneg cells. The addition of anti-estrogen treatment significantly enhanced cytokine sensitivity in ERpos, but not ERneg, cell lines. In two pooled phase-I clinical trials, patients with HER2pos early breast cancer were treated with neoadjuvant anti-HER2 dendritic cell vaccination; HER2pos/ERpos patients were treated with or without concurrent anti-estrogen therapy. The anti-HER2 Th1 immune response measured in the peripheral blood significantly increased following vaccination, but was similar across the three treatment groups (ERneg vaccination alone, ERpos vaccination alone, ERpos vaccination + anti-estrogen therapy). In the sentinel lymph nodes, however, the anti-HER2 Th1 immune response was significantly higher in ERpos patients treated with combination anti-HER2 vaccination plus anti-estrogen therapy compared to those treated with anti-HER2 vaccination alone. Similar rates of pathologic complete response (pCR) were observed in vaccinated ERneg patients and vaccinated ERpos patients treated with concurrent anti-estrogen therapy (31.4% vs. 28.6%); both were significantly higher than the pCR rate in vaccinated ERpos patients who did not receive anti-estrogen therapy (4.0%, p = 0.03). Since pCR portends long-term favorable outcomes, these results support additional clinical investigations using HER2-directed vaccines in combination with anti-estrogen treatments for ERpos/HER2pos DCIS and invasive breast cancer.
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Affiliation(s)
- Lea Lowenfeld
- Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Salman Zaheer
- Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Crystal Oechsle
- Department of Biological Sciences, Kent State University, Kent, OH, USA
| | - Megan Fracol
- Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Jashodeep Datta
- Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Shuwen Xu
- Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Elizabeth Fitzpatrick
- Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Robert E. Roses
- Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Carla S. Fisher
- Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Elizabeth S. McDonald
- Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Paul J. Zhang
- Department of Pathology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Angela DeMichele
- Division of Medical Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Rosemarie Mick
- Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA
| | - Gary K. Koski
- Department of Biological Sciences, Kent State University, Kent, OH, USA
| | - Brian J. Czerniecki
- Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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Lieberman NAP, Moyes KW, Crane CA. Developing immunotherapeutic strategies to target brain tumors. Expert Rev Anticancer Ther 2016; 16:775-88. [PMID: 27253692 DOI: 10.1080/14737140.2016.1192470] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
INTRODUCTION Recent years have seen rapid growth in cancer treatments that enhance the anti-tumor activities of the immune system. Collectively known as immunotherapy, modulation of the immune system has shown success treating some hematological malignancies, but has yet to be successfully applied to the treatment of patients with brain tumors. AREAS COVERED This review highlights mechanistic insights from murine studies and compiled recent clinical trial data, focusing on the most aggressive brain tumor, glioblastoma (GBM). The field has recently accumulated a critical mass of data, and we discuss past treatment failures in the context of newly developed approaches now entering clinical trials. This article provides an overview of the immunotherapeutic armamentarium currently in development for the treatment of patients with GBM, who are in dire need of safe and effective therapies. Expert commentary: Themes that emerge include the importance of mitigating the effects of an immunosuppressive tumor microenvironment and the potential for innate immune cell activation to enhance cytotoxic anti-tumor activity. Consideration of these studies as a collective may inform the design of new immunotherapies, as well as the immune monitoring protocols for patients participating in clinical trials.
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Affiliation(s)
- Nicole A P Lieberman
- a Seattle Children's Research Institute, Ben Towne Center for Childhood Cancer Research , Seattle , WA , USA
| | - Kara White Moyes
- a Seattle Children's Research Institute, Ben Towne Center for Childhood Cancer Research , Seattle , WA , USA
| | - Courtney A Crane
- a Seattle Children's Research Institute, Ben Towne Center for Childhood Cancer Research , Seattle , WA , USA.,b Department of Neurological Surgery , University of Washington School of Medicine , Seattle , WA , USA
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Anguille S, Smits EL, Bryant C, Van Acker HH, Goossens H, Lion E, Fromm PD, Hart DN, Van Tendeloo VF, Berneman ZN. Dendritic Cells as Pharmacological Tools for Cancer Immunotherapy. Pharmacol Rev 2015; 67:731-53. [PMID: 26240218 DOI: 10.1124/pr.114.009456] [Citation(s) in RCA: 117] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/21/2025] Open
Abstract
Although the earliest—rudimentary—attempts at exploiting the immune system for cancer therapy can be traced back to the late 18th Century, it was not until the past decade that cancer immunotherapeutics have truly entered mainstream clinical practice. Given their potential to stimulate both adaptive and innate antitumor immune responses, dendritic cells (DCs) have come under intense scrutiny in recent years as pharmacological tools for cancer immunotherapy. Conceptually, the clinical effectiveness of this form of active immunotherapy relies on the completion of three critical steps: 1) the DCs used as immunotherapeutic vehicles must properly activate the antitumor immune effector cells of the host, 2) these immune effector cells must be receptive to stimulation by the DCs and be competent to mediate their antitumor effects, which 3) requires overcoming the various immune-inhibitory mechanisms used by the tumor cells. In this review, following a brief overview of the pivotal milestones in the history of cancer immunotherapy, we will introduce the reader to the basic immunobiological and pharmacological principles of active cancer immunotherapy using DCs. We will then discuss how current research is trying to define the optimal parameters for each of the above steps to realize the full clinical potential of DC therapeutics. Given its high suitability for immune interventions, acute myeloid leukemia was chosen here to showcase the latest research trends driving the field of DC-based cancer immunotherapy.
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Affiliation(s)
- Sébastien Anguille
- Faculty of Medicine and Health Sciences, Vaccine & Infectious Disease Institute, Laboratory of Experimental Hematology, Tumor Immunology Group (S.A., H.H.V.A., H.G., E.L., V.F.V.T., Z.N.B.), and Faculty of Medicine and Health Sciences, Center for Oncological Research (E.L.S.), University of Antwerp, Antwerp, Belgium; Center for Cell Therapy & Regenerative Medicine, Antwerp University Hospital, Antwerp, Belgium (S.A., E.L.S., Z.N.B.); and ANZAC Research Institute, Dendritic Cell Biology and Therapeutics Group, University of Sydney, Sydney, New South Wales, Australia (C.B., P.D.F.)
| | - Evelien L Smits
- Faculty of Medicine and Health Sciences, Vaccine & Infectious Disease Institute, Laboratory of Experimental Hematology, Tumor Immunology Group (S.A., H.H.V.A., H.G., E.L., V.F.V.T., Z.N.B.), and Faculty of Medicine and Health Sciences, Center for Oncological Research (E.L.S.), University of Antwerp, Antwerp, Belgium; Center for Cell Therapy & Regenerative Medicine, Antwerp University Hospital, Antwerp, Belgium (S.A., E.L.S., Z.N.B.); and ANZAC Research Institute, Dendritic Cell Biology and Therapeutics Group, University of Sydney, Sydney, New South Wales, Australia (C.B., P.D.F.)
| | - Christian Bryant
- Faculty of Medicine and Health Sciences, Vaccine & Infectious Disease Institute, Laboratory of Experimental Hematology, Tumor Immunology Group (S.A., H.H.V.A., H.G., E.L., V.F.V.T., Z.N.B.), and Faculty of Medicine and Health Sciences, Center for Oncological Research (E.L.S.), University of Antwerp, Antwerp, Belgium; Center for Cell Therapy & Regenerative Medicine, Antwerp University Hospital, Antwerp, Belgium (S.A., E.L.S., Z.N.B.); and ANZAC Research Institute, Dendritic Cell Biology and Therapeutics Group, University of Sydney, Sydney, New South Wales, Australia (C.B., P.D.F.)
| | - Heleen H Van Acker
- Faculty of Medicine and Health Sciences, Vaccine & Infectious Disease Institute, Laboratory of Experimental Hematology, Tumor Immunology Group (S.A., H.H.V.A., H.G., E.L., V.F.V.T., Z.N.B.), and Faculty of Medicine and Health Sciences, Center for Oncological Research (E.L.S.), University of Antwerp, Antwerp, Belgium; Center for Cell Therapy & Regenerative Medicine, Antwerp University Hospital, Antwerp, Belgium (S.A., E.L.S., Z.N.B.); and ANZAC Research Institute, Dendritic Cell Biology and Therapeutics Group, University of Sydney, Sydney, New South Wales, Australia (C.B., P.D.F.)
| | - Herman Goossens
- Faculty of Medicine and Health Sciences, Vaccine & Infectious Disease Institute, Laboratory of Experimental Hematology, Tumor Immunology Group (S.A., H.H.V.A., H.G., E.L., V.F.V.T., Z.N.B.), and Faculty of Medicine and Health Sciences, Center for Oncological Research (E.L.S.), University of Antwerp, Antwerp, Belgium; Center for Cell Therapy & Regenerative Medicine, Antwerp University Hospital, Antwerp, Belgium (S.A., E.L.S., Z.N.B.); and ANZAC Research Institute, Dendritic Cell Biology and Therapeutics Group, University of Sydney, Sydney, New South Wales, Australia (C.B., P.D.F.)
| | - Eva Lion
- Faculty of Medicine and Health Sciences, Vaccine & Infectious Disease Institute, Laboratory of Experimental Hematology, Tumor Immunology Group (S.A., H.H.V.A., H.G., E.L., V.F.V.T., Z.N.B.), and Faculty of Medicine and Health Sciences, Center for Oncological Research (E.L.S.), University of Antwerp, Antwerp, Belgium; Center for Cell Therapy & Regenerative Medicine, Antwerp University Hospital, Antwerp, Belgium (S.A., E.L.S., Z.N.B.); and ANZAC Research Institute, Dendritic Cell Biology and Therapeutics Group, University of Sydney, Sydney, New South Wales, Australia (C.B., P.D.F.)
| | - Phillip D Fromm
- Faculty of Medicine and Health Sciences, Vaccine & Infectious Disease Institute, Laboratory of Experimental Hematology, Tumor Immunology Group (S.A., H.H.V.A., H.G., E.L., V.F.V.T., Z.N.B.), and Faculty of Medicine and Health Sciences, Center for Oncological Research (E.L.S.), University of Antwerp, Antwerp, Belgium; Center for Cell Therapy & Regenerative Medicine, Antwerp University Hospital, Antwerp, Belgium (S.A., E.L.S., Z.N.B.); and ANZAC Research Institute, Dendritic Cell Biology and Therapeutics Group, University of Sydney, Sydney, New South Wales, Australia (C.B., P.D.F.)
| | | | - Viggo F Van Tendeloo
- Faculty of Medicine and Health Sciences, Vaccine & Infectious Disease Institute, Laboratory of Experimental Hematology, Tumor Immunology Group (S.A., H.H.V.A., H.G., E.L., V.F.V.T., Z.N.B.), and Faculty of Medicine and Health Sciences, Center for Oncological Research (E.L.S.), University of Antwerp, Antwerp, Belgium; Center for Cell Therapy & Regenerative Medicine, Antwerp University Hospital, Antwerp, Belgium (S.A., E.L.S., Z.N.B.); and ANZAC Research Institute, Dendritic Cell Biology and Therapeutics Group, University of Sydney, Sydney, New South Wales, Australia (C.B., P.D.F.)
| | - Zwi N Berneman
- Faculty of Medicine and Health Sciences, Vaccine & Infectious Disease Institute, Laboratory of Experimental Hematology, Tumor Immunology Group (S.A., H.H.V.A., H.G., E.L., V.F.V.T., Z.N.B.), and Faculty of Medicine and Health Sciences, Center for Oncological Research (E.L.S.), University of Antwerp, Antwerp, Belgium; Center for Cell Therapy & Regenerative Medicine, Antwerp University Hospital, Antwerp, Belgium (S.A., E.L.S., Z.N.B.); and ANZAC Research Institute, Dendritic Cell Biology and Therapeutics Group, University of Sydney, Sydney, New South Wales, Australia (C.B., P.D.F.)
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Datta J, Berk E, Cintolo JA, Xu S, Roses RE, Czerniecki BJ. Rationale for a Multimodality Strategy to Enhance the Efficacy of Dendritic Cell-Based Cancer Immunotherapy. Front Immunol 2015; 6:271. [PMID: 26082780 PMCID: PMC4451636 DOI: 10.3389/fimmu.2015.00271] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Accepted: 05/15/2015] [Indexed: 02/03/2023] Open
Abstract
Dendritic cells (DC), master antigen-presenting cells that orchestrate interactions between the adaptive and innate immune arms, are increasingly utilized in cancer immunotherapy. Despite remarkable progress in our understanding of DC immunobiology, as well as several encouraging clinical applications – such as DC-based sipuleucel-T for metastatic castration-resistant prostate cancer – clinically effective DC-based immunotherapy as monotherapy for a majority of tumors remains a distant goal. The complex interplay between diverse molecular and immune processes that govern resistance to DC-based vaccination compels a multimodality approach, encompassing a growing arsenal of antitumor agents which target these distinct processes and synergistically enhance DC function. These include antibody-based targeted molecular therapies, immune checkpoint inhibitors, therapies that inhibit immunosuppressive cellular elements, conventional cytotoxic modalities, and immune potentiating adjuvants. It is likely that in the emerging era of “precision” cancer therapeutics, tangible clinical benefits will only be realized with a multifaceted – and personalized – approach combining DC-based vaccination with adjunctive strategies.
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Affiliation(s)
- Jashodeep Datta
- Division of Endocrine and Oncologic Surgery, Department of Surgery, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA , USA
| | - Erik Berk
- Division of Endocrine and Oncologic Surgery, Department of Surgery, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA , USA
| | - Jessica A Cintolo
- Division of Endocrine and Oncologic Surgery, Department of Surgery, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA , USA
| | - Shuwen Xu
- Division of Endocrine and Oncologic Surgery, Department of Surgery, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA , USA
| | - Robert E Roses
- Division of Endocrine and Oncologic Surgery, Department of Surgery, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA , USA
| | - Brian J Czerniecki
- Division of Endocrine and Oncologic Surgery, Department of Surgery, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA , USA ; Rena Rowen Breast Center, Hospital of the University of Pennsylvania , Philadelphia, PA , USA
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Datta J, Berk E, Xu S, Fitzpatrick E, Rosemblit C, Lowenfeld L, Goodman N, Lewis DA, Zhang PJ, Fisher C, Roses RE, DeMichele A, Czerniecki BJ. Anti-HER2 CD4(+) T-helper type 1 response is a novel immune correlate to pathologic response following neoadjuvant therapy in HER2-positive breast cancer. Breast Cancer Res 2015; 17:71. [PMID: 25997452 PMCID: PMC4488128 DOI: 10.1186/s13058-015-0584-1] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Accepted: 05/13/2015] [Indexed: 01/07/2023] Open
Abstract
INTRODUCTION A progressive loss of circulating anti-human epidermal growth factor receptor-2/neu (HER2) CD4(+) T-helper type 1 (Th1) immune responses is observed in HER2(pos)-invasive breast cancer (IBC) patients relative to healthy controls. Pathologic complete response (pCR) following neoadjuvant trastuzumab and chemotherapy (T + C) is associated with decreased recurrence and improved prognosis. We examined differences in anti-HER2 Th1 responses between pCR and non-pCR patients to identify modifiable immune correlates to pathologic response following neoadjuvant T + C. METHODS Anti-HER2 Th1 responses in 87 HER2(pos)-IBC patients were examined using peripheral blood mononuclear cells pulsed with 6 HER2-derived class II peptides via IFN-γ ELISPOT. Th1 response metrics were anti-HER2 responsivity, repertoire (number of reactive peptides), and cumulative response across 6 peptides (spot-forming cells [SFC]/10(6) cells). Anti-HER2 Th1 responses of non-pCR patients (n = 4) receiving adjuvant HER2-pulsed type 1-polarized dendritic cell (DC1) vaccination were analyzed pre- and post-immunization. RESULTS Depressed anti-HER2 Th1 responses observed in treatment-naïve HER2(pos)-IBC patients (n = 22) did not improve globally in T + C-treated HER2(pos)-IBC patients (n = 65). Compared with adjuvant T + C receipt, neoadjuvant T + C - utilized in 61.5 % - was associated with higher anti-HER2 Th1 repertoire (p = 0.048). While pCR (n = 16) and non-pCR (n = 24) patients did not differ substantially in demographic/clinical characteristics, pCR patients demonstrated dramatically higher anti-HER2 Th1 responsivity (94 % vs. 33 %, p = 0.0002), repertoire (3.3 vs. 0.3 peptides, p < 0.0001), and cumulative response (148.2 vs. 22.4 SFC/10(6), p < 0.0001) versus non-pCR patients. After controlling for potential confounders, anti-HER2 Th1 responsivity remained independently associated with pathologic response (odds ratio 8.82, p = 0.016). This IFN-γ(+) immune disparity was mediated by anti-HER2 CD4(+)T-bet(+)IFN-γ(+) (i.e., Th1) - not CD4(+)GATA-3(+)IFN-γ(+) (i.e., Th2) - phenotypes, and not attributable to non-pCR patients' immune incompetence, host-level T-cell anergy, or increased immunosuppressive populations. In recruited non-pCR patients, anti-HER2 Th1 repertoire (3.7 vs. 0.5, p = 0.014) and cumulative response (192.3 vs. 33.9 SFC/10(6), p = 0.014) improved significantly following HER2-pulsed DC1 vaccination. CONCLUSIONS Anti-HER2 CD4(+) Th1 response is a novel immune correlate to pathologic response following neoadjuvant T + C. In non-pCR patients, depressed Th1 responses are not immunologically "fixed" and can be restored with HER2-directed Th1 immune interventions. In such high-risk patients, combining HER2-targeted therapies with strategies to boost anti-HER2 Th1 immunity may improve outcomes and mitigate recurrence.
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Affiliation(s)
- Jashodeep Datta
- Department of Surgery, University of Pennsylvania Perelman School of Medicine, Rena Rowen Breast Center, 3400 Civic Center Drive, Philadelphia, PA, 19104, USA.
| | - Erik Berk
- Department of Surgery, University of Pennsylvania Perelman School of Medicine, Rena Rowen Breast Center, 3400 Civic Center Drive, Philadelphia, PA, 19104, USA.
| | - Shuwen Xu
- Department of Surgery, University of Pennsylvania Perelman School of Medicine, Rena Rowen Breast Center, 3400 Civic Center Drive, Philadelphia, PA, 19104, USA.
| | - Elizabeth Fitzpatrick
- Department of Surgery, University of Pennsylvania Perelman School of Medicine, Rena Rowen Breast Center, 3400 Civic Center Drive, Philadelphia, PA, 19104, USA.
| | - Cinthia Rosemblit
- Department of Surgery, University of Pennsylvania Perelman School of Medicine, Rena Rowen Breast Center, 3400 Civic Center Drive, Philadelphia, PA, 19104, USA.
| | - Lea Lowenfeld
- Department of Surgery, University of Pennsylvania Perelman School of Medicine, Rena Rowen Breast Center, 3400 Civic Center Drive, Philadelphia, PA, 19104, USA.
| | - Noah Goodman
- Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
| | - David A Lewis
- Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
| | - Paul J Zhang
- Department of Pathology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
| | - Carla Fisher
- Department of Surgery, University of Pennsylvania Perelman School of Medicine, Rena Rowen Breast Center, 3400 Civic Center Drive, Philadelphia, PA, 19104, USA.
| | - Robert E Roses
- Department of Surgery, University of Pennsylvania Perelman School of Medicine, Rena Rowen Breast Center, 3400 Civic Center Drive, Philadelphia, PA, 19104, USA.
| | - Angela DeMichele
- Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. .,Department of Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
| | - Brian J Czerniecki
- Department of Surgery, University of Pennsylvania Perelman School of Medicine, Rena Rowen Breast Center, 3400 Civic Center Drive, Philadelphia, PA, 19104, USA. .,Rena Rowen Breast Center, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
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Kodama T, Hatakeyama Y, Kato S, Mori S. Visualization of fluid drainage pathways in lymphatic vessels and lymph nodes using a mouse model to test a lymphatic drug delivery system. BIOMEDICAL OPTICS EXPRESS 2015; 6:124-34. [PMID: 25657881 PMCID: PMC4317120 DOI: 10.1364/boe.6.000124] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/22/2014] [Revised: 12/03/2014] [Accepted: 12/04/2014] [Indexed: 05/28/2023]
Abstract
Curing/preventing micrometastasis to lymph nodes (LNs) located outside the surgically resected area is essential for improving the morbidity and mortality associated with breast cancer and head and neck cancer. However, no lymphatic therapy system exists that can deliver drugs to LNs located outside the dissection area. Here, we demonstrate proof of concept for a drug delivery system using MXH10/Mo-lpr/lpr mice that exhibit systemic lymphadenopathy, with some peripheral LNs being as large as 10 mm in diameter. We report that a fluorescent solution injected into the subiliac LN (defined as the upstream LN within the dissection area) was delivered successfully to the proper axillary LN (defined as the downstream LN outside the dissection area) through the lymphatic vessels. Our results suggest that this approach could be used before surgical resection to deliver drugs to downstream LNs outside the dissection area. We anticipate that our methodology could be applied clinically, before surgical resection, to cure/prevent micrometastasis in LNs outside the dissection area, using techniques such as ultrasound-guided internal jugular vein catheterization.
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Affiliation(s)
- Tetsuya Kodama
- Graduate School of Biomedical Engineering, Tohoku University, 4-1 Seiryo, Aoba, Sendai, Miyagi 980-8575,
Japan
| | - Yuriko Hatakeyama
- Graduate School of Biomedical Engineering, Tohoku University, 4-1 Seiryo, Aoba, Sendai, Miyagi 980-8575,
Japan
| | - Shigeki Kato
- Graduate School of Biomedical Engineering, Tohoku University, 4-1 Seiryo, Aoba, Sendai, Miyagi 980-8575,
Japan
| | - Shiro Mori
- Department of Oral and Maxillofacial Surgery, Tohoku University Hospital, 1-1 Seiryo, Aoba, Sendai 980-8575,
Japan
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Vasaturo A, Verdoes M, de Vries J, Torensma R, Figdor CG. Restoring immunosurveillance by dendritic cell vaccines and manipulation of the tumor microenvironment. Immunobiology 2014; 220:243-8. [PMID: 25466585 DOI: 10.1016/j.imbio.2014.11.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2014] [Revised: 11/06/2014] [Accepted: 11/07/2014] [Indexed: 12/19/2022]
Abstract
Cancer cells evolve from normal cells throughout life and are usually recognized by our immune system and destroyed, a process called immunosurveillance. Unfortunately, in some instances cancer cells paralyze our immune system, resulting in outgrowth and spreading of the tumor. Understanding the complexity of immunomodulation by tumors is important for the development of therapeutical strategies. Nowadays, various approaches have been developed to enhance anti-tumor immune responses and abrogate the immune dampening effect of the tumor and its surrounding environment, including dendritic cell-based vaccines, therapies to counteract myeloid derived suppressor cell function within the tumor and antagonists of inhibitory signaling pathways to overcome 'immune checkpoints'. The challenge is now to find the right combination of immune based therapies to fully restore immune function and provide a more efficacious and enduring anti-tumor response.
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Affiliation(s)
- Angela Vasaturo
- Radboud Institute for Molecular Life Sciences, Radboudumc, Department of Tumorimmunology, Geert Grooteplein 26, 6525GA Nijmegen, The Netherlands
| | - Martijn Verdoes
- Radboud Institute for Molecular Life Sciences, Radboudumc, Department of Tumorimmunology, Geert Grooteplein 26, 6525GA Nijmegen, The Netherlands
| | - Jolanda de Vries
- Radboud Institute for Molecular Life Sciences, Radboudumc, Department of Tumorimmunology, Geert Grooteplein 26, 6525GA Nijmegen, The Netherlands
| | - Ruurd Torensma
- Radboud Institute for Molecular Life Sciences, Radboudumc, Department of Tumorimmunology, Geert Grooteplein 26, 6525GA Nijmegen, The Netherlands
| | - Carl G Figdor
- Radboud Institute for Molecular Life Sciences, Radboudumc, Department of Tumorimmunology, Geert Grooteplein 26, 6525GA Nijmegen, The Netherlands.
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Galluzzi L, Senovilla L, Vacchelli E, Eggermont A, Fridman WH, Galon J, Sautès-Fridman C, Tartour E, Zitvogel L, Kroemer G. Trial watch: Dendritic cell-based interventions for cancer therapy. Oncoimmunology 2014; 1:1111-1134. [PMID: 23170259 PMCID: PMC3494625 DOI: 10.4161/onci.21494] [Citation(s) in RCA: 140] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Dendritic cells (DCs) occupy a central position in the immune system, orchestrating a wide repertoire of responses that span from the development of self-tolerance to the elicitation of potent cellular and humoral immunity. Accordingly, DCs are involved in the etiology of conditions as diverse as infectious diseases, allergic and autoimmune disorders, graft rejection and cancer. During the last decade, several methods have been developed to load DCs with tumor-associated antigens, ex vivo or in vivo, in the attempt to use them as therapeutic anticancer vaccines that would elicit clinically relevant immune responses. While this has not always been the case, several clinical studies have demonstrated that DC-based anticancer vaccines are capable of activating tumor-specific immune responses that increase overall survival, at least in a subset of patients. In 2010, this branch of clinical research has culminated with the approval by FDA of a DC-based therapeutic vaccine (sipuleucel-T, Provenge®) for use in patients with asymptomatic or minimally symptomatic metastatic hormone-refractory prostate cancer. Intense research efforts are currently dedicated to the identification of the immunological features of patients that best respond to DC-based anticancer vaccines. This knowledge may indeed lead to personalized combination strategies that would extend the benefit of DC-based immunotherapy to a larger patient population. In addition, widespread enthusiasm has been generated by the results of the first clinical trials based on in vivo DC targeting, an approach that holds great promises for the future of DC-based immunotherapy. In this Trial Watch, we will summarize the results of recently completed clinical trials and discuss the progress of ongoing studies that have evaluated/are evaluating DC-based interventions for cancer therapy.
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Affiliation(s)
- Lorenzo Galluzzi
- Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France ; Institut Gustave Roussy; Villejuif, France
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Villarreal-Ramos B, Berg S, Chamberlain L, McShane H, Hewinson RG, Clifford D, Vordermeier M. Development of a BCG challenge model for the testing of vaccine candidates against tuberculosis in cattle. Vaccine 2014; 32:5645-9. [PMID: 25138291 PMCID: PMC5441994 DOI: 10.1016/j.vaccine.2014.08.009] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Revised: 07/25/2014] [Accepted: 08/06/2014] [Indexed: 11/19/2022]
Abstract
Recovery of BCG from bovine tissues after vaccination. Potential novel routes of inoculation. Development of a BCG “challenge” model for the testing of vaccine candidates against bovine TB. Vaccination is being considered as part of a sustainable strategy for the control of bovine tuberculosis (BTB) in the UK. The live attenuated Mycobacterium bovis bacillus Calmette-Guerin (BCG) has been used experimentally to vaccinate cattle against BTB. However, BCG confers partial protection against BTB and therefore, there is a need to develop improved vaccines. BTB vaccine efficacy experiments require the use of biosafety level 3 facilities which are expensive to maintain, generally oversubscribed and represent a bottle neck for the testing of vaccine candidates. One indicator of the induction of protective responses would be the ability of the host's immune response to control/kill mycobacteria. In this work we have evaluated an intranodal BCG challenge for the selection of vaccine candidates at biosafety level 2 which are capable of inducing mycobactericidal responses. To our knowledge, this is the first such report. Whilst BCG only confers partial protection, it is still the standard against which other vaccines are judged. Therefore we tested the BCG intranodal challenge in BCG (Danish strain) vaccinated cattle and showed that vaccinated cattle had lower BCG cfu counts than naïve cattle at 14 and 21 days after intranodal challenge with BCG (Tokyo strain). This model could help prioritize competing TB vaccine candidates and exploration of primary and secondary immune responses to mycobacteria.
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Affiliation(s)
| | - Stefan Berg
- Bovine TB, AHVLA-Weybridge, New Haw, Addlestone, Surrey KT15 3NB, UK
| | - Laura Chamberlain
- Bovine TB, AHVLA-Weybridge, New Haw, Addlestone, Surrey KT15 3NB, UK
| | - Helen McShane
- The Jenner Institute Old Road Campus Research Building Oxford University, Roosevelt Drive, Oxford OX3 7DQ, UK
| | - R Glyn Hewinson
- Bovine TB, AHVLA-Weybridge, New Haw, Addlestone, Surrey KT15 3NB, UK
| | - Derek Clifford
- Bovine TB, AHVLA-Weybridge, New Haw, Addlestone, Surrey KT15 3NB, UK
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Plantinga M, de Haar C, Nierkens S, Boelens JJ. Dendritic Cell Therapy in an Allogeneic-Hematopoietic Cell Transplantation Setting: An Effective Strategy toward Better Disease Control? Front Immunol 2014; 5:218. [PMID: 24904573 PMCID: PMC4032952 DOI: 10.3389/fimmu.2014.00218] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2014] [Accepted: 04/30/2014] [Indexed: 12/19/2022] Open
Abstract
Hematopoietic cell transplantation (HCT) is a last treatment resort and only potentially curative treatment option for several hematological malignancies resistant to chemotherapy. The induction of profound immune regulation after allogeneic HCT is imperative to prevent graft-versus-host reactions and, at the same time, allow protective immune responses against pathogens and against tumor cells. Dendritic cells (DCs) are highly specialized antigen-presenting cells that are essential in regulating this balance and are of major interest as a tool to modulate immune responses in the complex and challenging phase of immune reconstitution early after allo-HCT. This review focuses on the use of DC vaccination to prevent cancer relapses early after allo-HCT. It describes the role of host and donor-DCs, various vaccination strategies, different DC subsets, antigen loading, DC maturation/activation, and injection sites and dose. At last, clinical trials using DC vaccination post-allo-HCT and the future perspectives of DC vaccination in combination with other cancer immunotherapies are discussed.
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Affiliation(s)
- Maud Plantinga
- Utrecht - Dendritic cells AgaiNst CancEr (U-DANCE), Laboratory of Translational Immunology, Department of Immunology, University Medical Centre Utrecht , Utrecht , Netherlands
| | - Colin de Haar
- Utrecht - Dendritic cells AgaiNst CancEr (U-DANCE), Laboratory of Translational Immunology, Department of Immunology, University Medical Centre Utrecht , Utrecht , Netherlands
| | - Stefan Nierkens
- Utrecht - Dendritic cells AgaiNst CancEr (U-DANCE), Laboratory of Translational Immunology, Department of Immunology, University Medical Centre Utrecht , Utrecht , Netherlands
| | - Jaap Jan Boelens
- Utrecht - Dendritic cells AgaiNst CancEr (U-DANCE), Laboratory of Translational Immunology, Department of Immunology, University Medical Centre Utrecht , Utrecht , Netherlands ; Pediatric Blood and Marrow Transplantation Program, Department of Immunology, University Medical Centre Utrecht , Utrecht , Netherlands
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Strioga MM, Darinskas A, Pasukoniene V, Mlynska A, Ostapenko V, Schijns V. Xenogeneic therapeutic cancer vaccines as breakers of immune tolerance for clinical application: to use or not to use? Vaccine 2014; 32:4015-24. [PMID: 24837511 DOI: 10.1016/j.vaccine.2014.05.006] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2014] [Revised: 04/29/2014] [Accepted: 05/01/2014] [Indexed: 02/06/2023]
Abstract
Accumulation of firm evidence that clinically apparent cancer develops only when malignant cells manage to escape immunosurveillance led to the introduction of tumor immunotherapy strategies aiming to reprogramm the cancer-dysbalanced antitumor immunity and restore its capacity to control tumor growth. There are several immunotherapeutical strategies, among which specific active immunotherapy or therapeutic cancer vaccination is one of the most promising. It targets dendritic cells (DCs) which have a unique ability of inducing naive and central memory T cell-mediated immune response in the most efficient manner. DCs can be therapeutically targeted either in vivo/in situ or by ex vivo manipulations followed by their re-injection back into the same patient. The majority of current DC targeting strategies are based on autologous or allogeneic tumor-associated antigens (TAAs) which possess various degrees of inherent tolerogenic potential. Therefore still limited efficacy of various tumor immunotherapy approaches may be attributed, among various other mechanisms, to the insufficient immunogenicity of self-protein-derived TAAs. Based on such an idea, the use of homologous xenogeneic antigens, derived from different species was suggested to overcome the natural immune tolerance to self TAAs. Xenoantigens are supposed to differ sufficiently from self antigens to a degree that renders them immunogenic, but at the same time preserves an optimal homology range with self proteins still allowing xenoantigens to induce cross-reactive T cells. Here we discuss the concept of xenogeneic vaccination, describe the cons and pros of autologous/allogeneic versus xenogeneic therapeutic cancer vaccines, present the results of various pre-clinical and several clinical studies and highlight the future perspectives of integrating xenovaccination into rapidly developing tumor immunotherapy regimens.
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Affiliation(s)
- Marius M Strioga
- Department of Immunology, Center of Oncosurgery, Institute of Oncology, Vilnius University, Vilnius, Lithuania.
| | - Adas Darinskas
- Department of Immunology, Center of Oncosurgery, Institute of Oncology, Vilnius University, Vilnius, Lithuania.
| | - Vita Pasukoniene
- Department of Immunology, Center of Oncosurgery, Institute of Oncology, Vilnius University, Vilnius, Lithuania.
| | - Agata Mlynska
- Department of Immunology, Center of Oncosurgery, Institute of Oncology, Vilnius University, Vilnius, Lithuania.
| | - Valerijus Ostapenko
- Section of Breast Surgery, 3(rd) Department of Surgery, Center of Oncosurgery, Institute of Oncology, Vilnius University, Vilnius, Lithuania.
| | - Virgil Schijns
- Immune Intervention, Cell Biology & Immunology group, Wageningen University, Wageningen, the Netherlands; Epitopoietic Research Corporation (ERC), Namur, Belgium.
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Cicchelero L, de Rooster H, Sanders NN. Various ways to improve whole cancer cell vaccines. Expert Rev Vaccines 2014; 13:721-35. [PMID: 24758597 DOI: 10.1586/14760584.2014.911093] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Immunotherapy based on whole cancer cell vaccines is regarded as a promising avenue for cancer treatment. However, limited efficacy in the first human clinical trials calls for more optimized whole cancer cell vaccines and better patient selection. It is suggested that whole cancer cell vaccines consist preferably of immunogenically killed autologous cancer stem cells associated with dendritic cells. Adjuvants should stimulate both immune effector cells and memory cells, which could be achieved through their correct dosage and timing of administration. There are indications that whole cancer cell vaccination is less effective in patients who are immunocompromised, who have specific genetic defects in their immune or cancer cells, as well as in patients in an advanced cancer stage. However, such patients form the bulk of enrolled patients in clinical trials, prohibiting an objective evaluation of the true potential of whole cancer cell immunotherapy. Each key point will be discussed.
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Affiliation(s)
- Laetitia Cicchelero
- Laboratory of Gene Therapy, Department of Nutrition, Genetics and Ethology, Faculty of Veterinary Medicine, Ghent University, Heidestraat 19, B-9820 Merelbeke, Belgium
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Tesfatsion DA. Dendritic cell vaccine against leukemia: advances and perspectives. Immunotherapy 2014; 6:485-96. [PMID: 24815786 DOI: 10.2217/imt.14.12] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
As with many other types of malignancies, sustainable eradication of leukemia has been a challenge. This is related to the inevitable failure of conventional chemotherapeutic agents and radiation therapy to target the relatively quiescent leukemia stem cells, which are believed to have multidrug resistance, antiapoptotic capacity and enhanced DNA repair mechanisms allowing them to evade the immune system. Considering other therapeutic options that are minimally toxic to normal cells and effectively target not only the majority and more differentiated cancer cells, but also the rare residual leukemia cells, is of paramount importance. A number of immunotherapeutic options have been proposed to counter this challenge. One of the remarkable achievements in the field of immunotherapy has been the successful use of antigen presenting cells as vehicles of tumor/pathogenic antigens to the T-cell compartments. This review will focus on advances and perspectives of this arm of immunotherapy against leukemia.
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Abstract
Vaccines are typically injected subcutaneously or intramuscularly for stimulation of immune responses. The success of this requires efficient drainage of vaccine to lymph nodes where antigen presenting cells can interact with lymphocytes for generation of the wanted immune responses. The strength and the type of immune responses induced also depend on the density or frequency of interactions as well as the microenvironment, especially the content of cytokines. As only a minute fraction of peripherally injected vaccines reaches the lymph nodes, vaccinations of mice and humans were performed by direct injection of vaccine into inguinal lymph nodes, i.e. intralymphatic injection. In man, the procedure is guided by ultrasound. In mice, a small (5-10 mm) incision is made in the inguinal region of anesthetized animals, the lymph node is localized and immobilized with forceps, and a volume of 10-20 μl of the vaccine is injected under visual control. The incision is closed with a single stitch using surgical sutures. Mice were vaccinated with plasmid DNA, RNA, peptide, protein, particles, and bacteria as well as adjuvants, and strong improvement of immune responses against all type of vaccines was observed. The intralymphatic method of vaccination is especially appropriate in situations where conventional vaccination produces insufficient immunity or where the amount of available vaccine is limited.
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Affiliation(s)
- Pål Johansen
- Department of Dermatology, University Hospital Zurich
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Abstract
Effective antitumor immunity requires the generation and persistence of functional tumor-specific T-cell responses. Among the critical factors that often control these responses is how the antigen is delivered and presented to T cells. The use of peptide-based vaccination has been found to be a promising means to induce antitumor T-cell responses but with limited effects even if the peptide is co-delivered with a potent adjuvant. This limited response could be due to cancer-induced dysfunction in dendritic cells (DC), which play a central role in shaping the quantity and quality of antitumor immunity. Therefore, DC-based peptide delivery of tumor antigen is becoming a potential approach in cancer immunotherapy. In this approach, autologous DC are generated from their precursors in bone marrow or peripheral blood mononuclear cells, loaded with tumor antigen(s) and then infused back to the tumor-bearing host in about 7 days. This DC-based vaccination can act as an antigen delivery vehicle as well as a potent adjuvant, resulting in measurable antitumor immunity in several cancer settings in preclinical and clinical studies. This chapter focuses on DC-based vaccination and how this approach can be more efficacious in cancer immunotherapy.Effective antitumor immunity requires the generation and persistence of functional tumor-specific T-cell responses. Among the critical factors that often control these responses is how the antigen is delivered and presented to T cells. The use of peptide-based vaccination has been found to be a promising means to induce antitumor T-cell responses but with limited effects even if the peptide is co-delivered with a potent adjuvant. This limited response could be due to cancer-induced dysfunction in dendritic cells (DC), which play a central role in shaping the quantity and quality of antitumor immunity. Therefore, DC-based peptide delivery of tumor antigen is becoming a potential approach in cancer immunotherapy. In this approach, autologous DC are generated from their precursors in bone marrow or peripheral blood mononuclear cells, loaded with tumor antigen(s) and then infused back to the tumor-bearing host in about 7 days. This DC-based vaccination can act as an antigen delivery vehicle as well as a potent adjuvant, resulting in measurable antitumor immunity in several cancer settings in preclinical and clinical studies. This chapter focuses on DC-based vaccination and how this approach can be more efficacious in cancer immunotherapy.
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Affiliation(s)
- Mohamed L Salem
- Immunology and Biotechnology Unit, Zoology Department, Faculty of Science, Tanta University, Tanta, Egypt
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Abstract
Research shows that cancers are recognized by the immune system but that the immune recognition of tumors does not uniformly result in tumor rejection or regression. Quantitating the success or failure of the immune system in tumor elimination is difficult because we do not really know the total numbers of encounters of the immune system with the tumors. Regardless of that important issue, recognition of the tumor by the immune system implicitly contains the idea of the tumor antigen, which is what is actually recognized. We review the molecular identity of all forms of tumor antigens (antigens with specific mutations, cancer-testis antigens, differentiation antigens, over-expressed antigens) and discuss the use of these multiple forms of antigens in experimental immunotherapy of mouse and human melanoma. These efforts have been uniformly unsuccessful; however, the approaches that have not worked or have somewhat worked have been the source of many new insights into melanoma immunology. From a critical review of the various approaches to vaccine therapy we conclude that individual cancer-specific mutations are truly the only sources of cancer-specific antigens, and therefore, the most attractive targets for immunotherapy.
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Affiliation(s)
- Tatiana Blanchard
- Department of Immunology, and Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut School of Medicine, Farmington, CT 06030-1601, USA
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Fracol M, Xu S, Mick R, Fitzpatrick E, Nisenbaum H, Roses R, Fisher C, Tchou J, Fox K, Zhang P, Czerniecki BJ. Response to HER-2 pulsed DC1 vaccines is predicted by both HER-2 and estrogen receptor expression in DCIS. Ann Surg Oncol 2013; 20:3233-9. [PMID: 23851609 DOI: 10.1245/s10434-013-3119-y] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2013] [Indexed: 11/18/2022]
Abstract
BACKGROUND Patients with estrogen-independent (ER(neg)) human epidermal growth factor receptor-2 (HER-2)-positive ductal carcinoma in situ (DCIS) treated with lumpectomy alone or lumpectomy and radiation are at increased risk of developing subsequent breast cancer events. METHODS Thirty-eight patients with HER-2 expressing DCIS received a HER-2 pulsed autologous dendritic cell (DC1) vaccine administered over 4-6 weeks before surgical resection. HER-2 and estrogen receptor (ER) expression were determined by immunohistochemistry. In 35 patients, CD4(pos) T-cell sensitization to HER-2 peptides was identified by ELISPOT. In 19 patients, CD8(pos) T-cell responses were identified by ELISA. Clinical and immune responses postvaccination were compared between intermediate-expressing HER-2 (2+) and high-expressing HER-2 (3+) patients, as well as ER(neg) and estrogen-dependent (ER(pos)) patients. RESULTS There was no significant difference in immune response after HER-2 vaccination in patients with HER-2 (2+) and (3+) tumors or ER(neg) and ER(pos) tumors. Complete tumor regression rates were similar in patients with HER-2 (2+) and (3+) DCIS. Overall, clinical response rates were similar in patients with ER(neg) and ER(pos) DCIS, but complete tumor regression was significantly more common in patients with ER(neg) DCIS. CONCLUSIONS Despite equivalent immune responses after vaccination in patients with HER-2 (2+), HER-2 (3+), ER(neg) and ER(pos) DCIS, HER-2 pulsed DC1 induces more complete responses in patients with ER(neg) DCIS. These data provide a rationale for developing vaccinations to reduce recurrence in patients with ER(neg) DCIS for whom there are currently limited adjuvant options.
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Affiliation(s)
- Megan Fracol
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Carreno BM, Becker-Hapak M, Huang A, Chan M, Alyasiry A, Lie WR, Aft RL, Cornelius LA, Trinkaus KM, Linette GP. IL-12p70-producing patient DC vaccine elicits Tc1-polarized immunity. J Clin Invest 2013; 123:3383-94. [PMID: 23867552 DOI: 10.1172/jci68395] [Citation(s) in RCA: 134] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2012] [Accepted: 05/06/2013] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Systemic administration of IL-12p70 has demonstrated clinical activity in cancer patients, but dose-limiting toxicities have hindered its incorporation in vaccine formulations. Here, we report on the immunological and clinical outcomes upon vaccination with CD40L/IFN-γ-matured, IL-12p70-producing DCs. METHODS 7 HLA-A*0201+ newly diagnosed stage IV melanoma patients were immunized against the gp100 melanoma antigen using autologous peptide-pulsed, CD40L/IFN-γ-matured DCs. PBMCs were taken weekly for immune monitoring by tetramer analysis and functional assays. CT imaging was performed at baseline, week 9, and week 18 for clinical assessment using RECIST. RESULTS 6 of 7 treated patients developed sustained T cell immunity to all 3 melanoma gp100 antigen-derived peptides. 3 of the 6 immunological responders developed confirmed clinical responses (1 complete remission >4 years, 2 partial response). Importantly, DC vaccine-derived IL-12p70 levels positively correlated with time to progression (P = 0.019, log-rank), as did T-cytotoxic 1 (Tc1) immunity, as assessed by IFN-γ/IL-13 and IFN-γ/IL-5 ratios (P = 0.035 and P = 0.030, respectively, log-rank). In contrast, a pathway-specific defect in IL-12p35 transcription was identified upon CD40L/IFN-γ activation in clinical nonresponder patient DCs, and gp100-specific T cells from these patients displayed a Tc2 phenotype. Incorporation of TLR3 and TLR8 agonists into the CD40L/IFN-γ activation protocol corrected the IL-12p70 production defect in DCs derived from clinical nonresponder patients. CONCLUSION These findings underscore the essential role of IL-12p70 in the development of therapeutic type 1 antigen-specific CD8+ T cell immunity in humans with cancer.
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Affiliation(s)
- Beatriz M Carreno
- Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
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Chiang CLL, Kandalaft LE, Tanyi J, Hagemann AR, Motz GT, Svoronos N, Montone K, Mantia-Smaldone GM, Smith L, Nisenbaum HL, Levine BL, Kalos M, Czerniecki BJ, Torigian DA, Powell DJ, Mick R, Coukos G. A dendritic cell vaccine pulsed with autologous hypochlorous acid-oxidized ovarian cancer lysate primes effective broad antitumor immunity: from bench to bedside. Clin Cancer Res 2013; 19:4801-15. [PMID: 23838316 DOI: 10.1158/1078-0432.ccr-13-1185] [Citation(s) in RCA: 180] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
PURPOSE Whole tumor lysates are promising antigen sources for dendritic cell (DC) therapy as they contain many relevant immunogenic epitopes to help prevent tumor escape. Two common methods of tumor lysate preparations are freeze-thaw processing and UVB irradiation to induce necrosis and apoptosis, respectively. Hypochlorous acid (HOCl) oxidation is a new method for inducing primary necrosis and enhancing the immunogenicity of tumor cells. EXPERIMENTAL DESIGN We compared the ability of DCs to engulf three different tumor lysate preparations, produce T-helper 1 (TH1)-priming cytokines and chemokines, stimulate mixed leukocyte reactions (MLR), and finally elicit T-cell responses capable of controlling tumor growth in vivo. RESULTS We showed that DCs engulfed HOCl-oxidized lysate most efficiently stimulated robust MLRs, and elicited strong tumor-specific IFN-γ secretions in autologous T cells. These DCs produced the highest levels of TH1-priming cytokines and chemokines, including interleukin (IL)-12. Mice vaccinated with HOCl-oxidized ID8-ova lysate-pulsed DCs developed T-cell responses that effectively controlled tumor growth. Safety, immunogenicity of autologous DCs pulsed with HOCl-oxidized autologous tumor lysate (OCDC vaccine), clinical efficacy, and progression-free survival (PFS) were evaluated in a pilot study of five subjects with recurrent ovarian cancer. OCDC vaccination produced few grade 1 toxicities and elicited potent T-cell responses against known ovarian tumor antigens. Circulating regulatory T cells and serum IL-10 were also reduced. Two subjects experienced durable PFS of 24 months or more after OCDC. CONCLUSIONS This is the first study showing the potential efficacy of a DC vaccine pulsed with HOCl-oxidized tumor lysate, a novel approach in preparing DC vaccine that is potentially applicable to many cancers.
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Affiliation(s)
- Cheryl Lai-Lai Chiang
- Ovarian Cancer Research Center, Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
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Kandalaft LE, Chiang CL, Tanyi J, Motz G, Balint K, Mick R, Coukos G. A Phase I vaccine trial using dendritic cells pulsed with autologous oxidized lysate for recurrent ovarian cancer. J Transl Med 2013; 11:149. [PMID: 23777306 PMCID: PMC3693890 DOI: 10.1186/1479-5876-11-149] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2013] [Accepted: 06/12/2013] [Indexed: 02/04/2023] Open
Abstract
PURPOSE Ovarian cancer, like most solid tumors, is in dire need of effective therapies. The significance of this trial lies in its promise to spearhead the development of combination immunotherapy and to introduce novel approaches to therapeutic immunomodulation, which could enable otherwise ineffective vaccines to achieve clinical efficacy. RATIONALE Tumor-infiltrating T cells have been associated with improved outcome in ovarian cancer, suggesting that activation of antitumor immunity will improve survival. However, molecularly defined vaccines have been generally disappointing. Cancer vaccines elicit a modest frequency of low-to-moderate avidity tumor-specific T-cells, but powerful tumor barriers dampen the engraftment, expansion and function of these effector T-cells in the tumor, thus preventing them from reaching their full therapeutic potential. Our work has identified two important barriers in the tumor microenvironment: the blood-tumor barrier, which prevents homing of effector T cells, and T regulatory cells, which inactivate effector T cells. We hypothesize that cancer vaccine therapy will benefit from combinations that attenuate these two barrier mechanisms. DESIGN We propose a three-cohort sequential study to investigate a combinatorial approach of a new dendritic cell (DC) vaccine pulsed with autologous whole tumor oxidized lysate, in combination with antiangiogenesis therapy (bevacizumab) and metronomic cyclophosphamide, which impacts Treg cells. INNOVATION This study uses a novel autologous tumor vaccine developed with 4-day DCs pulsed with oxidized lysate to elicit antitumor response. Furthermore, the combination of bevacizumab with a whole tumor antigen vaccine has not been tested in the clinic. Finally the combination of bevacizumab and metronomic cyclophosphamide in immunotherapy is novel.
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Affiliation(s)
- Lana E Kandalaft
- Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, PA, USA
| | - Cheryl L Chiang
- Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, PA, USA
| | - Janos Tanyi
- Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, PA, USA
| | - Greg Motz
- Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, PA, USA
| | - Klara Balint
- Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, PA, USA
| | - Rosemarie Mick
- Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - George Coukos
- Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, PA, USA
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Garg NK, Dwivedi P, Prabha P, Tyagi RK. RNA pulsed dendritic cells: an approach for cancer immunotherapy. Vaccine 2013; 31:1141-1156. [PMID: 23306369 DOI: 10.1016/j.vaccine.2012.12.027] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2012] [Revised: 11/30/2012] [Accepted: 12/07/2012] [Indexed: 02/07/2023]
Abstract
The immunotherapy of cancer is aimed at evoking both branches of immune system to elicite specific immune responses directed against tumor antigens to deal with residual tumor cells upon interaction, and thereby decreases mortality as well as morbidity of cancer patients. As dendritic cells (DCs) are specialized for antigen presentation, and their immunogenicity leads to the induction of antigen specific immune responses, various immunotherapeutic approaches have been designed for using DCs to present tumor-associated antigens to T-lymphocytes. As a part of proposed strategy ex vivo generated DCs might be loaded with antigens and re-infused to the patients and/or they can be used for the ex vivo expansion of anti-tumor lymphocytes. The DCs loaded ex vivo with RNA can be safely administered which proves to be an asset for producing antigen specific immune responses. Furthermore, already conducted studies have prompted clinical trials to be designed to investigate immunological and clinical effects of RNA pulsed DCs administered as an engineered therapeutic vaccine in cancer patients. However, selection of the antigens of interest, methods for introducing TAAgs into MHC class I and II processing pathways, methods for isolation and activation of DCs, and route of administration are the parameters to be considered for designing and conducting clinical trials with engineered DCs. The enhanced RNA transfection efficiency would further improve antigen processing and presentation and T-cell co-stimulation, resulting in the induction of heightened anti-tumor immune responses. Therefore, RNA transfected dendritic cells continue to hold promise for cellular immunotherapy and opens new avenues to devising further strategies for cancer therapeutic interventions.
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Affiliation(s)
- Neeraj Kumar Garg
- Drug Delivery Research Group, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160 014, Chandigarh, India
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Aarntzen EH, De Vries IJM, Lesterhuis WJ, Schuurhuis D, Jacobs JF, Bol K, Schreibelt G, Mus R, De Wilt JH, Haanen JB, Schadendorf D, Croockewit A, Blokx WA, Van Rossum MM, Kwok WW, Adema GJ, Punt CJ, Figdor CG. Targeting CD4+ T-Helper Cells Improves the Induction of Antitumor Responses in Dendritic Cell–Based Vaccination. Cancer Res 2012; 73:19-29. [DOI: 10.1158/0008-5472.can-12-1127] [Citation(s) in RCA: 124] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Johansen P, von Moos S, Mohanan D, Kündig TM, Senti G. New routes for allergen immunotherapy. Hum Vaccin Immunother 2012; 8:1525-33. [PMID: 23095873 PMCID: PMC3660774 DOI: 10.4161/hv.21948] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2012] [Revised: 08/15/2012] [Accepted: 08/23/2012] [Indexed: 12/16/2022] Open
Abstract
IgE-mediated allergy is a highly prevalent disease in the industrialized world. Allergen-specific immunotherapy (SIT) should be the preferred treatment, as it has long lasting protective effects and can stop the progression of the disease. However, few allergic patients choose to undergo SIT, due to the long treatment time and potential allergic adverse events. Since the beneficial effects of SIT are mediated by antigen presenting cells inducing Th1, Treg and antibody responses, whereas the adverse events are caused by mast cells and basophils, the therapeutic window of SIT may be widened by targeting tissues rich in antigen presenting cells. Lymph nodes and the epidermis contain high density of dendritic cells and low numbers of mast cells and basophils. The epidermis has the added benefit of not being vascularised thereby reducing the chances of anaphylactic shock due to leakage of allergen. Hence, both these tissues represent highly promising routes for SIT and are the focus of discussion in this review.
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Affiliation(s)
- Pål Johansen
- Department of Dermatology; University Hospital Zurich; Zurich, Switzerland
| | - Seraina von Moos
- Clinical Trials Center; University Hospital Zurich; Zurich, Switzerland
| | - Deepa Mohanan
- Department of Dermatology; University Hospital Zurich; Zurich, Switzerland
| | - Thomas M. Kündig
- Department of Dermatology; University Hospital Zurich; Zurich, Switzerland
| | - Gabriela Senti
- Clinical Trials Center; University Hospital Zurich; Zurich, Switzerland
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A novel dendritic cell-based immunization approach for the induction of durable Th1-polarized anti-HER-2/neu responses in women with early breast cancer. J Immunother 2012; 35:54-65. [PMID: 22130160 DOI: 10.1097/cji.0b013e318235f512] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Twenty-seven patients with HER-2/neu overexpressing ductal carcinoma in situ of the breast were enrolled in a neoadjuvant immunization trial for safety and immunogenicity of DC1-polarized dendritic cells (DC1) pulsed with 6 HER-2/neu promiscuous major histocompatibility complex class II-binding peptides and 2 additional human leukocyte antigen (HLA)-A2.1 class I-binding peptides. DC1 were generated with interferon-γ and a special clinical-grade bacterial endotoxin (lipopolysaccharide) and administered directly into groin lymph nodes 4 times at weekly intervals before scheduled surgical resection of ductal carcinoma in situ. Patients were monitored for the induction of new or enhanced antipeptide reactivity by interferon-γ ELISPOT and enzyme-linked immunosorbentassays performed on Th cells obtained from peripheral blood or excised sentinel lymph nodes. Responses by cytotoxic T lymphocyte against HLA-A2.1-binding peptides were measured using peptide-pulsed T2 target cells or HER-2/neu-expressing or nonexpressing tumor cell lines. DC1 showed surface phenotype indistinct from "gold standard" inflammatory cocktail-activated DC, but displayed a number of distinguishing functional characteristics including the secretion of soluble factors and enhanced "killer DC" capacity against tumor cells in vitro. Postimmunization, we observed sensitization of Th cells to at least 1 class II peptide in 22 of 25 (88%; 95% exact confidence interval, 68.8%-97.5%) evaluable patients, whereas 11 of 13 (84.6%; 95% exact confidence interval, 64%-99.8%) HLA-A2.1 patients were successfully sensitized to class I peptides. Perhaps most importantly, anti-HER-2/neu peptide responses were observed up to 52-month postimmunization. These data show that even in the presence of early breast cancer such DC1 are potent inducers of durable type I-polarized immunity, suggesting potential clinical value for development of cancer immunotherapy.
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Sharma A, Koldovsky U, Xu S, Mick R, Roses R, Fitzpatrick E, Weinstein S, Nisenbaum H, Levine BL, Fox K, Zhang P, Koski G, Czerniecki BJ. HER-2 pulsed dendritic cell vaccine can eliminate HER-2 expression and impact ductal carcinoma in situ. Cancer 2012; 118:4354-62. [PMID: 22252842 DOI: 10.1002/cncr.26734] [Citation(s) in RCA: 131] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2011] [Revised: 09/27/2011] [Accepted: 11/01/2011] [Indexed: 11/11/2022]
Abstract
BACKGROUND HER-2/neu overexpression plays a critical role in breast cancer development, and its expression in ductal carcinoma in situ (DCIS) is associated with development of invasive breast cancer. A vaccine targeting HER-2/neu expression in DCIS may initiate immunity against invasive cancer. METHODS A HER-2/neu dendritic cell vaccine was administered to 27 patients with HER-2/neu-overexpressing DCIS. The HER-2/neu vaccine was administered before surgical resection, and pre- and postvaccination analysis was conducted to assess clinical results. RESULTS At surgery, 5 of 27 (18.5%) vaccinated subjects had no evidence of remaining disease, whereas among 22 subjects with residual DCIS, HER-2/neu expression was eradicated in 11 (50%). When comparing estrogen receptor (ER)(neg) with ER(pos) DCIS lesions, vaccination was more effective in hormone-independent DCIS. After vaccination, no residual DCIS was found in 40% of ER(neg) subjects compared with 5.9% in ER(pos) subjects. Sustained HER-2/neu expression was found in 10% of ER(neg) subjects compared with 47.1% in ER(pos) subjects (P = .04). Postvaccination phenotypes were significantly different between ER(pos) and ER(neg) subjects (P = .01), with 7 of 16 (43.8%) initially presenting with ER(pos) HER-2/neu(pos) luminal B phenotype finishing with the ER(pos) HER-2/neu(neg) luminal A phenotype, and 3 of 6 (50%) with the ER(neg) HER-2/neu(pos) phenotype changing to the ER(neg) HER-2/neu(neg) phenotype. CONCLUSIONS Results suggest that vaccination against HER-2/neu is safe and well tolerated and induces decline and/or eradication of HER-2/neu expression. These findings warrant further exploration of HER-2/neu vaccination in estrogen-independent breast cancer and highlight the need to target additional tumor-associated antigens and pathways.
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Affiliation(s)
- Anupama Sharma
- Rena Rowan Breast Center, Penn Medicine, Philadelphia, Pennsylvania, USA
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50
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Abstract
Glioblastoma, the most aggressive primary brain tumor, thrives in a microenvironment of relative immunosuppression within the relatively immune-privileged central nervous system. Despite treatments with surgery, radiation therapy, and chemotherapy, prognosis remains poor. The recent success of immunotherapy in the treatment of other cancers has renewed interest in vaccine therapy for the treatment of gliomas. In this article, we outline various immunotherapeutic strategies, review recent clinical trials data, and discuss the future of vaccine therapy for glioblastoma.
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Affiliation(s)
- Alissa A. Thomas
- Department of Neurology, Dartmouth Medical School and Dartmouth-Hitchcock Medical Center, Lebanon NH 03756
| | - Marc S. Ernstoff
- Department of Medicine, Section of Hematology/Oncology, Dartmouth Medical School and Dartmouth-Hitchcock Medical Center, Lebanon NH 03756
- Medical Oncology Immunotherapy Program, Dartmouth Medical School and Dartmouth-Hitchcock Medical Center, Lebanon NH 03756
| | - Camilo E. Fadul
- Department of Medicine, Section of Hematology/Oncology, Dartmouth Medical School and Dartmouth-Hitchcock Medical Center, Lebanon NH 03756
- Department of Neurology, Dartmouth Medical School and Dartmouth-Hitchcock Medical Center, Lebanon NH 03756
- Medical Oncology Immunotherapy Program, Dartmouth Medical School and Dartmouth-Hitchcock Medical Center, Lebanon NH 03756
- Neuro-oncology Program, Norris Cotton Cancer Center, Dartmouth Medical School and Dartmouth-Hitchcock Medical Center, Lebanon NH 03756
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