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Corica DA, Bell SD, Miller PJ, Kasperbauer DT, Lawler NJ, Wakefield MR, Fang Y. Into the Future: Fighting Melanoma with Immunity. Cancers (Basel) 2024; 16:4002. [PMID: 39682188 DOI: 10.3390/cancers16234002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 11/26/2024] [Accepted: 11/28/2024] [Indexed: 12/18/2024] Open
Abstract
Immunotherapy offers a novel and promising option in the treatment of late-stage melanoma. By utilizing the immune system to assist in tumor destruction, patients have additional options after tumor progression. Immune checkpoint inhibitors reduce the ability for tumors to evade the immune system by inhibiting key surface proteins used to inactivate T-cells. Without these surface proteins, T-cells can induce cytotoxic responses against tumors. Tumor infiltrating lymphocyte therapy is a form of adoptive cell therapy that takes advantage of a small subset of T-cells that recognize and infiltrate tumors. Isolation and rapid expansion of these colonies assist the immune system in mounting a charged response that can induce remission. Tumor vaccines deliver a high dose of unique antigens expressed by tumor cells to the entire body. The introduction of large quantities of tumor antigens upregulates antigen presenting cells and leads to effective activation of the immune system against tumors. Cytokine therapy introduces high amounts of chemical messengers that are endogenous to the immune system and support T-cell expansion. While other methods of immunotherapy exist, immune checkpoint inhibitors, tumor infiltrating lymphocytes, tumor vaccines, and cytokine therapy are commonly used to treat melanoma. Like many other cancer treatments, immunotherapy is not without adverse effects, as toxicities represent a major obstacle. However, immunotherapy has been efficacious in the treatment of melanoma.
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Affiliation(s)
- Derek A Corica
- Department of Microbiology, Immunology & Pathology, Des Moines University, West Des Moines, IA 50266, USA
| | - Scott D Bell
- Department of Microbiology, Immunology & Pathology, Des Moines University, West Des Moines, IA 50266, USA
| | - Peyton J Miller
- Department of Microbiology, Immunology & Pathology, Des Moines University, West Des Moines, IA 50266, USA
| | - Daniel T Kasperbauer
- Department of Microbiology, Immunology & Pathology, Des Moines University, West Des Moines, IA 50266, USA
| | - Nicholas J Lawler
- Department of Microbiology, Immunology & Pathology, Des Moines University, West Des Moines, IA 50266, USA
| | - Mark R Wakefield
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO 65212, USA
- Ellis Fischel Cancer Center, University of Missouri School of Medicine, Columbia, MO 65212, USA
| | - Yujiang Fang
- Department of Microbiology, Immunology & Pathology, Des Moines University, West Des Moines, IA 50266, USA
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO 65212, USA
- Ellis Fischel Cancer Center, University of Missouri School of Medicine, Columbia, MO 65212, USA
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Yang Y, Bo S, Liang L, Deng K, Bai L, Wang T, Wang Y, Liu K, Lu C. Delivery of Interferon β-Encoding Plasmid via Lipid Nanoparticle Restores Interferon β Expression to Enhance Antitumor Immunity in Colon Cancer. ACS NANO 2024. [PMID: 38319978 DOI: 10.1021/acsnano.3c10972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2024]
Abstract
Type I interferon (IFN-I) plays a critical role in host cancer immunosurveillance, but its expression is often impaired in the tumor microenvironment. We aimed at testing the hypothesis that cationic lipid nanoparticle delivery of interferon β (IFNβ)-encoding plasmid to tumors is effective in restoring IFNβ expression to suppress tumor immune evasion. We determined that IFN-I function in tumor suppression depends on the host immune cells. IFN-I activates the expression of Cxcl9 and Cxcl10 to enhance T cell tumor infiltration. RNA-Seq detected a low level of IFNα13 and IFNβ in colon tumor tissue. scRNA-Seq revealed that IFNβ is expressed in immune cell subsets in non-neoplastic human tissues and to a lesser degree in human colon tumor tissues. Forced expression of IFNα13 and IFNβ in colon tumor cells up-regulates major histocompatibility complex I (MHC I) expression and suppresses colon tumor growth in vivo. In human cancer patients, IFNβ expression is positively correlated with human leukocyte antigen (HLA) expression, and IFN-I signaling activation correlates with the patient response to PD-1 blockade immunotherapy. To translate this finding to colon cancer immunotherapy, we formulated a 1,2-dioleoyl-3-trimethylammonium propane (DOTAP)-cholesterol-encapsulated IFNβ-encoding plasmid (IFNBCOL01). IFNBCOL01 transfects colon tumor cells to express IFNβ to increase the level of MHC I expression. IFNBCOL01 therapy transfects tumor cells and tumor-infiltrating immune cells to produce IFNβ to activate MHC I and granzyme B expression and inhibits colon tumor growth in mice. Our data determine that lipid nanoparticle delivery of IFNβ-encoding plasmid DNA enhances tumor immunogenicity and T cell effector function to suppress colon tumor growth in vivo.
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Affiliation(s)
- Yingcui Yang
- School of Life Sciences, Tianjin University, Tianjin 300072, China
| | - Shixuan Bo
- School of Life Sciences, Tianjin University, Tianjin 300072, China
| | - Liyan Liang
- School of Life Sciences, Tianjin University, Tianjin 300072, China
| | - Kaidi Deng
- School of Life Sciences, Tianjin University, Tianjin 300072, China
| | - Liya Bai
- School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
| | - Tao Wang
- School of Life Sciences, Tianjin University, Tianjin 300072, China
| | - Yinsong Wang
- School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
| | - Kebin Liu
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia 30912, United States
- Georgia Cancer Center, Augusta, Georgia 30912, United States
| | - Chunwan Lu
- School of Life Sciences, Tianjin University, Tianjin 300072, China
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Klement JD, Redd PS, Lu C, Merting AD, Poschel DB, Yang D, Savage NM, Zhou G, Munn DH, Fallon PG, Liu K. Tumor PD-L1 engages myeloid PD-1 to suppress type I interferon to impair cytotoxic T lymphocyte recruitment. Cancer Cell 2023; 41:620-636.e9. [PMID: 36917954 PMCID: PMC10150625 DOI: 10.1016/j.ccell.2023.02.005] [Citation(s) in RCA: 62] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 10/05/2022] [Accepted: 02/07/2023] [Indexed: 03/14/2023]
Abstract
The cellular and molecular mechanisms underlying tumor cell PD-L1 (tPD-L1) function in tumor immune evasion are incompletely understood. We report here that tPD-L1 does not suppress cytotoxic T lymphocyte (CTL) activity in co-cultures of tumor cells and tumor-specific CTLs and exhibits no effect on primary tumor growth. However, deleting tPD-L1 decreases lung metastasis in a CTL-dependent manner in tumor-bearing mice. Depletion of myeloid cells or knocking out PD-1 in myeloid cells (mPD-1) impairs tPD-L1 promotion of tumor lung metastasis in mice. Single-cell RNA sequencing (scRNA-seq) reveals that tPD-L1 engages mPD-1 to activate SHP2 to antagonize the type I interferon (IFN-I) and STAT1 pathway to repress Cxcl9 and impair CTL recruitment to lung metastases. Human cancer patient response to PD-1 blockade immunotherapy correlates with IFN-I response in myeloid cells. Our findings determine that tPD-L1 engages mPD-1 to activate SHP2 to suppress the IFN-I-STAT1-CXCL9 pathway to impair CTL tumor recruitment in lung metastasis.
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Affiliation(s)
- John D Klement
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; Georgia Cancer Center, Augusta, GA 30912, USA; Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
| | - Priscilla S Redd
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; Georgia Cancer Center, Augusta, GA 30912, USA; Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
| | - Chunwan Lu
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; Georgia Cancer Center, Augusta, GA 30912, USA; Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
| | - Alyssa D Merting
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; Georgia Cancer Center, Augusta, GA 30912, USA; Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
| | - Dakota B Poschel
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; Georgia Cancer Center, Augusta, GA 30912, USA; Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
| | - Dafeng Yang
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; Georgia Cancer Center, Augusta, GA 30912, USA; Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
| | - Natasha M Savage
- Department of Pathology, Medical College of Georgia, Augusta, GA 30912, USA
| | - Gang Zhou
- Georgia Cancer Center, Augusta, GA 30912, USA
| | | | - Padraic G Fallon
- Trinity Biomedical Sciences Institute, School of Medicine, Trinity College Dublin, Dublin, Ireland
| | - Kebin Liu
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA; Georgia Cancer Center, Augusta, GA 30912, USA; Charlie Norwood VA Medical Center, Augusta, GA 30904, USA.
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Fares J, Cordero A, Kanojia D, Lesniak MS. The Network of Cytokines in Brain Metastases. Cancers (Basel) 2021; 13:E142. [PMID: 33466236 PMCID: PMC7795138 DOI: 10.3390/cancers13010142] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 12/30/2020] [Accepted: 12/31/2020] [Indexed: 12/20/2022] Open
Abstract
Brain metastases are the most common of all intracranial tumors and a major cause of death in patients with cancer. Cytokines, including chemokines, interferons, interleukins, lymphokines, and tumor necrosis factors are key regulators in the formation of brain metastases. They regulate the infiltration of different cellular subsets into the tumor microenvironment and affect the therapeutic outcomes in patients. Elucidating the cancer cell-cytokine interactions in the setting of brain metastases is crucial for the development of more accurate diagnostics and efficacious therapies. In this review, we focus on cytokines that are found in the tumor microenvironment of brain metastases and elaborate on their trends of expression, regulation, and roles in cellular recruitment and tumorigenesis. We also explore how cytokines can alter the anti-tumor response in the context of brain metastases and discuss ways through which cytokine networks can be manipulated for diagnosis and treatment.
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Affiliation(s)
| | | | | | - Maciej S. Lesniak
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; (J.F.); (A.C.); (D.K.)
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Schiller M, Tsianakas A, Sterry W, Dummer R, Hinke A, Nashan D, Stadler R. Dose-escalation study evaluating pegylated interferon alpha-2a in patients with cutaneous T-cell lymphoma. J Eur Acad Dermatol Venereol 2017; 31:1841-1847. [PMID: 28557110 DOI: 10.1111/jdv.14366] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2017] [Accepted: 04/28/2017] [Indexed: 11/30/2022]
Abstract
BACKGROUND This open-label, multicenter, dose-escalation study evaluated the safety, tolerability, and efficacy of subcutaneous pegylated (40 kD) interferon α-2a (PEG-IFN α-2a) in patients with cutaneous T-cell lymphoma (CTCL). PATIENTS AND METHODS PEG-IFN α-2a was administered subcutaneously at 180 (n = 4), 270 (n = 6), or 360 μg (n = 3) once weekly for 12 weeks. Efficacy was assessed by the proportion of patients with complete response (CR) or partial response (PR). RESULTS PEG-IFN α-2a was generally well tolerated, with a moderate number of reductions or withholding of doses because of adverse events (AEs) (25% (n = 1), 66% (n = 4), and 0% (n = 0) in the 180-, 270-, and 360-μg/week groups, respectively). The only dose-limiting toxicity was a grade 3 elevation of liver enzymes in the 270-μg dose group. The most common AEs were fatigue, acute flu-like symptoms, and hepatic toxicity. The major response rate (CR or PR) was 50% in the 180-μg group (CR, 50%; PR, 0%), 83% in the 270-μg group (CR, 67%; PR, 17%), and 66% in the 360-μg group (CR, 33%; PR, 33%). CONCLUSION PEG-IFN α-2a at doses up to 360 μg once weekly was well tolerated in patients with CTCL up to the highest dose group and showed good response rates. Due to their good tolerance even in high doses, they might be an option for patients not tolerating standard IFN-α preparations. However, for this purpose and to evaluate comparability between standard and PEG-IFN larger clinical trials are needed, alone and in combination with oral photochemotherapy (PUVA).
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Affiliation(s)
- M Schiller
- Department of Dermatology, University Hospital of Muenster, Muenster, Germany.,Dermatological Office Professor Schiller, Coesfeld, Germany
| | - A Tsianakas
- Department of Dermatology, University Hospital of Muenster, Muenster, Germany
| | - W Sterry
- Department of Dermatology, Charité, Berlin, Germany
| | - R Dummer
- Department of Dermatology, University Hospital, Zurich, Switzerland
| | - A Hinke
- WiSP Wissenschaftlicher Service Pharma GmbH, Langenfeld, Germany
| | - D Nashan
- Department of Dermatology, Klinikum Dortmund, Dortmund, Germany
| | - R Stadler
- Department of Dermatology, Johannes Wesling Klinikum Minden, University Hospital of Ruhr University of Bochum, Bochum, Germany
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Lei M, Wang J, Ma M, Yu M, Tan F, Li N. Dual drug encapsulation in a novel nano-vesicular carrier for the treatment of cutaneous melanoma: characterization and in vitro/in vivo evaluation. RSC Adv 2015. [DOI: 10.1039/c4ra16306k] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
The objective of this research was to develop and evaluate a dual drug-loaded dermal targeted vesicle for the treatment of cutaneous melanoma.
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Affiliation(s)
- Mingzhu Lei
- Tianjin Key Laboratory of Drug Delivery & High-Efficiency
- School of Pharmaceutical Science and Technology
- Tianjin University
- Tianjin
- PR China
| | - Jinping Wang
- Tianjin Key Laboratory of Drug Delivery & High-Efficiency
- School of Pharmaceutical Science and Technology
- Tianjin University
- Tianjin
- PR China
| | - Man Ma
- Tianjin Key Laboratory of Drug Delivery & High-Efficiency
- School of Pharmaceutical Science and Technology
- Tianjin University
- Tianjin
- PR China
| | - Meng Yu
- Tianjin Key Laboratory of Drug Delivery & High-Efficiency
- School of Pharmaceutical Science and Technology
- Tianjin University
- Tianjin
- PR China
| | - Fengping Tan
- Tianjin Key Laboratory of Drug Delivery & High-Efficiency
- School of Pharmaceutical Science and Technology
- Tianjin University
- Tianjin
- PR China
| | - Nan Li
- Tianjin Key Laboratory of Drug Delivery & High-Efficiency
- School of Pharmaceutical Science and Technology
- Tianjin University
- Tianjin
- PR China
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7
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Go RS, Lee SJ, Shin D, Callister SM, Jobe DA, Conry RM, Tarhini AA, Kirkwood JM. ECOG phase II trial of graded-dose peginterferon α-2b in patients with metastatic melanoma overexpressing basic fibroblast growth factor (E2602). Clin Cancer Res 2013; 19:6597-604. [PMID: 24122792 DOI: 10.1158/1078-0432.ccr-13-1414] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE We investigated the use of graded-dose peginterferon α-2b (Peg-IFN) in patients with stage IV melanoma overexpressing basic fibroblast growth factor (FGF-2). The primary objective was suppression of plasma FGF-2 to within reference range (≤ 7.5 pg/mL). EXPERIMENTAL DESIGN Plasma FGF-2 was measured at baseline (step 1), and patients with concentrations of 15 pg/mL or more were eligible for study treatment (step 2). Peg-IFN was given weekly at a starting dose of 0.5 μg/kg/wk with increment every 3 weeks based on serial FGF-2 concentrations. RESULTS Two hundred seven patients entered step 1; 45 (22%) overexpressed FGF-2 (median = 22 pg/dL). Twenty-nine eligible patients entered step 2 and received treatment. Patients' median age was 64 years (range, 29-84 years). Most had more than two prior therapies. FGF-2 decreased in 28 (97%) patients, with suppression to reference range in 10 (35%). Median time to FGF-2 suppression was 30 days. The best clinical responses were partial response (7%) and stable disease (17%). Median progression-free survival (PFS) and overall survival (OS) were 2.0 and 9.7 months, respectively. Patients who achieved FGF-2 suppression were more likely than those who did not to have a response or stable disease (P = 0.03). VEGF concentrations decreased in 27 patients (93%) during treatment and paralleled those of FGF-2 over time. We found no compensatory increase in VEGF among those with FGF-2 suppression. CONCLUSIONS Graded-dose Peg-IFN suppresses FGF-2 in patients with metastatic melanoma who overexpress FGF-2. Over one third of patients had complete suppression of plasma FGF-2, which correlated with clinical response to this therapy.
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Affiliation(s)
- Ronald S Go
- Authors' Affiliations: Gundersen Health System; Gundersen Medical Foundation, La Crosse, Wisconsin; Dana-Farber Cancer Institute, Boston, Massachusetts; University of Alabama Comprehensive Cancer Center, Birmingham, Alabama; and University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania
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8
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Favorable radiological outcome of skeletal Erdheim-Chester disease involvement with anakinra. Joint Bone Spine 2013; 80:206-7. [DOI: 10.1016/j.jbspin.2012.07.005] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2012] [Accepted: 07/04/2012] [Indexed: 11/18/2022]
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Mimeault M, Batra SK. Novel biomarkers and therapeutic targets for optimizing the therapeutic management of melanomas. World J Clin Oncol 2012; 3:32-42. [PMID: 22442756 PMCID: PMC3309891 DOI: 10.5306/wjco.v3.i3.32] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2011] [Revised: 02/12/2012] [Accepted: 03/05/2012] [Indexed: 02/06/2023] Open
Abstract
Cutaneous malignant melanoma is the most aggressive form of skin cancer with an extremely poor survival rate for the patients diagnosed with locally invasive and metastatic disease states. Intensive research has led in last few years to an improvement of the early detection and curative treatment of primary cutaneous melanomas that are confined to the skin by tumor surgical resection. However, locally advanced and disseminated melanomas are generally resistant to conventional treatments, including ionizing radiation, systemic chemotherapy, immunotherapy and/or adjuvant stem cell-based therapies, and result in the death of patients. The rapid progression of primary melanomas to locally invasive and/or metastatic disease states remains a major obstacle for an early effective diagnosis and a curative therapeutic intervention for melanoma patients. Importantly, recent advances in the melanoma research have led to the identification of different gene products that are often implicated in the malignant transformation of melanocytic cells into melanoma cells, including melanoma stem/progenitor cells, during melanoma initiation and progression to locally advanced and metastatic disease states. The frequent deregulated genes products encompass the oncogenic B-RafV600E and N-RasQ61R mutants, different receptor tyrosine kinases and developmental pathways such as epidermal growth factor receptor (EGFR), stem cell-like factor (SCF) receptor KIT, hedgehog, Wnt/β-catenin, Notch, stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor-4 (CXCR4) and vascular endothelial growth factor (VEGF)/VEGFR receptor. These growth factors can cooperate to activate distinct tumorigenic downstream signaling elements and epithelial-mesenchymal transition (EMT)-associated molecules, including phosphatidylinositol 3’-kinase (PI3K)/Akt/ molecular target of rapamycin (mTOR), nuclear factor-kappaB (NF-κB), macrophage inhibitory cytokine-1 (MIC-1), vimentin, snail and twist. Of therapeutic relevance, these deregulated signal transduction components constitute new potential biomarkers and therapeutic targets of great clinical interest for improving the efficacy of current diagnostic and prognostic methods and management of patients diagnosed with locally advanced, metastatic and/or relapsed melanomas.
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Affiliation(s)
- Murielle Mimeault
- Murielle Mimeault, Surinder K Batra, Department of Biochemistry and Molecular Biology, College of Medicine, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-5870, United States
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PTD4-apoptin protein and dacarbazine show a synergistic antitumor effect on B16-F1 melanoma in vitro and in vivo. Eur J Pharmacol 2011; 654:17-25. [DOI: 10.1016/j.ejphar.2010.12.004] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2010] [Revised: 12/12/2010] [Accepted: 12/13/2010] [Indexed: 01/19/2023]
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Friebe A, Horn M, Schmidt F, Janssen G, Schmid-Wendtner MH, Volkenandt M, Hauschild A, Goldsmith CH, Schaefer M. Dose-Dependent Development of Depressive Symptoms During Adjuvant Interferon-α Treatment of Patients With Malignant Melanoma. PSYCHOSOMATICS 2010. [DOI: 10.1016/s0033-3182(10)70738-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
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Alexandrescu DT, Ichim TE, Riordan NH, Marincola FM, Di Nardo A, Kabigting FD, Dasanu CA. Immunotherapy for melanoma: current status and perspectives. J Immunother 2010; 33:570-90. [PMID: 20551839 PMCID: PMC3517185 DOI: 10.1097/cji.0b013e3181e032e8] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Immunotherapy is an important modality in the therapy of patients with malignant melanoma. As our knowledge about this disease continues to expand, so does the immunotherapeutic armamentarium. Nevertheless, successful preclinical models do not always translate into clinically meaningful results. The authors give a comprehensive analysis of most recent advances in the immune anti-melanoma therapy, including interleukins, interferons, other cytokines, adoptive immunotherapy, biochemotherapy, as well as the use of different vaccines. We also present the fundamental concepts behind various immune enhancement strategies, passive immunotherapy, as well as the use of immune adjuvants. This review brings into discussion the results of newer and older clinical trials, as well as potential limitations and drawbacks seen with the utilization of various immune therapies in malignant melanoma. Development of novel therapeutic approaches, along with optimization of existing therapies, continues to hold a great promise in the field of melanoma therapy research. Use of anti-CTLA4 and anti-PD1 antibodies, realization of the importance of co-stimulatory signals, which translated into the use of agonist CD40 monoclonal antibodies, as well as activation of innate immunity through enhanced expression of co-stimulatory molecules on the surface of dendritic cells by TLR agonists are only a few items on the list of recent advances in the treatment of melanoma. The need to engineer better immune interactions and to boost positive feedback loops appear crucial for the future of melanoma therapy, which ultimately resides in our understanding of the complexity of immune responses in this disease.
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Affiliation(s)
- Doru T Alexandrescu
- Division of Dermatology, University of California at San Diego, San Diego, CA, USA.
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13
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Tumor angiogenesis: insights and innovations. JOURNAL OF ONCOLOGY 2010; 2010:132641. [PMID: 20445741 PMCID: PMC2860112 DOI: 10.1155/2010/132641] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/29/2009] [Revised: 02/12/2010] [Accepted: 02/12/2010] [Indexed: 12/21/2022]
Abstract
Angiogenesis is a vital process resulting in the formation of new blood vessels. It is normally a highly regulated process that occurs during human development, reproduction, and wound repair. However, angiogenesis can also become a fundamental pathogenic process found in cancer and several other diseases. To date, the inhibition of angiogenesis has been researched at both the bench and the bedside. While several studies have found moderate improvements when treating with angiogenesis inhibitors, greater success is being seen when the inhibition of angiogenesis is combined with other traditional forms of available therapy. This review summarizes several important angiogenic factors, examines new research and ongoing clinical trials for such factors, and attempts to explain how this new knowledge may be applied in the fight against cancer and other angiogenic-related diseases.
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14
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Kaehler KC, Sondak VK, Schadendorf D, Hauschild A. Pegylated interferons: prospects for the use in the adjuvant and palliative therapy of metastatic melanoma. Eur J Cancer 2010; 46:41-6. [PMID: 19857957 DOI: 10.1016/j.ejca.2009.10.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2009] [Revised: 09/23/2009] [Accepted: 10/10/2009] [Indexed: 11/18/2022]
Abstract
Classic interferon-alpha formulations have antitumour activity in a variety of neoplastic diseases, including the adjuvant and palliative setting of metastatic melanoma, as single agents or in combination with chemotherapy and/or interleukin-2. Pegylated interferon, widely used for the treatment of hepatitis, seems to be at least equally efficacious as standard recombinant interferon in the treatment of metastatic melanoma, and the available evidence suggests that equi-efficacious doses have somewhat lower acute toxicity. Moreover, the favourable pharmacokinetic properties of pegylated interferon allow the administration on a weekly basis, with sustained exposure to interferon during that entire period. Several clinical trials have been conducted testing adjuvant and palliative treatment with pegylated interferon-alpha in high-risk melanoma patients with promising results. The role of pegylated interferons in the setting of advanced metastatic melanoma will need further investigation in clinical trials, potentially in combination with targeted or cytotoxic agents with regard to synergistic antiangiogenic and cytotoxic effects. The use of pegylated interferons in earlier stage melanomas will be investigated in upcoming trials.
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15
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Schadendorf D, Algarra SM, Bastholt L, Cinat G, Dreno B, Eggermont AMM, Espinosa E, Guo J, Hauschild A, Petrella T, Schachter J, Hersey P. Immunotherapy of distant metastatic disease. Ann Oncol 2009; 20 Suppl 6:vi41-50. [PMID: 19617297 PMCID: PMC2712591 DOI: 10.1093/annonc/mdp253] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Immunotherapy of metastatic melanoma consists of various approaches leading to specific or non-specific immunomodulation. The use of FDA-approved interleukin (IL)-2 alone, in combination with interferon alpha, and/or with various chemotherapeutic agents (biochemotherapy) is associated with significant toxicity and poor efficacy that does not improve overall survival of 96% of patients. Many studies with allogeneic and autologous vaccines have demonstrated no clinical benefit, and some randomised trials even showed a detrimental effect in the vaccine arm. The ongoing effort to develop melanoma vaccines based on dendritic cells and peptides is driven by advances in understanding antigen presentation and processing, and by new techniques of vaccine preparation, stabilisation and delivery. Several agents that have shown promising activity in metastatic melanoma including IL-21 and monoclonal antibodies targeting cytotoxic T lymphocyte-associated antigen 4 (anti-CTLA-4) or CD137 are discussed. Recent advances of intratumour gene transfer technologies and adoptive immunotherapy, which represents a promising although technically challenging direction, are also discussed.
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Affiliation(s)
- D Schadendorf
- Department of Dermatology, University Hospital Essen, Essen, Germany.
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Abstract
Conventional interferons including interferon-alpha (IFN-alpha) are cytokines used for years in the treatment of solid tumors and hematological malignancies. Their half-life is short. Pegylated forms of IFN-alpha present an improved pharmacokinetic profile that rendered them the preferred IFNs in hepatitis therapy. In the last decade, pegylated interferons (PegIFNs) have been investigated in melanoma patients. We review the scientific published literature on biology, pharmacokinetics, side effects and clinical applications of PegIFN-alpha in the treatment of stage III and IV melanoma. In the adjuvant setting, PegIFNalpha-2b has significant prolonged distant metastases free survival in patients with microscopic nodal involvement (stage TxN1aM0) and therefore is a promising treatment option in this patient population. In the palliative setting, monotherapy with PegIFNalpha-2alpha can induce complete remissions in a minority of stage IV melanoma patients. The combination of monochemotherapy is feasible and may result in lasting complete remissions. Ongoing research must focus on the identification of patients who mostly benefit, so that unnecessary toxicity would be avoided. Combining PegIFNs and chemotherapy or targeted agents deserves further exploration.
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Affiliation(s)
- Reinhard Dummer
- Department of Dermatology, University Hospital, Zürich, Switzerland.
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