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Genetically engineered mesenchymal stem cells: targeted delivery of immunomodulatory agents for tumor eradication. Cancer Gene Ther 2020; 27:854-868. [PMID: 32418986 DOI: 10.1038/s41417-020-0179-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 04/28/2020] [Accepted: 05/05/2020] [Indexed: 12/17/2022]
Abstract
Cancer immunotherapy emerged as a novel therapeutic option that employs enhanced or amended native immune system to create a robust response against malignant cells. The systemic therapies with immune-stimulating cytokines have resulted in substantial dose-limiting toxicities. Targeted cytokine immunotherapy is being explored to overcome the heterogeneity of malignant cells and tumor cell defense with a remarkable reduction of systemic side effects. Cell-based strategies, such as dendritic cells (DCs), fibroblasts or mesenchymal stem cells (MSCs) seek to minimize the numerous toxic side effects of systemic administration of cytokines for extended periods of time. The usual toxicities comprised of a vascular leak, hypotension, and respiratory insufficiency. Natural and strong tropism of MSCs toward malignant cells made them an ideal systemic delivery vehicle to direct the proposed therapeutic genes to the vicinity of a tumor where their expression could evoke an immune reaction against the tumor. Compared with other methods, the delivery of cytokines via engineered MSCs is safer and renders a more practical, and promising strategy. Large numbers of genes code for cytokines have been utilized to reengineer MSCs as therapeutic cells. This review highlights the recent findings on the cytokine gene therapy for human malignancies by focusing on MSCs application in cancer immunotherapy.
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Teulings HE, Limpens J, Jansen SN, Zwinderman AH, Reitsma JB, Spuls PI, Luiten RM. Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis. J Clin Oncol 2015; 33:773-81. [PMID: 25605840 DOI: 10.1200/jco.2014.57.4756] [Citation(s) in RCA: 457] [Impact Index Per Article: 45.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
PURPOSE Vitiligo-like depigmentation in patients with melanoma may be associated with more favorable clinical outcome. We conducted a systematic review of patients with stage III to IV melanoma treated with immunotherapy to determine the cumulative incidence of vitiligo-like depigmentation and the prognostic value of vitiligo development on survival. METHODS We systemically searched and selected all studies on melanoma immunotherapy that reported on autoimmune toxicity and/or vitiligo between 1995 and 2013. Methodologic quality of each study was appraised using adapted criteria for systematic reviews in prognostic studies. Random-effect models were used to calculate summary estimates of the cumulative incidence of vitiligo-like depigmentation across studies. The prognostic value of vitiligo-like depigmentation on survival outcome was assessed using random-effects Cox regression survival analyses. RESULTS One hundred thirty-seven studies were identified comprising 139 treatment arms (11 general immune stimulation, 84 vaccine, 28 antibody-based, and 16 adoptive transfer) including a total of 5,737 patients. The overall cumulative incidence of vitiligo was 3.4% (95% CI, 2.5% to 4.5%). In 27 studies reporting individual patient data, vitiligo development was significantly associated with both progression-free-survival (hazard ratio [HR], 0.51; 95% CI, 0.32 to 0.82; P < .005) and overall survival (HR, 0.25; 95% CI, 0.10 to 0.61; P < .003), indicating that these patients have two to four times less risk of disease progression and death, respectively, compared with patients without vitiligo development. CONCLUSION Although vitiligo occurs only in a low percentage of patients with melanoma treated with immunotherapy, our findings suggest clear survival benefit in these patients. Awareness of vitiligo induction in patients with melanoma is important as an indicator of robust antimelanoma immunity and associated improved survival.
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Affiliation(s)
- Hansje-Eva Teulings
- Hansje-Eva Teulings, Jacqueline Limpens, Sophia N. Jansen, Aeilko H. Zwinderman, Johannes B. Reitsma, Phyllis I. Spuls, and Rosalie M. Luiten, Academic Medical Centre, University of Amsterdam, Amsterdam; Johannes B. Reitsma, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
| | - Jacqueline Limpens
- Hansje-Eva Teulings, Jacqueline Limpens, Sophia N. Jansen, Aeilko H. Zwinderman, Johannes B. Reitsma, Phyllis I. Spuls, and Rosalie M. Luiten, Academic Medical Centre, University of Amsterdam, Amsterdam; Johannes B. Reitsma, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Sophia N Jansen
- Hansje-Eva Teulings, Jacqueline Limpens, Sophia N. Jansen, Aeilko H. Zwinderman, Johannes B. Reitsma, Phyllis I. Spuls, and Rosalie M. Luiten, Academic Medical Centre, University of Amsterdam, Amsterdam; Johannes B. Reitsma, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Aeilko H Zwinderman
- Hansje-Eva Teulings, Jacqueline Limpens, Sophia N. Jansen, Aeilko H. Zwinderman, Johannes B. Reitsma, Phyllis I. Spuls, and Rosalie M. Luiten, Academic Medical Centre, University of Amsterdam, Amsterdam; Johannes B. Reitsma, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Johannes B Reitsma
- Hansje-Eva Teulings, Jacqueline Limpens, Sophia N. Jansen, Aeilko H. Zwinderman, Johannes B. Reitsma, Phyllis I. Spuls, and Rosalie M. Luiten, Academic Medical Centre, University of Amsterdam, Amsterdam; Johannes B. Reitsma, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Phyllis I Spuls
- Hansje-Eva Teulings, Jacqueline Limpens, Sophia N. Jansen, Aeilko H. Zwinderman, Johannes B. Reitsma, Phyllis I. Spuls, and Rosalie M. Luiten, Academic Medical Centre, University of Amsterdam, Amsterdam; Johannes B. Reitsma, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Rosalie M Luiten
- Hansje-Eva Teulings, Jacqueline Limpens, Sophia N. Jansen, Aeilko H. Zwinderman, Johannes B. Reitsma, Phyllis I. Spuls, and Rosalie M. Luiten, Academic Medical Centre, University of Amsterdam, Amsterdam; Johannes B. Reitsma, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
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Byers BA, Temple-Oberle CF, Hurdle V, McKinnon JG. Treatment of in-transit melanoma with intra-lesional interleukin-2: a systematic review. J Surg Oncol 2014; 110:770-5. [PMID: 24996052 DOI: 10.1002/jso.23702] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2013] [Accepted: 05/27/2014] [Indexed: 11/11/2022]
Abstract
BACKGROUND Several phase II studies have assessed intra-lesional interleukin-2 (IL-2) for the treatment of in-transit melanoma. This systematic review addresses the efficacy and side effect profile of IL-2. METHODS MEDLINE, EMBASE, Cochrane Library, and Google Scholar databases were searched from 1980 to 2012 for studies evaluating the clinical response to IL-2 for in-transit melanoma. Titles and abstracts were screened by two independent researchers for suitability using predetermined inclusion and exclusion criteria. A modified quality assessment tool for observational studies was used. Data were pooled and analyzed to determine lesion and patient response rates. RESULTS Forty-nine studies were identified. Forty-three did not meet inclusion criteria, leaving six observational trials. Heterogeneity was seen in IL-2 dosage and treatment interval. Response rate was variable as well. Overall, 2,182 lesions and 140 patients were treated in these six studies. Pooling the lesions, complete response was seen in 78%. Pooling subjects, 50% achieved a complete response. Treatment was generally well tolerated, with localized pain and swelling, and mild flu-like symptoms. There were only three grade 3 adverse events reported, including rigors, headache, and fever with arthralgia. CONCLUSIONS Intra-lesional IL-2 safely and effectively provides locoregional control of in-transit melanoma.
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Affiliation(s)
- Brett A Byers
- Division of Plastic Surgery, Department of Surgery, University of Calgary, Calgary, AB, Canada
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Liu SY, Wei W, Yue H, Ni DZ, Yue ZG, Wang S, Fu Q, Wang YQ, Ma GH, Su ZG. Nanoparticles-based multi-adjuvant whole cell tumor vaccine for cancer immunotherapy. Biomaterials 2013; 34:8291-300. [DOI: 10.1016/j.biomaterials.2013.07.020] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Accepted: 07/03/2013] [Indexed: 01/22/2023]
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Comparative antitumor effect of preventive versus therapeutic vaccines employing B16 melanoma cells genetically modified to express GM-CSF and B7.2 in a murine model. Toxins (Basel) 2012. [PMID: 23202306 PMCID: PMC3509698 DOI: 10.3390/toxins4111058] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Cancer vaccines have always been a subject of gene therapy research. One of the most successful approaches has been working with genetically modified tumor cells. In this study, we describe our approach to achieving an immune response against a murine melanoma model, employing B16 tumor cells expressing GM-CSF and B7.2. Wild B16 cells were injected in C57BL6 mice to cause the tumor. Irradiated B16 cells transfected with GM-CSF, B7.2, or both, were processed as a preventive and therapeutic vaccination. Tumor volumes were measured and survival curves were obtained. Blood samples were taken from mice, and IgGs of each treatment group were also measured. The regulatory T cells (Treg) of selected groups were quantified using counts of images taken by confocal microscopy. Results: one hundred percent survival was achieved by preventive vaccination with the group of cells transfected with p2F_GM-CSF. Therapeutic vaccination achieved initial inhibition of tumor growth but did not secure overall survival of the animals. Classical Treg cells did not vary among the different groups in this therapeutic vaccination model.
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Abstract
Devitalized tumor cells either autologous or allogeneic have been used as anti-cancer vaccines with the purpose of facilitating the induction of an immune response able to destroy growing tumor cells since the identification of tumor antigens was deemed not to be necessary, particularly in the autologous system. Such vaccines were tested first in animal models and then in the clinics as unmodified tumor cells or after insertion of genes coding for factors known to increase the immune response against tumors. These vaccines were usually given by subcutaneous injections along with different immunological adjuvants. Such immunization approaches were found to be effective in mice when carried out in a tumor preventive setting but significantly less in the therapeutic context, that is, in the presence of an established tumor. By analyzing several clinical trials of vaccination using either autologous or allogeneic unmodified and gene-modified tumor cells published in the last 10 to 15 years, we conclude for a lack of sufficient evidence for efficacy of this strategy in inducing both a strong immune response and a therapeutic response. A potential variant of this strategy is the direct intratumoral injection of immunostimulatory genes delivered by vectors in vivo. But even this approach failed to provide a statistically significant clinical benefit for the cancer patients.We also point out the inherent drawbacks of the tumor cell-based vaccine strategy that include (a) a limited frequency by which human tumor lines can be obtained from clinical samples, (b) the low number of available cells for vaccination, (c) the release of immune-suppressive factors by tumor cells, and (d) the cost and time necessary for standardization and collecting/expanding a number of cells according to the approved regulatory requirements. Thus, taking into consideration the new developments in cancer vaccines, we believe that tumor cell-based vaccines should be dismissed as anti-cancer vaccines unless a clear benefit could be demonstrated by the few ongoing trials of combination with new immunomodulating reagents (eg, anti-CTLA4, PD-1, chemotherapy).
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Klein O, Schmidt C, Knights A, Davis ID, Chen W, Cebon J. Melanoma vaccines: developments over the past 10 years. Expert Rev Vaccines 2011; 10:853-73. [PMID: 21692705 DOI: 10.1586/erv.11.74] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Decades of preclinical evaluation and clinical trials into melanoma vaccines have yielded spectacular progress in our understanding of melanoma antigens and the immune mechanisms of tumor rejection. Key insights and the results of their clinical evaluation are reviewed in this article. Unfortunately, durable clinical benefit following vaccination remains uncommon. Two recent clinical advances that will impact on melanoma vaccine development are trials with inhibitors of CTLA-4 and oncogenic BRAF. Long-term therapeutic control of melanoma will require integration of specific active immunotherapy with these emerging successful therapies from the disparate fields of immune regulation and signal transduction.
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Affiliation(s)
- Oliver Klein
- Ludwig Institute for Cancer Research, Austin Branch, Austin Hospital, Studley Road, Heidelberg, Victoria, 3084, Australia
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Brill TH, Kübler HR, Pohla H, Buchner A, Fend F, Schuster T, van Randenborgh H, Paul R, Kummer T, Plank C, Eisele B, Breul J, Hartung R, Schendel DJ, Gansbacher B. Therapeutic Vaccination with an Interleukin-2–Interferon-γ-Secreting Allogeneic Tumor Vaccine in Patients with Progressive Castration-Resistant Prostate Cancer: A Phase I/II Trial. Hum Gene Ther 2009; 20:1641-51. [DOI: 10.1089/hum.2009.101] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Affiliation(s)
- Thomas H. Brill
- Institut für Experimentelle Onkologie und Therapieforschung, Technische Universität München, Klinikum rechts der Isar, 81675 Munich, Germany
| | - Hubert R. Kübler
- Urologische Klinik und Poliklinik, Technische Universität München, Klinikum rechts der Isar, 81675 Munich, Germany
| | - Heike Pohla
- Laboratory of Tumor Immunology, LIFE Center University Clinic–Grosshadern, Ludwig Maximilians University, 81377 Munich, Germany
- Institute of Molecular Immunology and Clinical Cooperation Group “Immune Monitoring,” Helmholtz Zentrum München, German Research Center for Environmental Health, 81377 Munich, Germany
| | - Alexander Buchner
- Laboratory of Tumor Immunology, LIFE Center University Clinic–Grosshadern, Ludwig Maximilians University, 81377 Munich, Germany
- Department of Urology, University Clinic-Grosshadern, Ludwig Maximilians University, 81377 Munich, Germany
| | - Falko Fend
- Institut für Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, 81675 Munich, Germany
- Institute of Pathology, University Hospital Tuebingen, Eberhard Karls University, 72076 Tuebingen, Germany
| | - Tibor Schuster
- Institut für Medizinische Statistik und Epidemiologie, Technische Universität München, Klinikum rechts der Isar, 81675 Munich, Germany
| | - Heiner van Randenborgh
- Urologische Klinik und Poliklinik, Technische Universität München, Klinikum rechts der Isar, 81675 Munich, Germany
| | - Roger Paul
- Urologische Klinik und Poliklinik, Technische Universität München, Klinikum rechts der Isar, 81675 Munich, Germany
| | - Tania Kummer
- Institut für Experimentelle Onkologie und Therapieforschung, Technische Universität München, Klinikum rechts der Isar, 81675 Munich, Germany
| | - Christian Plank
- Institut für Experimentelle Onkologie und Therapieforschung, Technische Universität München, Klinikum rechts der Isar, 81675 Munich, Germany
| | - Bernd Eisele
- Vakzine Projekt Management, 30625 Hannover, Germany
| | - Jürgen Breul
- Urologische Klinik und Poliklinik, Technische Universität München, Klinikum rechts der Isar, 81675 Munich, Germany
| | - Rudolf Hartung
- Urologische Klinik und Poliklinik, Technische Universität München, Klinikum rechts der Isar, 81675 Munich, Germany
| | - Dolores J. Schendel
- Institute of Molecular Immunology and Clinical Cooperation Group “Immune Monitoring,” Helmholtz Zentrum München, German Research Center for Environmental Health, 81377 Munich, Germany
| | - Bernd Gansbacher
- Institut für Experimentelle Onkologie und Therapieforschung, Technische Universität München, Klinikum rechts der Isar, 81675 Munich, Germany
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Abstract
Whole-cell tumor vaccines have been investigated for more than 20 years for their efficacy in both preclinical models and in clinical trials in humans. There are clear advantages of whole-cell/polyepitope vaccination over those types of immunotherapy that target specific epitopes. Multiple and unknown antigens may be targeted to both the innate and adaptive immune system, and this may be further augmented by genetic modification of the vaccine cells to provide cytokines and costimulation. In this review, we give an overview of the field including the preclinical and clinical advances using unmodified and modified tumor-cell vaccines.
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Affiliation(s)
- John Copier
- Division of Cellular and Molecular Medicine, Department of Oncology, St. George's University of London, London, UK
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Abstract
Recent understanding of the molecular events crucial in overcoming immunosuppressive tumor microenvironments and generating effective antitumor immunity provides us with the wreath opportunity to manipulate genes that have a key role in antitumor immune responses. Granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin-12 (IL-12) are two indispensable cytokines for activating dendritic cells and boosting the strong immune responses against cancer. In this review, we describe the antitumor mechanisms and clinical application of gene-modified tumor cells and dendritic cells to secrete GM-CSF or IL-12, respectively, in various preclinical and clinical settings. The principles operative in these vaccination strategies may prove applicable to other immunotherapy strategies, especially in combination with other therapeutic modalities, such as chemotherapy and targeted therapy.
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Affiliation(s)
- Masahisa Jinushi
- Department of Surgery and Bioengineering Advanced Clinical Research Center, Institute of Medical Sciences, University of Tokyo, Tokyo, Japan
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Chiang CLL, Ledermann JA, Aitkens E, Benjamin E, Katz DR, Chain BM. Oxidation of ovarian epithelial cancer cells by hypochlorous acid enhances immunogenicity and stimulates T cells that recognize autologous primary tumor. Clin Cancer Res 2008; 14:4898-907. [PMID: 18676764 DOI: 10.1158/1078-0432.ccr-07-4899] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Hypochlorous acid, a product of neutrophil myeloperoxidase, is a powerful enhancer of antigen processing and presentation. In this study, we examine whether ovarian epithelial cells (SK-OV-3) exposed to hypochlorous acid can stimulate T cells from patients with ovarian epithelial cancer that recognize common tumor antigens as well as autologous tumor. EXPERIMENTAL DESIGN T cells from human leukocyte antigen (HLA)-A2(+) and HLA-A2(-) patients or healthy controls were stimulated with autologous dendritic cells cocultured with the generic ovarian tumor line SK-OV-3, previously exposed to hypochlorous acid. RESULTS Hypochlorous acid-treated SK-OV-3 cells drove expansion of CD8(+) T cells from HLA-A2(+) individuals, which recognized the HLA-A2-restricted tumor antigen epitopes of HER-2/neu (E75 and GP2) and MUC1 (M1.1 and M1.2). Up to 4.1% of the T cells were positive for the HER-2/neu KIFGSLAFL epitope using pentamer staining. Dendritic cells loaded with oxidized SK-OV-3 cells and further matured with CD40 agonistic antibody or monophosphoryl lipid A additionally induced CD4(+) class II-restricted responses. Critically, T cells stimulated with mature oxidized SK-OV-3 (but not a control oxidized melanoma cell line) directly recognized autologous tumor cells isolated from patient ascites. CONCLUSIONS Immunization with mature dendritic cells loaded with a generic oxidized tumor cell line stimulates a polyclonal antitumor response that recognizes autologous tumor. These findings suggest a new immunotherapeutic strategy to extend remission in ovarian cancer.
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Affiliation(s)
- Cheryl L-L Chiang
- Division of Infection and Immunity, University College London, London, United Kingdom
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Nashan D, Müller ML, Grabbe S, Wustlich S, Enk A. Systemic therapy of disseminated malignant melanoma: an evidence-based overview of the state-of-the-art in daily routine. J Eur Acad Dermatol Venereol 2007; 21:1305-18. [DOI: 10.1111/j.1468-3083.2007.02475.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Minuzzo S, Moserle L, Indraccolo S, Amadori A. Angiogenesis meets immunology: Cytokine gene therapy of cancer. Mol Aspects Med 2007; 28:59-86. [PMID: 17306360 DOI: 10.1016/j.mam.2006.12.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2006] [Accepted: 12/29/2006] [Indexed: 01/19/2023]
Abstract
Delivery of cytokine genes at the tumor site in pre-clinical models has been shown to recruit host inflammatory cells followed by inhibition of tumor growth. This local effect is often accompanied by systemic protection mediated by the immune system, mainly by CD8(+) T and NK cells. On this basis, cytokine gene-transduced tumor cells have widely been used as vaccines in clinical trials, which have shown good safety profiles and some local responses but substantial lack of systemic efficacy. Are these findings the end of the story? Possibly not, if major improvements will be attained in the coming years. These should be directed at the level of gene selection and delivery, in order to identify the optimal cytokine and achieve efficient and durable cytokine expression, and at the level of improving immune stimulation, i.e. by co-administration of co-stimulatory molecules including B7 and CD40, or boosting the expression of tumor antigens or MHC class I molecules. Interestingly, some of the cytokines which have shown encouraging anti-tumor activity, including IFNs, IL-4, IL-12 and TNF-alpha, are endowed with anti-angiogenic or vasculotoxic effects, which may significantly contribute to local tumor control. Therapeutic exploitation of this property may result in the design of novel approaches which, by maximizing immune-stimulating and anti-angiogenic effects, could possibly lead to starvation of established tumors in patients.
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Affiliation(s)
- Sonia Minuzzo
- Department of Oncology and Surgical Sciences, University of Padova, via Gattamelata 64, 35128 Padova, Italy
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Brill TH, Kübler HR, von Randenborgh H, Fend F, Pohla H, Breul J, Hartung R, Paul R, Schendel DJ, Gansbacher B. Allogeneic retrovirally transduced, IL-2- and IFN-γ-secreting cancer cell vaccine in patients with hormone refractory prostate cancer—a phase I clinical trial. J Gene Med 2007; 9:547-60. [PMID: 17514769 DOI: 10.1002/jgm.1051] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The purpose of this vaccine study was to determine the safety and feasibility of vaccination with an allogeneic prostate carcinoma cell line, LNCaP, expressing recombinant interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) and to evaluate the efficacy of inducing tumor-specific immune responses in HLA-A2-matched patients with hormone refractory prostate cancer (HRPC). METHODS In a dose-escalating phase I study, HLA-A2-matched HRPC patients received four vaccinations of irradiated allogeneic LNCaP cells retrovirally transduced to secrete IL-2 and IFN-gamma at study day 1, 15, 29 and 92 and subsequently every 91 days unless tumor progression was evident. RESULTS Three patients receiving the first dose level (7.5 million cells) showed no evidence of dose-limiting toxicity or vaccine-related adverse events including autoimmunity. One of three patients receiving the second dose level (15 million cells) developed a transient self-limiting grade 3 local injection site reaction (ulceration) after the eighth vaccination. Vaccine-induced immune responses against a broad array of prostate tumor associated antigens were detected in all six patients. Two of the three patients receiving the higher dose showed a decline in serum prostate-specific antigen (PSA) values of more than 50%, with one patient remaining on protocol for 3 years. CONCLUSIONS Immunisation with the allogeneic LNCaP/IL-2/IFN-gamma vaccine is safe and feasible without any dose-limiting toxicity or autoimmunity. A 50% PSA decline was achieved in two of the six patients. This encouraging data provides the scientific rationale for further investigation of the vaccine in a phase II trial.
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Affiliation(s)
- T H Brill
- Institute for Experimental Oncology, Technical University, Klinikum rechts der Isar, Munich, Germany.
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Chiang CLL, Ledermann JA, Rad AN, Katz DR, Chain BM. Hypochlorous acid enhances immunogenicity and uptake of allogeneic ovarian tumor cells by dendritic cells to cross-prime tumor-specific T cells. Cancer Immunol Immunother 2006; 55:1384-95. [PMID: 16463039 PMCID: PMC11030995 DOI: 10.1007/s00262-006-0127-9] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2005] [Accepted: 01/09/2006] [Indexed: 10/25/2022]
Abstract
BACKGROUND Ovarian cancer commonly relapses after remission and new strategies to target microscopic residual diseases are required. One approach is to activate tumor-specific cytotoxic T cells with dendritic cells loaded with tumor cells. In order to enhance their immunogenicity, ovarian tumor cells (SK-OV-3, which express two well-characterized antigens HER-2/neu and MUC-1) were killed by oxidation with hypochlorous acid (HOCl). RESULTS Treatment for 1 h with 60 microM HOCl was found to induce necrosis in all SK-OV-3 cells. Oxidized, but not live, SK-OV-3 was rapidly taken up by monocyte-derived dendritic cells, and induced partial dendritic cell maturation. Dendritic cells cultured from HLA-A2 healthy volunteers were loaded with oxidized SK-OV-3 (HLA-A2-) and co-cultured with autologous T cells. Responding T cells were tested for specificity after a further round of antigen stimulation. In ELISPOT assays, T cells produced interferon-gamma (IFN-gamma) in response to the immunizing cellular antigen, and also to peptides coding for MUC-1 and HER-2/neu HLA-A2 restricted epitopes, demonstrating efficient cross-presentation of cell-associated antigens. In contrast, no responses were seen after priming with heat-killed or HCl-killed SK-OV-3, indicating that HOCl oxidation and not cell death/necrosis per se enhanced the immunogenicity of SK-OV-3. Finally, T cells stimulated with oxidized SK-OV-3 showed no cross-reaction to oxidized melanoma cells, nor vice versa, demonstrating that the response was tumor-type specific. CONCLUSIONS Immunization with oxidized ovarian tumor cell lines may represent an improved therapeutic strategy to stimulate a polyclonal anti-tumor cellular immune response and hence extend remission in ovarian cancer.
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Affiliation(s)
- Cheryl L.-L. Chiang
- Department of Immunology and Molecular Pathology, Division of Infection and Immunity, UCL, Windeyer Building, 46 Cleveland Street, W1T 4JF London, UK
| | | | - Ariel N. Rad
- Department of Immunology and Molecular Pathology, Division of Infection and Immunity, UCL, Windeyer Building, 46 Cleveland Street, W1T 4JF London, UK
| | - David R. Katz
- Department of Immunology and Molecular Pathology, Division of Infection and Immunity, UCL, Windeyer Building, 46 Cleveland Street, W1T 4JF London, UK
| | - Benjamin M. Chain
- Department of Immunology and Molecular Pathology, Division of Infection and Immunity, UCL, Windeyer Building, 46 Cleveland Street, W1T 4JF London, UK
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Sapin A, Clavreul A, Garcion E, Benoit JP, Menei P. Evaluation of particulate systems supporting tumor cell fractions in a preventive vaccination against intracranial rat glioma. J Neurosurg 2006; 105:745-52. [PMID: 17121138 DOI: 10.3171/jns.2006.105.5.745] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Object
Irradiated autologous tumor cells are commonly used as a source of antigens in antiglioma vaccinations to activate the immune system. As cell number is often a limiting factor in these cells’ preparation, the aim of the present study was to find a means that can lower the amount of cells required. Among strategies currently developed, adjuvant particulate systems offer a promising means to improve the antitumor immune response. In this study, the authors were interested in evaluating the role of particulate systems containing biodegradable microspheres that carry tumor cell fractions on their surfaces in the induction of a protective immunity in the 9L/Fischer 344 rat glioma model. The efficiency of these particulate systems was compared to that of irradiated 9L cells.
Methods
Particulate systems composed of poly(d,l-lactide-co-glycolide) (PLGA) microspheres that support 9L cell fractions on their surfaces (cell lysates or plasma membranes) or irradiated 9L cells alone were injected subcutaneously into the flanks of syngeneic Fischer 344 rats. Eighteen days later, the rats were intracranially injected with nonirradiated 9L cells. A study of survival in these animals and an analysis of the resulting immune response were then conducted.
For the same amount of protein (50 μg) injected, irradiated 9L cells provided long-term survival in 30% of animals, whereas 9L plasma membranes adsorbed onto PLGA microspheres provided long-term survival in 10% of animals and cell lysates adsorbed onto microspheres provided long-term survival in 0%. Accordingly, particulate systems induced a lower T helper cell Type 1 (Th1) peripheral immune response than irradiated 9L cells. However, greater secretion of Th1 cytokines was observed when particulate systems were used than when cell fractions separated from microspheres were used, indicating the adjuvant property of these particulate systems.
Conclusions
Particulate systems have adjuvant properties but are still less efficient than irradiated whole tumor cells for vaccinations. Encapsulation of an activating molecule in the microsphere will be the next developmental step in the search for efficient antiglioma vaccinations.
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Affiliation(s)
- Anne Sapin
- L'Institut National de la Santé et de la Recherche Médicale U 646, Angers, France
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17
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El-Sayed IH, Singer MI, Civantos F. Sentinel lymph node biopsy in head and neck cancer. Otolaryngol Clin North Am 2005; 38:145-60, ix-x. [PMID: 15649505 DOI: 10.1016/j.otc.2004.09.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Sentinel lymph node biopsy (SLNB) offers a minimally invasive technique to examine the proximal lymph node basin for micrometastases in clinically N0 necks in patients head and neck cancer. This technique has been validated in the management of breast cancer and cutaneous malignant melanoma (CMM) and is under active investigation in the management of multiple other solid tumors.SLNB is used routinely in the management of head and neck melanoma and is investigational for other cancers of the head and neck. SLNB provides prognostic information for patients with CMM and identifies those patients that may benefit from additional treatment. This article examines the history, rationale,science, and current status of SLNB in head and neck with emphasis on melanoma.
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Affiliation(s)
- Ivan H El-Sayed
- Department of Otolaryngology-Head and Neck Surgery, University of California Comprehensive Cancer Center, 400 Parnassus Avenue, San Francisco, CA 94143, USA.
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18
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Moiseyenko VM, Danilov AO, Baldueva IA, Danilova AB, Tyukavina NV, Larin SS, Kiselev SL, Orlova RV, Anisimov VV, Semenova AI, Shchekina LA, Gafton GI, Kochnev VA, Barchuk AS, Kanaev SV, Hanson KP, Georgiev GP. Phase I/II trial of gene therapy with autologous tumor cells modified with tag7/PGRP-S gene in patients with disseminated solid tumors: miscellaneous tumors. Ann Oncol 2005; 16:162-168. [PMID: 15598955 DOI: 10.1093/annonc/mdi028] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The use of genetically modified autologous tumor cells appears to be a promising approach for cancer therapy. A phase I/II trial was undertaken to define the feasibility, safety and antitumor effects of the autologous vaccine prepared by transferring tag7/PGRP-S gene into malignant melanoma and renal cell carcinoma cells. PATIENTS AND METHODS Twenty-one patients (17 with disseminated malignant melanoma and four with metastatic renal cell carcinoma) were enrolled in this study. Cytoreduction was performed in all cases prior to therapy. Autologous tumor cells were transfected with the tag7/PGRP-S gene, irradiated and injected intradermally every 3 weeks. RESULTS Vaccinations were well tolerated by all patients, without clinically significant signs of toxicity. Delayed-type hypersensitivity was observed in 48% of cases. Antitumor immune response was observed in 95% of patients. There were no complete or partial responses; however, a minor response was achieved in one patient with renal cell carcinoma. The stabilization of neoplastic disease was observed in eight patients (seven with malignant melanoma and one with renal cell carcinoma). Median time to tumor progression was 3 months. CONCLUSIONS The approach suggested here appears to be well tolerated and produces a number of durable clinical effects. Further studies are required to determine whether promising effects on immune activation will result in an actual clinical benefit for patients with malignant melanoma and renal cell carcinoma.
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Affiliation(s)
- V M Moiseyenko
- N.N. Petrov Research Institute of Oncology, St Petersburg, Russian Federation
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19
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Spicer J, Quatan N, Plunkett T, Pandha H. Cellular immunotherapy for cancer: current concepts and clinical perspectives. Clin Oncol (R Coll Radiol) 2004; 16:395-404. [PMID: 15487131 DOI: 10.1016/j.clon.2004.03.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Affiliation(s)
- J Spicer
- Department of Urology, St George's Hospital Medical School, London, UK
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20
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Hsueh EC, Morton DL. Antigen-based immunotherapy of melanoma: Canvaxin therapeutic polyvalent cancer vaccine. Semin Cancer Biol 2004; 13:401-7. [PMID: 15001158 DOI: 10.1016/j.semcancer.2003.09.003] [Citation(s) in RCA: 61] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
As yet there are no FDA-approved cancer vaccines for malignant melanoma, but encouraging response rates and low toxicities reported in phase I/II trials suggest that antigen-based active immunotherapy may complement current treatment modalities. The cumulative data for Canvaxin therapeutic polyvalent cancer vaccine represent the largest phase II clinical trial of any cancer vaccine. Univariate and multivariate analyses of these data have demonstrated the prognostic significance of this allogeneic whole-cell preparation as a postoperative adjuvant treatment for patients with stage III and IV melanoma. The vaccine has also been shown promising results after resection of stage II melanoma and in patients with regional in-transit disease. The consistent correlation between immune and clinical responses to the vaccine suggests that immune parameters may be used to monitor a patient's response to vaccine therapy.
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Affiliation(s)
- Eddy C Hsueh
- Roy E. Coats Research Laboratories, John Wayne Cancer Institute, 2200 Santa Monica Blvd., Santa Monica, CA 90404, USA
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21
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Stagg J, Lejeune L, Paquin A, Galipeau J. Marrow Stromal Cells for Interleukin-2 Delivery in Cancer Immunotherapy. Hum Gene Ther 2004; 15:597-608. [PMID: 15212718 DOI: 10.1089/104303404323142042] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Marrow stromal cells (MSCs) can be easily gene-modified and clonally expanded making them ideal candidates for transgenic cell therapy. However, recent reports suggest that MSCs possess immunosuppressive effects, which may limit their clinical applications. We investigated whether interleukin (IL)-2 gene-modified MSCs can be used to mount an effective immune response against the poorly immunogenic B16 melanoma model. We first show that primary MSCs mixed with B16 cells and injected subcutaneously in syngeneic recipients do not affect tumor growth. On the other hand, IL-2-producing MSCs mixed with B16 cells significantly delayed tumor growth in an IL-2 dose-dependent manner. Furthermore, we observed that matrix-embedded IL-2-producing MSCs injected in the vicinity of preestablished B16 tumors led to absence of tumor growth in 90% of treated mice (p < 0.001). We demonstrated that tumor-bearing mice treated with IL-2-producing MSCs developed CD8-mediated tumor-specific immunity and significantly delayed tumor growth of a B16 cell challenge (p < 0.05). In addition, treatment of cd8-/-, cd4-/- and beige mice revealed that CD8+ and natural killer (NK) cells, but not CD4+ cells, were required to achieve antitumor effect. In conclusion, MSCs can be exploited to deliver IL-2 and generate effective immune responses against melanoma in mice with normal immune systems.
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Affiliation(s)
- John Stagg
- Lady Davis Institute for Medical Research, McGill University, 3755 Côte Ste-Catherine Road, Montreal, Quebec, Canada H3T 1E2
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22
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Abstract
The field of cancer gene therapy is in continuous expansion, and technology is quickly moving ahead as far as gene targeting and regulation of gene expression are concerned. This review focuses on the endocrine aspects of gene therapy, including the possibility to exploit hormone and hormone receptor functions for regulating therapeutic gene expression, the use of endocrine-specific genes as new therapeutic tools, the effects of viral vector delivery and transgene expression on the endocrine system, and the endocrine response to viral vector delivery. Present ethical concerns of gene therapy and the risk of germ cell transduction are also discussed, along with potential lines of innovation to improve cell and gene targeting.
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Affiliation(s)
- Luisa Barzon
- Department of Histology, Microbiology, and Medical Biotechnologies, University of Padova, I-35121 Padua, Italy
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23
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Mukaida N. CANCER GENE THERAPY USING CYTOKINE AND CHEMOKINE GENES. ANNALS OF CANCER RESEARCH AND THERAPY 2004; 12:33-51. [DOI: 10.4993/acrt.12.33] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
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24
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Ge NL, Ye SL, Zheng N, Sun RX, Liu YK, Tang ZY. Prevention of hepatocellular carcinoma in mice by IL-2 and B7-1 genes co-transfected liver cancer cell vaccines. World J Gastroenterol 2003; 9:2182-5. [PMID: 14562374 PMCID: PMC4656459 DOI: 10.3748/wjg.v9.i10.2182] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the immunoprotective effect of liver cancer vaccine with co-transfected IL-2 and B7-1 genes on hepatocarcinogenesis in mice.
METHODS: The murine liver cancer cell line Hepal-6 was transfected with IL-2 and/or B7-1 gene via recombinant adenoviral vectors and the liver cancer vaccines were prepared. C57BL/6 mice were immunized with these vaccines and challenged with the parental Hepal-6 cells afterwards. The immunoprotection was investigated and the reactive T cell line was assayed.
RESULTS: The immunoprotection of the tumor vaccine was demonstrated. The effect of IL-2 and B7-1 genes co-transfected Hepal-6 liver cancer vaccine (Hep6-IL2/B7 vaccine) on the onset of tumor formation was the strongest. When attacked with wild Hepal-6 cells, the median survival period of the mice immunized with Hep6-IL2/B7 vaccine was the longest (68 d, χ2 = 7.70-11.69, P < 0.05) and the implanted tumor was the smallest (z = 3.20-44.10, P < 0.05). The effect of single IL-2 or B7-1 gene-transfected vaccine was next to the IL2/B7 gene co-transfected group, and the mean survival periods were 59 and 54 d, respectively. The mean survival periods of wild or enhanced green fluorescence protein gene modified vaccine immunized group were 51 and 48 d, respectively. The mice in control group all died within 38 d and the implanted tumor was the largest (z = 3.20-40.21, P < 0.05). The cellular immunofunction test and cytotoxicity study showed that the natural killer (NK) cell, lymphokine activated killer (LAK) cell and cytotoxic T lymphocyte (CTL) activities were significantly increased in mice immunized with the Hep6-IL2/B7 vaccine, (29.5% ± 2.5%, 65.0% ± 2.9%, 83.1% ± 1.5% respectively, compared with other groups, P < 0.05).
CONCLUSION: The Hep6-IL2/B7 liver cancer vaccines can induce the mice to produce activated and specific CTL against the parental tumor cells, and demonstrate stronger effect on the hepatocarcinogenesis than single gene modified or the regular tumor vaccine. Therefore, the vaccines may become a novel potential therapy for recurrence and metastasis of HCC.
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Affiliation(s)
- Ning-Ling Ge
- Liver Cancer Institute of Zhongshan Hospital Affiliated to Fudan University, Shanghai 200032, China
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25
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[Gene therapy of melanoma: review of published clinical trials]. Rev Med Interne 2003; 24:443-51. [PMID: 12829217 DOI: 10.1016/s0248-8663(03)00061-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
INTRODUCTION Melanoma frequency increases. Conventional antitumoral treatments fail. Gene therapy for metastatic melanoma is studied in 17 phase I-II clinical trials. ACTUALITES ET POINTS FORTS: Sixteen use cytokine genes. These studies are heterogenous as far as methodology is concerned. Gene therapy clinical tolerance is acceptable. Security is rarely discuted. In these studies overall response rate is 8%, with histological complete responses. PERSPECTIVES Presently, three new studies are opened in United States.
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26
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Martin F, Chowdhury S, Neil SJ, Chester KA, Cosset FL, Collins MK. Targeted retroviral infection of tumor cells by receptor cooperation. J Virol 2003; 77:2753-6. [PMID: 12552017 PMCID: PMC141083 DOI: 10.1128/jvi.77.4.2753-2756.2003] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Retroviruses expressing two different receptor-binding domains linked by proline-rich spacers infect only cells expressing both retroviral receptors (Valsesia-Wittman et al., EMBO J. 6:1214-1223, 1997). Here we apply this receptor cooperation strategy to target human tumor cells by linking single-chain antibodies recognizing tumor antigens via proline-rich spacers to the 4070A murine leukemia virus surface protein.
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Affiliation(s)
- Francisco Martin
- Department of Immunology and Molecular Pathology, Windeyer Institute, 46 Cleveland Street, London W1T 2AH, United Kingdom
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27
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Abstract
Unusual neuro-ophthalmologic symptoms and signs that go unexplained should warrant a thorough investigation for paraneoplastic syndromes. Although these syndromes are rare, these clinical manifestations can herald an unsuspected, underlying malignancy that could be treated early and aggressively. This point underscores the importance of distinguishing and understanding the various, sometimes subtle, presentations of ocular paraneoplastic syndromes. Outlined in this review article are diagnostic features useful in differentiating cancer-associated retinopathy, melanoma-associated retinopathy, and paraneoplastic optic neuropathy. These must also be distinguished from non-cancer-related eye disorders that may clinically resemble cancer-associated retinopathy. The associated antibodies and histopathology of each syndrome are presented to help in the understanding of these autoimmune phenomena. Treatment outcomes from reported cases are summarized, and some potential novel immunotherapies are also discussed.
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Affiliation(s)
- Jane W Chan
- Department of Internal Medicine, Division of Neurology, University of Nevada School of Medicine, Las Vegas 89102, USA
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28
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Abstract
Skin cancers continue to present a major therapeutic challenge to physicians. Recent advances in molecular genetics and improved understanding of immune responses to tumors have generated an interest in using gene-based immunotherapy for treating these malignancies. Two major forms of gene-based immunotherapy are currently being investigated. One focuses on genetic modification of some target cell populations of the host using immunostimulatory genes such as cytokines, in order to improve tumor immunogenicity and antitumor responses; the other is genetic immunization with the genes coding for melanoma-associated antigens recognized by cytotoxic T cells. This paper reviews these novel strategies and summarizes the most recent data recorded in either experimental studies or clinical trials.
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Affiliation(s)
- Yuansheng Sun
- Klinische Kooperationseinheit für Dermatoonkologie (DKFZ) an der Universitats-Hautklinik Mannheim, Universität Heidelberg, Germany
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29
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Abstract
The incidence of malignant melanoma is increasing faster than that of any other malignancy in the United States, and therefore this disease represents a significant health threat now and in the future. The impact of conventional systemic therapy for metastatic melanoma is minimal, with best response rates for conventional therapy nearing only 30% and cure rates well below 10%. This justifies the development of immunotherapy as a new treatment modality for patients with melanoma. This review summarizes the most recent findings and the newest approaches in the design of vaccines for melanoma. The antigens associated with melanoma and their uses in the vaccine development are described. Possible clinical applications of the new vaccines for melanoma and future directions for their development are also discussed.
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Affiliation(s)
- Boris R Minev
- Cancer Center, University of California-San Diego, La Jolla, CA 92093-0063, USA
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30
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Abstract
Melanoma continues to present a major therapeutic challenge to oncologists, oncologic surgeons, and dermatologists. Recent advances in molecular genetics and improvement in our understanding of immune responses to tumors have generated an interest in using gene-based treatment strategies to fight melanoma. Several basic strategies have emerged: (1) strengthening of the immune response against tumors by genetic modification of some target cell populations of the host using immunostimulatory genes such as cytokines and by genetic immunization with the genes coding for melanoma-associated antigens recognized by cytotoxic T cells; (2) interference with signaling cascades; and (3) suicide gene strategies. This article reviews these novel strategies and summarizes the most recent data generated by European groups either in experimental studies or in clinical trials.
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Affiliation(s)
- Dirk Schadendorf
- Skin Cancer Unit of the German Cancer Research Center at the Department of Dermatology, University Hospital Mannheim, University of Heidelberg, Mannheim, Germany
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31
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Affiliation(s)
- Edward Podczaski
- Department of Obstetrics and Gynecology at The Pennsylvania State University School of Medicine, Milton S Hershey Medical Center, Hershey 17033, USA.
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32
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Abstract
The immune system can recognize tumors, but may be actively tolerized to tumors during the tumorigenesis process. The identity of most tumor antigens remains unknown, but the number is growing due to new techniques. Most clinical trials using genetically modified tumor vaccines have shown immunological responses (DTH), but few clinical responses. Certain chemotherapeutic agents may enhance the immune effects of genetically modified tumor vaccines.
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Affiliation(s)
- Todd D Armstrong
- Bunting-Blaustein Cancer Research Building, Room 4M86, Johns Hopkins Medical Institutions, 1650 Orleans Street, Baltimore, MD 21231, USA
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33
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Phase I Trial of a B7-1 (CD80) Gene Modified Autologous Tumor Cell Vaccine in Combination With Systemic Interleukin-2 in Patients With Metastatic Renal Cell Carcinoma. J Urol 2002. [DOI: 10.1097/00005392-200205000-00014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Antonia SJ, Seigne J, Diaz J, Muro-Cacho C, Extermann M, Farmelo MJ, Friberg M, Alsarraj M, Mahany JJ, Pow-Sang J, Cantor A, Janssen W. Phase I trial of a B7-1 (CD80) gene modified autologous tumor cell vaccine in combination with systemic interleukin-2 in patients with metastatic renal cell carcinoma. J Urol 2002. [PMID: 11956426 DOI: 10.1016/s0022-5347(05)65071-9] [Citation(s) in RCA: 86] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
PURPOSE A reason that the immune system may fail to reject tumors is that T cells encounter tumor antigen derived peptides on the surface of tumor cells in a tolerizing rather than activating context since tumor cells do not express T cell co-stimulatory molecules such as B7-1 (CD80). In preclinical models over expression of B7-1 on the surface of tumor cells has been shown to activate T cells which kill tumor cells. We conducted a phase I clinical trial testing this approach in patients with metastatic renal cell carcinoma. MATERIALS AND METHODS Resected tumors from 15 patients were disaggregated and adapted to tissue culture, transduced with the B7-1 gene and injected subcutaneously as a vaccine. The dose of the vaccine was escalated in 3 separate cohorts of patients, and systemic interleukin-2 (IL-2) was administered as an adjuvant designed to enhance the proliferation of the vaccine activated T cells. RESULTS Of the 15 patients 9 had measurable disease, 2 had a partial response and 2 had stable disease. Perivascular T cell infiltrates at autologous tumor delayed type hypersensitivity skin test sites developed in 3 of the 4 patients with stable disease or partial response. Although the patients experienced the usual and expected toxicity from the IL-2, there was no significant toxicity observed with the vaccine. CONCLUSIONS The B7-1 gene modified autologous tumor cell vaccine is safe and can be combined with systemic IL-2 with acceptable toxicity. Immunological and clinical responses were observed in some of the patients. A phase II trial is reasonable to determine the efficacy of this approach.
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Affiliation(s)
- Scott J Antonia
- Interdisciplinary Oncology Program and Genitourinary Program, H. Lee Moffitt Cancer Center, Tampa, Florida 33612, USA
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35
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Mulcahy KA, Alexander S, Platts KE, Wardle C, Sisley K, Rennie IG, Murray AK. CD80-mediated induction of immunostimulation in two ocular melanoma cell lines is augmented by interferon-gamma. Melanoma Res 2002; 12:129-38. [PMID: 11930109 DOI: 10.1097/00008390-200204000-00005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Although the transfection of the T-cell costimulatory molecule CD80 cDNA into human tumours can augment their immunogenicity in vitro, its expression alone is ineffective in many tumour systems. We evaluated the influence of CD80 expression on the immunostimulatory activity of ocular melanoma cell lines and determined whether IFN-gamma could enhance the effect. Two ocular melanoma cell lines were transfected with CD80 cDNA. The immunostimulatory capacity of the CD80+ transfectants was determined by their ability to stimulate the proliferation of allogeneic peripheral blood mononuclear cells (PBMC). The influence of additional accessory molecules on PBMC proliferation was assessed by pre-treating the CD80 transfectants with IFN-gamma. The CD80+ transfectants induced proliferation of allogeneic PBMC. IFN-gamma treatment of the tumour cells induced upregulated expression of MHC class I, de novo expression of MHC class II and CD54, and enhanced the ability of the CD80+ transfectants to stimulate PBMC proliferation. CD4+ T cells were not required for the proliferative response against untreated CD80+ tumour cells but were necessary for the augmentation of proliferation observed following IFN-gamma treatment. CD80+ ocular melanoma cells possess immunostimulatory potential which is augmented by IFN-gamma induced upregulation of cell surface molecules. Further studies on the role of costimulatory molecules in inducing anti-tumour immunity in ocular melanoma may help to define new strategies for application of immunotherapeutic approaches to treat this aggressive disease.
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Affiliation(s)
- K A Mulcahy
- Section of Oncology and Pathology (Cancer Studies), University of Sheffield Medical School, Beech Hill Road, Sheffield, S10 2RX, UK
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36
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Harrington KJ, Melcher AA, Bateman AR, Ahmed A, Vile RG. Cancer gene therapy: Part 2. Candidate transgenes and their clinical development. Clin Oncol (R Coll Radiol) 2002; 14:148-69. [PMID: 12069125 DOI: 10.1053/clon.2001.0004] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
- Kevin J Harrington
- CRC Centre for Cell and Molecular Biology, Institute for Cancer Research, London, UK.
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37
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Rochlitz C, Dreno B, Jantscheff P, Cavalli F, Squiban P, Acres B, Baudin M, Escudier B, Heinzerling L, Morant R, Herrmann R, Dietrich PY, Dummer R. Immunotherapy of metastatic melanoma by intratumoral injections of Vero cells producing human IL-2: phase II randomized study comparing two dose levels. Cancer Gene Ther 2002; 9:289-95. [PMID: 11896446 DOI: 10.1038/sj.cgt.7700441] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2001] [Indexed: 02/05/2023]
Abstract
BACKGROUND Systemic IL-2 has shown some activity in metastatic melanoma, but its use is severely limited by toxicity. TG2001 is a product in which the human IL-2 cDNA was incorporated into the genome of Vero cells, a monkey fibroblast cell line. The goal of this intratumorally applied therapy was to create an antitumor immune response stimulated by xeno-antigens and local production of IL-2 in the close vicinity of tumor-specific antigens. TG2001 was reported to have a good safety profile in two previous dose-escalating phase I studies performed in 18 patients with various solid tumors, with encouraging clinical responses in three patients. The objectives of this study were to evaluate the tolerance and incidence of tumor regression in patients with metastatic melanoma, following repeated administration of Vero-IL-2 cells. PATIENTS AND METHODS This was on open-label, randomized phase II study comparing two doses of Vero-IL-2, 5x10(5) and 5x10(6) cells. Twenty-eight patients with metastatic melanoma were enrolled in the study, 14 in each treatment group. Patients received TG2001 by intratumoral injection on days 1, 3, and 5 every 4 weeks for four cycles, and every 8 weeks thereafter, until evidence of progressive disease (PD). Criteria for patient selection included histologically proven metastatic melanoma, with one tumor accessible for product administration, and at least another tumor site for response assessment. Evaluation included tumor measurements, humoral and T cell-mediated local and systemic immune response, humoral response to Vero cells, adverse events and standard laboratory parameters. RESULTS None of the patients achieved a confirmed objective response. Stable disease (SD) was seen in six (43%) and eight patients (57%) at the 5x10(5) and the 5x10(6) dose level, respectively. Two patients, one in each group, died during the study (i.e., within 1 month after the last injection) due to PD. Three patients exhibited antibody responses to Vero cells. T-cell immunity, serum cytokine levels and cytokine mRNA expression in tumor biopsies did not show meaningful alterations after therapy, except for a trend toward an increase in intratumoral TH2 cytokine (IL-4 and/or IL-10) levels. The study drug was well tolerated at both dose levels and side effects mainly consisted of injection site pain and erythema, and pyrexia. CONCLUSION The intratumoral administration of TG2001 was generally well tolerated in patients with metastatic melanoma, and transient disease stabilization was observed in 50% of patients.
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Affiliation(s)
- Christoph Rochlitz
- Departement Innere Medizin, Abteilung für Onkologie, Kantonsspital, Petersgraben 4, CH-4031 Basel, Switzerland.
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38
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Abstract
Immune responses appear to play a role in the natural history of melanoma and immunotherapy has therefore been the subject of a number of studies. The results of several large randomised studies using allogeneic melanoma vaccines have shown minimal benefit and Phase I/II studies with gene transfected melanoma cells do not appear particularly encouraging. The majority of current interest now centres on development of vaccines using defined melanoma antigens recognised by T-cells and given as dendritic vaccines or injected directly as melanoma peptides or DNA. It can be expected that the most effective antigens and method of administration will become apparent over the next few years. It is clear, however, that melanoma shows low response rates to immunotherapy, as for chemotherapy. Both forms of therapy appear to kill melanoma by induction of apoptosis, so it is possible that resistance to apoptosis may underlie the low responses to these forms of therapy. Much is already known about agents that may sensitise melanoma to apoptosis and combining these with chemotherapy and/or immunotherapy provides a promising new approach in treatment of melanoma.
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Affiliation(s)
- Peter Hersey
- Immunology and Oncology Unit, Room 443, David Maddison Clinical Sciences Building, Cnr. King & Watt Streets, Newcastle, NSW 2300, Australia.
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39
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Keltner JL, Thirkill CE, Yip PT. Clinical and immunologic characteristics of melanoma-associated retinopathy syndrome: eleven new cases and a review of 51 previously published cases. J Neuroophthalmol 2001; 21:173-87. [PMID: 11725182 DOI: 10.1097/00041327-200109000-00004] [Citation(s) in RCA: 163] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE To evaluate the signs, symptoms, and immune responses of patients with melanoma-associated retinopathy (MAR) syndrome. MATERIALS AND METHODS We reviewed the clinical and immunologic findings of 62 MAR syndrome patients. They include 25 patients from our institution (11 not previously reported) and 37 patients reported from other institutions. RESULTS There were 33 men and seven women (no gender information is available for the remaining 22 cases). Age at onset of the visual disturbance averaged 57.5 years (range, 30-78). Visual acuity of 20/60 or better was initially present in 82%. Fundus examination was normal in 44%, optic disc pallor was present in 23%, and retinal vessel attenuation was present in 30%. Vitreous cells were present in 30%. The latency from melanoma diagnosis to recognition of MAR syndrome averaged 3.6 years (range, 2 months to 19 years). Seven patients sustained visual improvement with various treatment regimens, especially with intravenous immunoglobulin and cytoreductive surgery (metastasectomy). Indirect immunohistochemical staining of the bipolar layer was typical, but several other retinal elements were also reactive. Tissue from a metastatic melanoma excised from one of the patients expressed antigens that reacted with antiretinal antibodies. CONCLUSION MAR syndrome demonstrates diverse clinical and immunologic features. Treatment, especially intravenous immunoglobulin and cytoreductive surgery (metastasectomy), improves vision in some cases.
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Affiliation(s)
- J L Keltner
- Department of Ophthalmology, University of California, Davis, Sacramento, California 95817, USA.
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Abstract
Attempts to generate an anticancer immune response in vivo in patients with cancer have taken several forms. Although to date there have been relatively few published studies describing the effects of the approach in hematologic malignancy, that circumstance is expected to change rapidly during the next few years. In solid tumors, it is not known which, if any, of the approaches being explored will be able to produce responses of sufficient effectiveness and duration to be of general clinical value. Despite the documented increase in survival of patients developing an immune response to tumor immunization, no randomized clinical trial has been entirely convincing. As knowledge of the molecular basis of the immune response and of the immune defenses used by cancer cells improves, it is reasonable to expect to see increasing benefits from tumor vaccines, which are likely to complement, long before they replace, conventional therapies.
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Affiliation(s)
- Peter J. DeMaria
- Genitourinary Malignancies Branch, Center for Cancer Research, National
Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Marijo Bilusic
- Genitourinary Malignancies Branch, Center for Cancer Research, National
Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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Trudel S, Li Z, Dodgson C, Nanji S, Wan Y, Voralia M, Hitt M, Gauldie J, Graham FL, Stewart AK. Adenovector engineered interleukin-2 expressing autologous plasma cell vaccination after high-dose chemotherapy for multiple myeloma - a phase 1 study. Leukemia 2001; 15:846-54. [PMID: 11368448 DOI: 10.1038/sj.leu.2402077] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Eight multiple myeloma patients participated in a phase I trial evaluating the feasibility and safety of subcutaneous vaccination with adenovirus engineered, autologous plasma cells after high-dose therapy. Plasma cells were concentrated from bone marrow harvests by negative selection and high gradient magnetic separation. The mean plasma cell yield was 2.61 x 10(8). Transgene expression measured 48 h after plasma cell infection with an IL-2 expressing adenovirus averaged 2.95 ng/ml/10(6) cells. Vaccine production was successful for 88% of patients. Two months after high-dose therapy, six patients received from one to five injections of 3.5-9.0 x 10(7) cells/vaccine. Vaccines were well tolerated with only minor systemic symptoms reported. Injection with tumor cells induced a local inflammatory response consisting predominantly of CD8+ and/or TIA-1+ T-lymphocytes. Myeloma specific anti-tumor responses, assessed by interferon-gamma (IFN-gamma) release and cytotoxic T cell killing of autologous tumor cells, were not enhanced after vaccination in one evaluable patient. Clinical response, manifested as a decrease in serum paraprotein, was not observed in the one patient who had measurable disease at the time of vaccination. These results demonstrate that the generation of adenovector modified plasma cell vaccines is technically feasible and can be safely administered post-transplant. Further studies of immunlogic and clinical efficacy are required.
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Affiliation(s)
- S Trudel
- Division of Hematology-Oncology, The Princess Margaret Hospital, Toronto, Ontario, Canada
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Gilligan MG, Knox PG, Searle PF. Gene therapy: development of immunostimulatory treatments for cancer. Biotechnol Genet Eng Rev 2001; 17:497-529. [PMID: 11255679 DOI: 10.1080/02648725.2000.10648003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Affiliation(s)
- M G Gilligan
- University of Birmingham CRC Institute for Cancer Studies, Medical School, Edgbaston, Birmingham B15 2TA, U.K
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Todryk SM, Birchall LJ, Erlich R, Halanek N, Orleans-Lindsay JK, Dalgleish AG. Efficacy of cytokine gene transfection may differ for autologous and allogeneic tumour cell vaccines. Immunology 2001; 102:190-8. [PMID: 11260324 PMCID: PMC1783163 DOI: 10.1046/j.1365-2567.2001.01176.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Whole tumour cells are a logical basis for generating immunity against the cancers they comprise or represent. A number of human trials have been initiated using cytokine-transfected whole tumour cells of autologous (patient-derived) or allogeneic [major histocompatibility complex (MHC)-disparate] origin as vaccines. Although precedent exists for the efficacy of autologous-transfected cell vaccines in animal models, little preclinical evidence confirms that these findings will extrapolate to allogeneic-transfected cell vaccines. In order to address this issue a murine melanoma cell line (K1735) was transfected to secrete interleukin (IL)-2, IL-4, IL-7 or granulocyte-macrophage colony-stimulating factor (GM-CSF); cytokines currently in use in trials. The efficacy of these cells as irradiated vaccines was tested head-to-head in syngeneic (C3H) mice and in MHC-disparate (C57BL/6) mice, the former being subsequently challenged with K1735 cells and the latter with naturally cross-reactive B16-F10 melanoma cells. Whilst the GM-CSF-secreting vaccine was the most effective at generating protection in C3H mice, little enhancement in protection above the wild-type vaccine was seen with any of the transfections for the allogeneic vaccines, even though the wild-type vaccine was more effective than the autologous B16-F10 vaccine. Anti-tumour cytotoxic T-lymphocyte (CTL) activity was detected in both models but did not correlate well with protection, whilst in vitro anti-tumour interferon-gamma (IFN-gamma) secretion tended to be higher following the GM-CSF-secreting vaccine. Cytokine transfection of vaccines generally increased anti-tumour CTL activity and IFN-gamma secretion (T helper type 1 response). Further studies in other model systems are required to confirm this apparent lack of benefit of cytokine transduction over wild-type allogeneic vaccines, and to determine which in vitro assays will correlate best with protection in vivo.
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Affiliation(s)
- S M Todryk
- The Onyvax Collaboration Laboratory, Division of Oncology, St. George's Hospital Medical School, London, UK
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Abstract
Modification of the tumor microenvironment with gene transfer techniques stimulates two immune mechanisms that effectuate tumor destruction. One involves improved tumor-antigen presentation for the development of specific cellular and humoral immunity. The second involves compromise of the tumor vasculature by soluble factors and leukocytes.
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Affiliation(s)
- N Mach
- Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
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Collins M. Retroviral vectors for cancer gene therapy. ERNST SCHERING RESEARCH FOUNDATION WORKSHOP 2000:99-104. [PMID: 10943318 DOI: 10.1007/978-3-662-04183-3_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Affiliation(s)
- M Collins
- Department of Immunology, Windeyer Institute of Medical Sciences, London, UK
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Bonnet MC, Tartaglia J, Verdier F, Kourilsky P, Lindberg A, Klein M, Moingeon P. Recombinant viruses as a tool for therapeutic vaccination against human cancers. Immunol Lett 2000; 74:11-25. [PMID: 10996623 DOI: 10.1016/s0165-2478(00)00244-3] [Citation(s) in RCA: 63] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Viral vectors can be used to express a variety of genes in vivo, that encode tumor associated antigens, cytokines, or accessory molecules. For vaccination purposes, the ideal viral vector should be safe and enable efficient presentation of expressed antigens to the immune system. It should also exhibit low intrinsic immunogenicity to allow for its re-administration in order to boost relevant specific immune responses. Furthermore, the vector system must meet criteria that enable its industrialization. The characteristics of the most promising viral vectors, including retroviruses, poxviruses, adenoviruses, adeno-associated viruses, herpes simplex viruses, and alphaviruses, will be reviewed in this communication. Such recombinant viruses have been successfully used in animal models as therapeutic cancer vaccines. Based on these encouraging results, a series of clinical studies, reviewed herein, have been undertaken. Human clinical trials, have as of today, allowed investigators to establish that recombinant viruses can be safely used in cancer patients, and that such recombinants can break immune tolerance against tumor-associated antigens. These promising results are now leading to improved immunization protocols associating recombinant viruses with alternate antigen-presentation platforms (prime-boost regimens), in order to elicit broad tumor-specific immune responses (humoral and cellular) against multiple target antigens.
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Affiliation(s)
- M C Bonnet
- Aventis Pasteur, Campus Mérieux, 1541 Avenue Marcel Mérieux, 69280, Marcy l'Etoile, France
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Affiliation(s)
- J Stebbing
- Institute of Cancer Research, The Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK.
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