Abstract
Activating the immune system for therapeutic benefit in cancer has long been a goal in immunology and oncology. After decades of disappointment, the tide has finally changed due to the success of recent proof-of-concept clinical trials. Most notable has been the ability of the anti-CTLA4 antibody, ipilimumab, to achieve a significant increase in survival for patients with metastatic melanoma, for which conventional therapies have failed. In the context of advances in the understanding of how tolerance, immunity and immunosuppression regulate antitumour immune responses together with the advent of targeted therapies, these successes suggest that active immunotherapy represents a path to obtain a durable and long-lasting response in cancer patients.
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References
Dougan, M. & Dranoff, G. Immune therapy for cancer. Annu. Rev. Immunol. 27, 83–117 (2009)
Hall, S. S. A Commotion in the Blood: Life, Death, and the Immune System (Henry Holt, 1997)
Sylvester, R. J. Bacillus Calmette-Guerin treatment of non-muscle invasive bladder cancer. Int. J. Urol. 18, 113–120 (2011)
Boon, T., Coulie, P. G., Van den Eynde, B. J. & van der Bruggen, P. Human T cell responses against melanoma. Annu. Rev. Immunol. 24, 175–208 (2006)
Segal, N. H. et al. Epitope landscape in breast and colorectal cancer. Cancer Res. 68, 889–892 (2008)
Mellman, I. & Steinman, R. M. Dendritic cells: specialized and regulated antigen processing machines. Cell 106, 255–258 (2001)
Trombetta, E. S. & Mellman, I. Cell biology of antigen processing in vitro and in vivo. Annu. Rev. Immunol. 23, 975–1028 (2005)
Zitvogel, L. & Kroemer, G. Anticancer immunochemotherapy using adjuvants with direct cytotoxic effects. J. Clin. Invest. 119, 2127–2130 (2009)This paper reviews the argument for certain forms of apoptotic cell death as enhancing antitumour immune responses.
Palucka, K., Banchereau, J. & Mellman, I. Designing vaccines based on biology of human dendritic cell subsets. Immunity 33, 464–478 (2010)
Darrasse-Jeze, G. et al. Feedback control of regulatory T cell homeostasis by dendritic cells in vivo. J. Exp. Med. 206, 1853–1862 (2009)
Jiang, A. et al. Disruption of E-cadherin-mediated adhesion induces a functionally distinct pathway of dendritic cell maturation. Immunity 27, 610–624 (2007)
Steinman, R. M., Turley, S., Mellman, I. & Inaba, K. The induction of tolerance by dendritic cells that have captured apoptotic cells. J. Exp. Med. 191, 411–416 (2000)
Steinman, R. M., Hawiger, D. & Nussenzweig, M. C. Tolerogenic dendritic cells. Annu. Rev. Immunol. 21, 685–711 (2003)
Curiel, T. J. et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nature Med. 10, 942–949 (2004)
Kono, K. et al. CD4+CD25high regulatory T cells increase with tumor stage in patients with gastric and esophageal cancers. Cancer Immunol. Immunother. 55, 1064–1071 (2006)
Kooi, S. et al. HLA class I expression on human ovarian carcinoma cells correlates with T-cell infiltration in vivo and T-cell expansion in vitro in low concentrations of recombinant interleukin-2. Cell. Immunol. 174, 116–128 (1996)
Hamanishi, J. et al. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc. Natl Acad. Sci. USA 104, 3360–3365 (2007)
Parsa, A. T. et al. Loss of tumor suppressor PTEN function increases B7–H1 expression and immunoresistance in glioma. Nature Med. 13, 84–88 (2006)
Mellor, A. L. & Munn, D. H. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nature Rev. Immunol. 4, 762–774 (2004)
Munn, D. H. & Mellor, A. L. IDO and tolerance to tumors. Trends Mol. Med. 10, 15–18 (2004)
Marigo, I., Dolcetti, L., Serafini, P., Zanovello, P. & Bronte, V. Tumor-induced tolerance and immune suppression by myeloid derived suppressor cells. Immunol. Rev. 222, 162–179 (2008)
Ohta, A. et al. A2A adenosine receptor protects tumors from antitumor T cells. Proc. Natl. Acad. Sci. USA 103, 13132–13137 (2006)
Facciabene, A. et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and Treg cells. Nature 475, 226–230 (2011)
Aggarwal, S. & Pittenger, M. F. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105, 1815–1822 (2005)
Bouzin, C., Brouet, A., De Vriese, J., Dewever, J. & Feron, O. Effects of vascular endothelial growth factor on the lymphocyte-endothelium interactions: identification of caveolin-1 and nitric oxide as control points of endothelial cell anergy. J. Immunol. 178, 1505–1511 (2007)
Buckanovich, R. J. et al. Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy. Nature Med. 14, 28–36 (2008)
Zhang, L. et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J. Med. 348, 203–213 (2003)
Galon, J. et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313, 1960–1964 (2006)
Rosenberg, S. A., Yang, J. C. & Restifo, N. P. Cancer immunotherapy: moving beyond current vaccines. Nature Med. 10, 909–915 (2004)
Schwartzentruber, D. J. et al. gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N. Engl. J. Med. 364, 2119–2127 (2011)
Kenter, G. G. et al. Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia. N. Engl. J. Med. 361, 1838–1847 (2009)
Leffers, N. et al. Immunization with a P53 synthetic long peptide vaccine induces P53-specific immune responses in ovarian cancer patients, a phase II trial. Int. J. Cancer 125, 2104–2113 (2009)
Vansteenkiste, J. et al. Final results of a multi-center, double-blind, randomized, placebo-controlled phase II study to assess the efficacy of MAGE-A3 immunotherapeutic as adjuvant therapy in stage IB/II non-small cell lung cancer (NSCLC). J. Clin. Oncol. 25. (18S). 7554 (2007)
Freedman, A. et al. Placebo-controlled phase III trial of patient-specific immunotherapy with mitumprotimut-T and granulocyte-macrophage colony-stimulating factor after rituximab in patients with follicular lymphoma. J. Clin. Oncol. 27, 3036–3043 (2009)
Kantoff, P. W. et al. Overall survival analysis of a phase II randomized controlled trial of a poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J. Clin. Oncol. 28, 1099–1105 (2010)
Neller, M. A., López, J. A. & Schmidt, C. W. Antigens for cancer immunotherapy. Semin. Immunol. 20, 286–295 (2008)
Copier, J. & Dalgleish, A. Whole-cell vaccines: a failure or a success waiting to happen? Curr. Opin. Mol. Ther. 12, 14–20 (2010)
Schuler, G. Dendritic cells in cancer immunotherapy. Eur. J. Immunol. 40, 2123–2130 (2010)The authors summarize the current state of the art use of autologous dendritic cell vaccines.
Neller, M. A., Lopez, J. A. & Schmidt, C. W. Antigens for cancer immunotherapy. Semin. Immunol. 20, 286–295 (2008)
Cheever, M. A. et al. Translational Research Working Group developmental pathway for immune response modifiers. Clin. Cancer Res. 14, 5692–5699 (2008)
Rammensee, H. G., Weinschenk, T., Gouttefangeas, C. & Stevanovic, S. Towards patient-specific tumor antigen selection for vaccination. Immunol. Rev. 188, 164–176 (2002)
Small, E. J. et al. Immunotherapy of hormone-refractory prostate cancer with antigen-loaded dendritic cells. J. Clin. Oncol. 18, 3894–3903 (2000)
Kantoff, P. W. et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 363, 411–422 (2010)This paper describes the clinical trial results that led to the FDA approval of Provenge for prostate cancer.
Wolchok, J. D. et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin. Cancer Res. 15, 7412–7420 (2009)The authors summarize the argument for using a different set of criteria to evaluate the efficacy of immunotherapies given the mechanistic differences from conventional anticancer drugs.
Leach, D. R., Krummel, M. F. & Allison, J. P. Enhancement of antitumor immunity by CTLA-4 blockade. Science 271, 1734–1736 (1996)
Hodi, F. S. et al. Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc. Natl Acad. Sci. USA 105, 3005–3010 (2008)
Dudley, M. E. et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298, 850–854 (2002)
Rosenberg, S. A., Restifo, N. P., Yang, J. C., Morgan, R. A. & Dudley, M. E. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nature Rev. Cancer 8, 299–308 (2008)
June, C. H. Principles of adoptive T cell cancer therapy. J. Clin. Invest. 117, 1204–1212 (2007)
Robbins, P. F. et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J. Clin. Oncol. 29, 917–924 (2011)
Kalos, M. et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci. Transl. Med. 3, 95ra73 (2011)
Topp, M. S. et al. Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J. Clin. Oncol. 29, 2493–2498 (2011)This paper describes the clinical results for an intriguing approach to tumour targeting of T cells using bispecific antibodies.
Chambers, C. A., Kuhns, M. S., Egen, J. G. & Allison, J. P. CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy. Annu. Rev. Immunol. 19, 565–594 (2001)A recent review describing the current understanding of the mechanism of action of CTLA-4.
Waterhouse, P. et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270, 985–988 (1995)
Tivol, E. A. et al. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3, 541–547 (1995)
Wing, K. et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science 322, 271–275 (2008)
Cipponi, A., Wieers, G., van Baren, N. & Coulie, P. G. Tumor-infiltrating lymphocytes: apparently good for melanoma patients. But why? Cancer Immunol. Immunother. 60, 1153–1160 (2011)
Disis, M. L. et al. High-titer HER-2/neu protein-specific antibody can be detected in patients with early-stage breast cancer. J. Clin. Oncol. 15, 3363–3367 (1997)
Novellino, L., Castelli, C. & Parmiani, G. A listing of human tumor antigens recognized by T cells: March 2004 update. Cancer Immunol. Immunother. 54, 187–207 (2005)
Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010)This paper reports the pivotal clinical trial data that shortly thereafter led to the FDA approval of anti-CTLA4 for the treatment of metastatic melanoma.
Robert, C. et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364, 2517–2526 (2011)
Hoos, A. et al. Improved endpoints for cancer immunotherapy trials. J. Natl. Cancer Inst. 102, 1388–1397 (2010)
Suntharalingam, G. et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N. Engl. J. Med. 355, 1018–1028 (2006)
Workman, C. J. & Vignali, D. A. Negative regulation of T cell homeostasis by lymphocyte activation gene-3 (CD223). J. Immunol. 174, 688–695 (2005)
Huang, C. T. et al. Role of LAG-3 in regulatory T cells. Immunity 21, 503–513 (2004)
Woo, S. R. et al. Differential subcellular localization of the regulatory T-cell protein LAG-3 and the coreceptor CD4. Eur. J. Immunol. 40, 1768–1777 (2010)
Okazaki, T. et al. PD-1 and LAG-3 inhibitory co-receptors act synergistically to prevent autoimmunity in mice. J. Exp. Med. 208, 395–407 (2011)
Keir, M. E., Butte, M. J., Freeman, G. J. & Sharpe, A. H. PD-1 and its ligands in tolerance and immunity. Annu. Rev. Immunol. 26, 677–704 (2008)This article reviews the evidence for immunosuppression by the induction of T cell exhaustion via activation of PD-1.
Watanabe, T., Bertoletti, A. & Tanoto, T. A. PD-1/PD-L1 pathway and T-cell exhaustion in chronic hepatitis virus infection. J. Viral Hepat. 17, 453–458 (2010)
Sakuishi, K. et al. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J. Exp. Med. 207, 2187–2194 (2010)
Gadiot, J. et al. Overall survival and PD-L1 expression in metastasized malignant melanoma. Cancer 117, 2192–2201 (2011)
Gao, Q. et al. Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin. Cancer Res. 15, 971–979 (2009)
Brahmer, J. R. et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J. Clin. Oncol. 28, 3167–3175 (2010)
Nishimura, H., Nose, M., Hiai, H., Minato, N. & Honjo, T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11, 141–151 (1999)
Nishimura, H. et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 291, 319–322 (2001)
Ito, T. et al. OX40 ligand shuts down IL-10-producing regulatory T cells. Proc. Natl Acad. Sci. USA 103, 13138–13143 (2006)
Cohen, A. D. et al. Agonist anti-GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell stability and intra-tumor accumulation. PLoS ONE 5, e10436 (2010)
Golovina, T. N. & Vonderheide, R. H. Regulatory T cells: overcoming suppression of T-cell immunity. Cancer J. 16, 342–347 (2010)
Emens, L. A. et al. Timed sequential treatment with cyclophosphamide, doxorubicin, and an allogeneic granulocyte-macrophage colony-stimulating factor-secreting breast tumor vaccine: a chemotherapy dose-ranging factorial study of safety and immune activation. J. Clin. Oncol. 27, 5911–5918 (2009)
Ghiringhelli, F. et al. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol. Immunother. 56, 641–648 (2007)
Muller, A. J. & Scherle, P. A. Targeting the mechanisms of tumoral immune tolerance with small-molecule inhibitors. Nature Rev. Cancer 6, 613–625 (2006)
Manning, E. A. et al. A vascular endothelial growth factor receptor-2 inhibitor enhances antitumor immunity through an immune-based mechanism. Clin. Cancer Res. 13, 3951–3959 (2007)
Shrimali, R. K. et al. Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res. 70, 6171–6180 (2010)
Wang, L. et al. IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway. J. Exp. Med. 206, 1457–1464 (2009)
Chapman, P. B. et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364, 2507–2516 (2011)
Dougan, M. et al. IAP inhibitors enhance co-stimulation to promote tumor immunity. J. Exp. Med. 207, 2195–2206 (2010)
Ferrer, I. R. et al. Cutting edge: rapamycin augments pathogen-specific but not graft-reactive CD8+ T cell responses. J. Immunol. 185, 2004–2008 (2010)
Machiels, J. P. et al. Cyclophosphamide, doxorubicin, and paclitaxel enhance the antitumor immune response of granulocyte/macrophage-colony stimulating factor-secreting whole-cell vaccines in HER-2/neu tolerized mice. Cancer Res. 61, 3689–3697 (2001)
Alagkiozidis, I. et al. Time-dependent cytotoxic drugs selectively cooperate with IL-18 for cancer chemo-immunotherapy. J. Transl. Med. 9, 77 (2011)
Obeid, M. et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nature Med. 13, 54–61 (2006)
Senzer, N. N. et al. Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second-generation oncolytic herpesvirus in patients with unresectable metastatic melanoma. J. Clin. Oncol. 27, 5763–5771 (2009)
Beatty, G. L. et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331, 1612–1616 (2011)Although it is unclear if activation of CD40 works by activating innate or adaptive immunity, the results reported in this paper are impressive.
Schreiber, R. D., Old, L. J. & Smyth, M. J. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331, 1565–1570 (2011)
Nahta, R. & Esteva, F. J. Herceptin: mechanisms of action and resistance. Cancer Lett. 232, 123–138 (2006)
Taylor, C. et al. Augmented HER-2 specific immunity during treatment with trastuzumab and chemotherapy. Clin. Cancer Res. 13, 5133–5143 (2007)
Lewis Phillips, G. D. et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 68, 9280–9290 (2008)
Porter, D. L., Levine, B. L., Kalos, M., Bagg, A. & June, C. H. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365, 725–733 (2011)A recent and clinically impressive attempt at adoptive T-cell therapy using genetically altered, patient-derived T cells.
Gogas, H. et al. Prognostic significance of autoimmunity during treatment of melanoma with interferon. N. Engl. J. Med. 354, 709–718 (2006)
Shin, J. Y., Yoon, I. H., Kim, J. S., Kim, B. & Park, C. G. Vascular endothelial growth factor-induced chemotaxis and IL-10 from T cells. Cell. Immunol. 256, 72–78 (2009)
Gabrilovich, D. I. & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nature Rev. Immunol. 9, 162–174 (2009)
Acknowledgements
This article is dedicated to the memory of our mentor, friend and inspiration Ralph Steinman, whose scientific life was dedicated to advancing the field of immunology in general and cancer immunotherapy in particular (he died shortly before being awarded the Nobel prize).
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I.M. prepared the first draft of the manuscript, which was then modified by G.D., and further modified by G.C.; all three authors worked on and approved the final version.
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I.M. is an employee of Genentech, although no Genentech programs are specifically referred to in this review.
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Mellman, I., Coukos, G. & Dranoff, G. Cancer immunotherapy comes of age. Nature 480, 480–489 (2011). https://doi.org/10.1038/nature10673
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DOI: https://doi.org/10.1038/nature10673
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