Therapeutic Vaccines for Cancer: an Overview of Clinical Trials
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REVIEWS Therapeutic vaccines for cancer: an overview of clinical trials Ignacio Melero, Gustav Gaudernack, Winald Gerritsen, Christoph Huber, Giorgio Parmiani, Suzy Scholl, Nicholas Thatcher, John Wagstaff, Christoph Zielinski, Ian Faulkner and Håkan Mellstedt Abstract | The therapeutic potential of host-specific and tumour-specific immune responses is well recognized and, after many years, active immunotherapies directed at inducing or augmenting these responses are entering clinical practice. Antitumour immunization is a complex, multi-component task, and the optimal combinations of antigens, adjuvants, delivery vehicles and routes of administration are not yet identified. Active immunotherapy must also address the immunosuppressive and tolerogenic mechanisms deployed by tumours. This Review provides an overview of new results from clinical studies of therapeutic cancer vaccines directed against tumour-associated antigens and discusses their implications for the use of active immunotherapy. Melero, I. et al. Nat. Rev. Clin. Oncol. 11, 509–524 (2014); published online 8 July 2014; doi:10.1038/nrclinonc.2014.111 Centro de Investigación Medica Aplicada (CIMA) Introduction and Clínica Universitaria (CUN), Universidad de Immunotherapies against existing cancers include active, unstable leading to numerous changes in the repertoire Navarra, Spain (I.M.). passive or immunomodulatory strategies. Whereas active of epitopes (so-called neo-antigens) they present, sug- Department of Immunology, immunotherapies increase the ability of the patient’s gesting that, in theory, tumours should be ‘visible’ to The Norwegian Radium own immune system to mount an immune response T lymphocytes. Hospital, Cancer to recognize tumour-associated antigens and eliminate The mechanisms required to mount effective anti Research Institute, University of Oslo, malignant cells, passive immunotherapy involves admin- tumour responses have been reviewed by Mellman and Norway (G.G.). istration of exogenously produced components, such colleagues (Figure 2).3 In the first step, tumour-associated Department of Medical Oncology, VUmc Cancer as lymphocytes or antibodies, to mediate an immune antigens (TAAs) must be directly presented by tumour Center Amsterdam, response. Immunomodulatory agents are not targeted at cells or captured, processed and presented by dendri 1081 HV Amsterdam, specific antigens, but enhance general immune respon- tic cells. The second step requires presence of suitable acti- Netherlands (W.G.). Department of siveness and are intended to amplify anticancer immune vation and/or maturation signals that allow dendritic cells Haematology/Oncology, responses. Although there is some overlap between these to differentiate, migrate to the lymph nodes, and present Johannes Gutenberg University, Germany categories, they provide a useful conceptual framework. TAAs to naive T cells. The third step involves expan (C.H.). San Raffaele Active immunotherapy has been in clinical use for a sion of T cells in sufficient numbers so as to recognize Foundation Scientific Institute, Italy (G.P.). long time (Figure 1 (Timeline)). The concept that the and eliminate tumour cells. However, in the absence of Department of Medical immune system can be harnessed by vaccination to suitable maturation signals, antigen presentation leads to Oncology, Institut Curie, specifically eradicate malignant cells has been repeat- T‑cell anergy or production of regulatory T cells (T ) France (S.S.). CRC REG Department of Medical edly demonstrated in animal models, but was sometimes that suppress effector T cells. Finally, antigen-educated Oncology, Christie questioned by the results of trials in humans.1,2 Malignant T cells must leave the lymph node, traffic to infiltrate the Hospital NHS Trust, UK (N.T.). South West cells always harbour mutations and are often genetically tumour and persist for long enough to kill the malignant Wales Cancer Institute, cells. In this Review, we focus on immunotherapies that Singleton Hospital, UK Competing interests aim to induce or augment immune responses against TAA. (J.W.). Clinical I.M. has provided consultancy to and received honoraria and Division of Oncology, research funding from Bristol-Myers Squibb. G.G. is employed by The use of vaccines directed against oncogenic viruses for Department of Ultimovacs AS and has stocks in Ultimovacs AS and Targovax AS the prevention or treatment of cancer are not discussed. Medicine I, and he has provided consultancy to and received honoraria from Comprehensive Cancer KAEL-GemVax and Lytix AS. C.H. is an employee and has stocks Centre Vienna, Medical Principles of active immunotherapy in BioNTech and GANYMED Pharmaceuticals, has provided University Vienna, Antigens Austria (C.Z.). consultancy to Apceth, Bayer, Baxter, BioNTech, GANYMED, International Medical immatics, Merck KGaA, SuppreMol and TRON, and received Active immunotherapy encompasses a diverse range Press, UK (I.F.). Cancer honoraria from the Clinical Cancer Research (CCR, UK), Karolinska of strategies, some of which target multiple, undefined Centre Karolinska, University, Stockholm (Sweden), Kurume Cluster (Japan), and antigens whereas others specifically target a particular Department of Oncology, Swiss National Science Foundation. G.P. has provided consultancy Karolinska University to CureVac and received honoraria from Recombio. S.S. and N.T. antigen or a group of antigens. Natural immune surveil- Hospital, have provided consultancy and received honoraria from Merck SE‑171 76 Stockholm, lance and artificial immunotherapy can lead to selective Sweden (H.M.). KGaA and KAELGemVax, and has stocks in Kancera AB. I.F. has survival of tumour cells that lack immunogenic epi received a research grant from Merck KGaA. Views and opinions topes, a process called immunoediting.4 Polyvalent vac- Correspondence to: H.M. described do not necessarily reflect those of Merck KGaA. hakan.mellstedt@ H.M. has received honoraria and research funding from Merck cines (autologous or allogeneic) are derived from whole karolinska.se KGaA. W.G., J.W. and C.Z. declare no competing interests. tumour cells or dendritic cells—fused with tumour cells, NATURE REVIEWS | CLINICAL ONCOLOGY VOLUME 11 | SEPTEMBER 2014 | 509 © 2014 Macmillan Publishers Limited. All rights reserved REVIEWS Key points Many TAAs have been identified, some of which are shared with normal tissues, whereas others are unique to ■ Development of vaccines for the treatment of cancer has posed many ■ tumours (Box 1). Shared TAAs include cancer–testis and challenges, but results from some recent studies have confirmed the potential for clinical benefit differentiation antigens that are either silent or expressed ■■ Progress has been driven by advances in our understanding of cancer at low levels in normal tissues, but are transcription- immunology and, in particular, the nature and dynamics of the tumour ally activated in certain tumours. Individual TAAs are microenvironment characteristic of single neoplasms, but the identification ■■ Many clinical trials may have failed to adequately account for how vaccines of these TAAs through mass screening is currently not differ from other cancer therapies, and for immunosuppressive mechanisms feasible in routine practice. Immune peptidome analysis that operate in the tumour microenvironment of HLA-bound peptides,13 and whole-exome sequenc- ■■ Predictive biomarkers that can identify subpopulations of patients most likely 14 to benefit from active immunotherapy are needed ing of tumour cells coupled with epitope prediction by ■■ Evidence from clinical trials suggest that clinical benefit might be greatest bioinformatics are being used to identify new TAAs and in patients with less advanced-stage malignancies disease biomarkers and might bring truly personalized ■■ Future strategies should include steps to modify the tumour microenvironment immunotherapy a step closer to becoming an affordable to optimize tumour-specific immune responses reality in clinical practice. Adjuvants and delivery vehicles loaded with tumour lysates, or transfected with tumour- Adjuvants are substances or interventions that, when derived RNA or DNA—and should in theory be less combined with an antigen, enhance antigen immuno susceptible to tumour antigen loss. Additionally, poly genicity and elicit the desired immune response. In valent vaccines are likely to carry mutations that drive cancer therapy, the desired response involves pre- the tumour’s malignant phenotype. However, only a frac- dominantly the activation of IFNγ-producing type 1 tion of the targeted antigens will be specific to tumour T helper cells (TH1) and cytotoxic T lymphocytes (CTLs). cells, and the production of personalized polyvalent Classical adjuvants—such as alum, used in prophy immunotherapies is often time and labour intensive. lactic vaccines—promote type 2 T helper cells (TH2)- Antigen-specific active immunotherapies are more dependent humoral immunity, but rarely induce strong 15 suitable for reproducible, large-scale production than TH1-dependent responses. This shortcoming has driven whole tumour or dendritic cell vaccines. Most antigen- the development of a range of new adjuvants (Box 1). specific immunotherapies have incorporated a single Water-in-oil emulsions, such as Freund’s adjuvants, antigen, and narrow epitope specificity might have have been used widely in cancer vaccines, but failed to contributed to lack of efficacy in some trials.5,6 Moreover, prove efficacy in clinical trials.