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Therapeutic Cancer Vaccine: Building the Future from Lessons of the Past

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Therapeutic Cancer Vaccine: Building the Future from Lessons of the Past Seminars in Immunopathology (2019) 41:69–85 https://doi.org/10.1007/s00281-018-0691-z REVIEW Therapeutic cancer vaccine: building the future from lessons of the past T. Tran1,2 & C. Blanc1,2 & C. Granier1,2 & A. Saldmann1,2 & C. Tanchot1,2 & Eric Tartour1,2,3,4 Received: 6 June 2018 /Accepted: 11 June 2018 /Published online: 5 July 2018 # Springer-Verlag GmbH Germany, part of Springer Nature 2018 Abstract Anti-cancer vaccines have raised many hopes from the start of immunotherapy but have not yet been clinically successful. The few positive results of anti-cancer vaccines have been observed in clinical situations of low tumor burden or preneoplastic lesions. Several new concepts and new results reposition this therapeutic approach in the field of immunotherapy. Indeed, cancers that respond to anti-PD-1/PD-L1 (20–30%) are those that are infiltrated by anti-tumor T cells with an inflammatory infiltrate. However, 70% of cancers do not appear to have an anti-tumor immune reaction in the tumor microenvironment. To induce this anti-tumor immunity, therapeutic combinations between vaccines and anti-PD-1/PD-L1 are being evaluated. In addition, the identification of neoepitopes against which the immune system is less tolerated is giving rise to a new enthusiasm by the first clinical results of the vaccine including these neoepitopes in humans. The ability of anti-cancer vaccines to induce a population of anti-tumor T cells called memory resident T cells that play an important role in immunosurveillance is also a new criterion to consider in the design of therapeutic vaccines. Keywords Cancer vaccine . Checkpoint inhibitor . Tumor antigens . CD8+ T cells . Resident memory T cells . Therapeutic combination Introduction CAR T cells tends to marginalize anti-cancer vaccines in this therapeutic field. Nevertheless, a better understanding of the Anti-cancer vaccines began to develop with the identification mechanisms of resistance to these vaccines, the need for a of tumor-associated antigens in the early 1990s [1]. Despite preexisting immune response for the success of PD-1/PD- some clinical successes and a cancer vaccine approved in L1-blocking antibodies, and the identification of mutated tu- prostate cancer patients [2], their clinical position in cancer mor antigens as novel targets for vaccine foster new clinical therapy remains limited. The recent emergence of new immu- development of cancer vaccines [3]. notherapeutic strategies based on blocking inhibitory check- points (anti-PD-1/PD-L1, anti-CTLA-4) or cellular therapy by The right choice of tumor antigens in the design of cancer vaccine T. Tran and C. Blanc contributed equally to this work. The aim of cancer immunotherapy is to stimulate the immune This article is a contribution to the special issue on Anti-cancer system against tumors cells while preserving normal tissues. Immunotherapy: Breakthroughs and Future Strategies - Guest Editor: Mads Hald Andersen Tumors express antigens that could be recognized by the im- mune system. Humoral and cellular immune responses to * Eric Tartour tumor-specific antigens, either spontaneously or vaccination- [email protected] induced, have been detected in cancer patients [4]. The first tumor antigen recognized by T cells, MAGE-A1, 1 INSERM U970, Paris Cardiovascular Research Center (PARCC), was discovered in 1991 [1, 5], and many more tumor antigens Paris, France have been identified since then [4]. 2 Université Paris Descartes, Sorbonne Paris Cité, Paris, France Tumor antigens can be classified according to their expres- 3 Hôpital Européen Georges Pompidou, Laboratory of Immunology, sion and localization, and two main categories of tumor anti- Assistance Publique des Hôpitaux de Paris, Paris, France gens can be distinguished: tumor associated antigens (TAA) 4 Equipe Labellisée Ligue Nationale contre le Cancer, Paris, France and tumor specific antigens (TSA) (Fig. 1). 70 Semin Immunopathol (2019) 41:69–85 TAA : T nadetaicossaromu negit ST A : tumor specific angen Angen category Differenciaon Overexpressed Cancer tess angen Oncogenic virus- Mutated angen angen angen derived angen (neoangen) Descripon Expressed on tumor cells Expressed on normal Normally expressed in Absent in normal cells Absent in normal cells and normal cells originate cells at low levels germs cells but Arise from ongenic viral Arise from somac from the same ssu Overexpressed on aberrantly expressed in protein mutaon tumors cells tumor cells Can be subject to central toleranceNo t subject to central tolerance Locaon of expression Mart1, gp100 in melanomas Her2/neu in breast MAGE-3 in melanoma, HPV oncoproteins E6 and P53 mutaons in various and ovarian cancers, bladder cancers E7 in HPV associated head cancer PSA, PAP in prostate kidney carcinomas and neck and gynecologic RAS mutaons in various cancers NY-ESO1 in melanomas cancers cancers MUC1 in lung and and ovarian cancers Bcl-Abl fusion protein in breast HBs Hepas B virus in leukemia adenocarcinomas hepatocarcinoma Examples of cancer Prostate cancer : Overexpressed NSC lung cancer : HPV associated cervical Melanoma : vaccines targeng the Sipuleucel-T : autologous Her2/neu breast and vaccinaon with MAGE- intraepithelial cancer : vaccinaon with synthec angen DC-based vaccine against gastric cancers : 3 protein, MAGRIT ( VGX-3100, synthec RNAs coding for mutated PAP, approved in US and in Trastuzumab, an phase 3 trial)(15) plasmide coding for pepdes ( phase Itrial) Europe (2) Her2/neu monoclonal HPV16-18 E6 and E7 (35) Ab, associated with proteins, ( phase 2b trial) chemotheray Melanoma and sarcoma (130) vaccinaon with : adopve transfert of neopepdes (Phase I trial) autologous T cells (34) transduced with NY- ESO1 TCR (12) No central tolerance Tumor specificity Immunogenicity Personalized immunotherapy Central tolerance : potenal auto- immunity a er vaccinaon Low tumor specificity Well idenfied in a wide range of tumors Fig. 1 Tumor antigens: main characteristics TAA are expressed in normal cells and include differentia- Her2/neu monoclonal antibodies (trastuzumab, pertuzumab) tion antigens, overexpressed antigens, and cancer testis anti- are approved for the treatment of Her2neu overexpressed gens. Many studies have shown that TAA are immunogenic breast and gastric cancers [7]. Moreover, many clinical trials and are able to induce specific T cells [6]. Differentiation using peptides or proteins derived from Her2neu induce cyto- antigens are expressed only in tumor cells and in the healthy toxic antigen-specific T cell responses in metastatic breast tissue of origin; for example, the prostatic specific antigens cancer [8, 9]. (PSA) and prostatic acid phosphatase (PAP) are found in nor- Cancer testis antigens are normally expressed in germ cells mal prostate and in cancer prostate, and MART1/Melan-A in (testis, fetal ovaries), whereas they are aberrantly expressed in normal melanocytes an in melanoma. Sipuleucel-T, an autol- various tumors such as lung or bladder cancers and in melano- ogous DC-based immunotherapy targeting PAP, was the first ma [10]. Many cancer testis antigens have been identified like FDA-approved cancer vaccine for metastatic castration- MAGE family antigens or NY-ESO1. These antigens are more resistant prostate cancer [2]. Tumors cells can also overex- attractive targets for immunotherapy than the previous one due press proteins, which are normally expressed at low levels in to their restricted expression in tumor cells despite their expres- healthy cells (e.g., Her2/neu, TERT (telomerase), survivin). sion in germ cells, as these cells do not express MHC mole- Some of these overexpressed antigens, such as Her2/neu in cules, thus precluding antigen presentation to T cells [11]. ovarian, breast, and gastric cancers, can directly participate in In many clinical studies, the targeting of these antigens in the oncogenic process by promoting growth and survival of melanoma, lung or ovarian cancer, elicits antigen-specific tumor cells. Overexpressed proteins in tumors are potential CD4+ and CD8+ Tcell responses. However, despite their dem- targets, and may provide a Tcell specific response, as a thresh- onstrated immunogenicity, they were not associated with clin- old level of antigen is required for presentation and recogni- ical benefit [12–15]. tion by T cells. Immunotherapies targeting the overexpressed So, TAA are attractive targets in cancer immunotherapy as antigen Her2/neu have proven clinically efficacy. The anti- they are shared antigens across many tumors able to elicit Semin Immunopathol (2019) 41:69–85 71 specific T cell and humoral responses. However, as TAA are for these neoantigens. Results from mice reported than from expressed in normal cells, specific mechanisms of tolerance 1000 mutations identified, only 10–40 appear to be may have occurred for some of them. In some cases, second- immunogenic. ary to the negative thymic selection of self-antigen, these TAA Recent clinical trials with personalized neoantigen vac- elicit low avidity rather than high-avidity T cells. Interestingly, cines (DC-based vaccine, long neopeptides, or synthetics some TAA antigens such as hypoglycosylated MUC1 are ab- RNA coding for neopeptides) have been able to induce effec- normally expressed during some acute viral infection such as tive T cell response and provide some clinical benefits in mel- in mumps and trigger an immune response. It has been shown anoma after vaccination [34–36]. that a history of childhood mumps may protect against ovarian These studies confirm the feasibility of personalized cancer [16].
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