Towards Personalized, Tumour-Specific, Therapeutic Vaccines for Cancer
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REVIEWS Towards personalized, tumour-specific, therapeutic vaccines for cancer Zhuting Hu1, Patrick A. Ott1–3 and Catherine J. Wu1–4 Abstract | Cancer vaccines, which are designed to amplify tumour-specific T cell responses through active immunization, have long been envisioned as a key tool of effective cancer immunotherapy. Despite a clear rationale for such vaccines, extensive past efforts were unsuccessful in mediating clinically relevant antitumour activity in humans. Recently, however, next-generation sequencing and novel bioinformatics tools have enabled the systematic discovery of tumour neoantigens, which are highly desirable immunogens because they arise from somatic mutations of the tumour and are therefore tumour specific. As a result of the diversity of tumour neoepitopes between individuals, the development of personalized cancer vaccines is warranted. Here, we review the emerging field of personalized cancer vaccination and discuss recent developments and future directions for this promising treatment strategy. Adoptive cell transfer Methods to harness the exquisite specificity of the individuals with B cell tumours, in which tumour cells (ACT). A form of immune system to eliminate tumours have been under are mostly uniform and express a common dominant immunotherapy in which development since the start of the 20th century1–3. antigen (such as CD19). Solid tumours typically lack a naturally occurring or Several effective strategies have emerged over the common surface antigen target, which poses a consider- genetically engineered past decade, such that immunotherapy is now widely able challenge for this approach. Similarly, despite some tumour-specific lymphocytes, objective response rate which may be autologous considered to be an important additional tool for the promising results from CPB, the (patient’s own) or allogeneic treatment of individuals with cancer. One powerful (ORR) of single-agent CPB is limited to 30% in most (donor), are activated and approach is adoptive cell transfer (ACT)4,5. Autologous tumour types for which activity has been shown9–11 selected in vitro for tumour tumour-reactive T cells derived from tumour-infiltrating (exceptions include microsatellite-instable tumours12, reactivity and expanded to 13 14 reach high numbers for lymphocytes (TILs) and genetically engineered lympho Merkel cell carcinoma and Hodgkin lymphoma , for reinfusion into the patient. cytes that express highly active T cell receptors (TCRs) which ORRs of CPB are 50–80%). Furthermore, anti or chimeric antigen receptors (CARs) have shown potent tumour activity of CPB has been reported as being antitumour activity6. CAR–T cell therapy targeting absent to minimal in several types of malignancy, the B cell antigen CD19 was approved by the US Food including microsatellite-stable colorectal cancer15 and and Drug Administration (FDA) for childhood acute pancreatic cancer16. lymphoblastic leukaemia in 2017. Immune checkpoint Therefore, increasing research attention has shifted blockade 1Department of Medical (CPB) has emerged as another clinically to understanding the biological basis of these variable 7,8 Oncology, Dana-Farber effective approach . Monoclonal antibodies directed responses and to identifying biomarkers that can pre- Cancer Institute, Boston, against the programmed cell death protein 1 (PD1) and dict which patients are likely to respond or not respond Massachusetts 02215, USA. cytotoxic T lymphocyte antigen 4 (CTLA4) signalling to these therapies. Currently, a large number of clini- 2 Department of Medicine, pathways have shown clinical efficacy in a wide range of cal trials assessing combination therapies, which are Brigham and Women’s 17 Hospital, Boston, solid and haematological malignancies, which has led typically based on PD1 targeting, are under way . For Massachusetts 02115, USA. to approvals by the FDA for the treatment of a rapidly CPB, growing evidence supports the idea that individ- 3Harvard Medical School, growing list of tumour types7,8. The distinct immune- uals with tumours that lack pre-existing TILs are less Boston, Massachusetts based strategies of ACT and CPB illustrate the prom- likely to respond to therapy. However, the presence of 02115, USA. 4Broad Institute of MIT and ise of how cancer can be eradicated when active T cells pre-existing T cell responses at the site of the tumour 18 Harvard, Cambridge, recognize their cognate antigens. does not guarantee an antitumour response . One Massachusetts 02142, USA. Nevertheless, both ACT and CPB have limitations, approach to increasing the effectiveness of CPB is the Correspondence to C.J.W. which are reflected by the restricted patient populations combined administration of PD1‑blocking antibodies [email protected] that benefit from either therapy. By design, CAR–T cell and CTLA4‑blocking antibodies, which has been doi:10.1038/nri.2017.131 therapy is directed against a single antigen target, and approved for the treatment of melanoma and is being Published online 11 Dec 2017 clinical efficacy has thus far been achieved primarily in investigated in many other malignancies. Although this 168 | MARCH 2018 | VOLUME 18 www.nature.com/nri ©2018 Mac millan Publishers Li mited, part of Spri nger Nature. All ri ghts reserved. CANCER IMMUNOTHERAPYREVIEWS Chimeric antigen receptors approach can increase response rates in individuals with antitumour immune responses, as extensively reviewed 29,30 (CARs). Engineered receptors advanced melanoma, it also leads to substantially higher elsewhere . Fundamental to the generation of an anti- that are formed by fusing the toxicity19,20. Clearly, alternative approaches are needed tumour immune response is the activation or priming antigen-recognition domain of to achieve maximal benefit from these agents while of naive antigen-specific T cells by professional antigen- a specific antibody to an intracellular signalling domain. minimizing toxicity. presenting cells (APCs), such as dendritic cells (DCs), They can be used to modify A rational approach to achieve this goal is to com- which requires interactions between diverse cell types effector T cells or natural killer bine CPB with a therapy that can presensitize the host and distinct tissue compartments31 (FIG. 2a). In both mice cells. immune system to the tumour. Given their potential and humans, there has been a growing appreciation of to both generate new antigen-specific T cell responses the various defects at the level of antigen processing and Immune checkpoint 32 blockade against tumour cells and amplify existing responses, can- presentation that occur in tumour-bearing hosts , as (CPB). The reversion of T cell cer vaccines may be an effective combinatorial partner well as of the impaired functionality of tumour-specific exhaustion using monoclonal with CPB (FIG. 1). By selecting suitable antigen targets, T cells within the immunosuppressive tumour micro antibodies that inhibit the a potent and tumour-specific immune response can environment due to various mechanisms of primary function of inhibitory immune adaptive immune resistance33 receptors on the cell surface, be induced while minimizing autoimmunity. Recent immune resistance and . 34 such as programmed cell death studies have shown that tumour neoantigens are key Tumour heterogeneity between and within tumours is protein 1 (PD1), PD1 ligand 1 targets for ACT, CPB and therapeutic vaccination21–28. also a major challenge to the development of cancer (PDL1) and cytotoxic T In this Review, we focus on the current development immunotherapy; a crucial factor in this regard is the lymphocyte antigen 4 (CTLA4). of neoantigen-based, personalized, tumour-specific, clonal evolution of tumour cells arising from selective therapeutic vaccines for cancer. pressure, which leads some mutant clones to expand, whereas it leads others to become extinct35. Building cancer vaccines In this context, an open question remains regarding Increased knowledge of methods for antigen discov- whether therapeutic cancer vaccines designed to activate ery and of soluble immunomodulatory factors has APCs can overcome these challenges to facilitate tumour led to our current understanding of the key cellular antigen presentation and to promote an efficient anti- components that are involved in mounting effective tumour immune response. On the basis of our under- standing of how productive antigen-specific immune Naive T cell responses are generated, the active ingredients of cancer vaccines comprise four key components: tumour anti- Vaccination gens, formulations, immune adjuvants and delivery vehi- a Tumour cles, which are described below (FIG. 2b). As we discuss, despite the large number of antigens, adjuvants, delivery De novo tumour- strategies and formulations that have been tested so far, specific T cell comparative data on these different approaches, par- response Tumour cell ticularly in humans, are scarce. Therefore, fundamental questions such as the most effective type of adjuvant Tumour antigens (including different adjuvants for different types of anti- gen), delivery approach, dose, route of administration b Pre-existing tumour-specific and schedule remain unanswered. T cell Tumour antigens The identification of the optimal antigen to target Amplification of for a particular tumour type has long been a priority existing tumour- for the field of cancer immunotherapy (BOXES 1,2). specific T cell Tumour antigens can generally be categorized as being response tumour associated or tumour specific. As described below,