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Cancer vaccinesAuthor(s): Lisa H Butterfield Source: BMJ: British Medical Journal , Vol. 350 (20 Apr 2015 - 26 Apr 2015) Published by: BMJ Stable URL: https://www.jstor.org/stable/10.2307/26519563

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Cancer

Lisa H Butterfield

Departments of Medicine, Surgery and Immunology, University of ABSTRACT Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA Cancer vaccines are designed to promote tumor specific immune responses, Correspondence to: L H Butterfield particularly cytotoxic CD8 positive T cells that are specific to tumor . The [email protected] Cite this as: BMJ 2015;350:h988 earliest vaccines, which were developed in 1994-95, tested non-mutated, shared doi: 10.1136/bmj.h988 tumor associated antigens that had been shown to be immunogenic and capable of inducing clinical responses in a minority of people with late stage cancer. Technological developments in the past few years have enabled the investigation of vaccines that target mutated antigens that are patient specific. Several platforms for cancer are being tested, including peptides, proteins, presenting cells, tumor cells, and viral vectors. Standard of care treatments, such as surgery and ablation, chemotherapy, and radiotherapy, can also induce antitumor immunity, thereby having cancer effects. The monitoring of patients’ immune responses at baseline and after standard of care treatment is shedding light on immune biomarkers. Combination therapies are being tested in clinical trials and are likely to be the best approach to improving patient outcomes.

Introduction ACRONYMS Cancer is one of the major killers in the Western world, CEA: Carcinoembryonic antigen with lung, breast, prostate, and colorectal being GM-CSF: Granulocyte-macrophage colony stimulating the most common. As demographics and treatments factor change, thyroid, liver, and pancreatic cancers are pre- HPV: Human papillomavirus dicted to increase significantly.1 Each histological type HMGB1: High mobility group B1 of cancer contains several molecularly defined subtypes, hTERT: Human telomerase reverse transcriptase which have altered gene expression patterns and differ- IFA: Incomplete Freund’s adjuvant ing arrays of mutations.2 Several clinical approaches to IL: Interleukin the are available, including surgery, KLH: Keyhole limpet hemocyanin chemotherapy, radiotherapy, and treatment with small MDSC: Myeloid derived suppressor cell molecule signaling pathway inhibitors (such as vemu- NCI: National Cancer Institute rafenib for BRAF mutant ), which can each PADRE peptides: Pan-DR binding synthetic helper peptides be used in specific clinical settings. Importantly, each of PSA: Prostate specific antigen these “standard” approaches has been shown to modu- TLR: Toll-like receptor late antitumor immunity. Treg: Circulating regulatory T cell It has been known for decades that the can be activated against tumors spontaneously, despite lation of the tumor. Importantly, standard of care cancer the lack (in most cancers) of an infectious agent. In mela- treatments (surgery and ablation, chemotherapy, and noma and renal cancer, the presence of tumor infiltrating radiotherapy) and small molecule signaling pathway lymphocytes (TILs; see Glossary) in tumor deposits is a inhibitors (see Glossary) can have similar effects to can- positive prognostic factor.3 More recently, CD8+ memory cer vaccines. They do this by increasing the expression of T cells (see Glossary) have been identified as a significant tumor antigens within the tumor or causing the release of positive prognostic factor in ,4 a tumor antigens from dying tumor cells and by promoting anti- type not previously considered to be “immunogenic.” tumor immunity for therapeutic benefit.7 8 TILs are also a positive prognostic factor in breast and This review summarizes the field of cancer vaccination, ovarian cancer.5 6 including different types of tumor antigens, approaches Cancer vaccination comprises an array of approaches to inducing antitumor immunity, and the preclinical and that seek to generate, amplify, or skew (or a combina- clinical data so far. It also discusses aspects of standard of tion thereof) antitumor immunity. To accomplish this care treatments that promote antitumor immunity. Recent goal many approaches involve administration of tumor controversies in the field and the importance of careful antigens, often with antigen presenting cells (APCs; ; see immunologic monitoring of patients in clinical trials are Glossary) or other immune modulators, or direct modu- also covered.

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Prevalence of cancer GLOSSARY Cancer is a leading cause of death worldwide. Currently, Adjuvants: Non-antigen specific triggers of the immune system that increase the immune more than 8.2 million people die from cancer each year, response to an associated antigen. Adjuvants can include components of infectious agents, and the current burden of 14 million cases of cancer a immune cell growth factors, and tissue damage signals year is expected to increase to 22 million cases in the next Allogeneic cell lines: Cell lines derived from another person; autologous cell lines are derived from the person being treated two decades. The most common types of cancer world- Antigen presenting cells (APCs): Cells that capture proteins by various mechanisms and wide are lung, liver, stomach, colorectal, and breast can- 9 process and present them in association with MHC class I and II molecules to activate cers. In the United States, the most common cancers are CD8+ and CD4+ T cells, respectively. APCs include dendritic cells, B cells, monocytes, and prostate or breast, lung, and colorectal cancers, and the macrophages highest mortality is from lung, breast or prostate, colo- Avidity: Strength of molecular interaction rectal, and pancreatic cancers.10 The molecular charac- Chimeric antigen receptor (CAR) therapeutics: Use of an antibody-T cell receptor fusion terization of human cancers has shown the complexity molecule to retarget a transfected cell to the specificity of the antibody with the signaling of of individual tumors and the diversity between tumors the T cell receptor in different patients. Therefore, a more personalized + CD8 T cells: T cells that can be cytotoxic (“killer” cells) or secretors of (and other approach to treatment may maximize benefit. Treatments molecules). They are triggered by recognition of peptide-MHC class I complexes on the are increasingly changing from being tissue based to surface of cells being based on the mutation profile of the specific tumor. CD4+ T cells: T cells that generally secrete cytokines to support (or “help”) T cells and B cells For example, anti-Her2 antibody (trastuzumab) was origi- Checkpoint blockade: Antibody mediated blockade of a molecule that serves as a nally used just for but it is now used for “checkpoint” for the immune response—for example the use of anti-CTLA-4 (anti-cytotoxic T lymphocyte associated protein 4) and anti-PD-1 (anti-programmed death 1) or anti-PD-L1 other tumors with increased cell surface Her2. (anti-programmed death ligand-1). CpG molecule: Section of DNA comprising cytosine then guanine, with a phosphate group Sources and selection criteria in between In May and June 2014, I performed PubMed searches for : Linear section of a protein (peptide) that is processed and presented by APCs in “cancer vaccine” and “ and cancer” to association with MHC class I and II molecules and is recognized by T cell receptors clonally identify recent publications (within the past five years) expressed on the surface of CD8+ and CD4+ T cells. CD8+ T cells recognize 8-11 amino acid and accessed World Health Organization and American + long peptides in association with MHC class I molecules and CD4 T cells recognize longer Cancer Society websites for current cancer statistics. The (13-17 amino acids) peptides in association with MHC class II molecules recent presentations at the 2013 Foreign pathogen pattern recognition receptors: Family of receptors that recognize annual Society for Immunotherapy of Cancer and at the pathogen molecules shared by multiple pathogens, such as lipopolysaccharide or flagellin 2013 and 2014 American Society for Clinical Oncology A foreign protein designed to promote a non-specific immune Foreign helper proteins: meetings were also reviewed. Peer reviewed publica- response to “help” or assist in the desired immune response tions in English language journals covering the areas of G-Vax: Tumor cells transfected to express high amounts of granulocyte-macrophage colony investigation were included and studies that have led to stimulating factor + clinical trials were prioritized. I also prioritized studies Heterologous helper peptide: A peptide that is used to activate CD4 T cells against a non- cancer related protein (such as tetanus ) with the goal that the tetanus specific CD4+ that included immune monitoring and biomarkers of helper T cells will promote cancer specific CD8+ T cells as a bystander effect response. Induced antibody neutralization: An antibody response that blocks an interaction between other proteins Vaccination approaches MART-1/Melan-A, tyrosinase, and gp100: Antigens that are overexpressed in melanoma Vaccination with target antigens: tumor specific and MHC class I and II molecules: Major histocompatibility molecules that help to define an tumor associated antigens individual’s tissue type The most common approach to cancer vaccination MHC restriction: MHC class I molecules present intracellular peptides to CD8+ T cells; MHC involves with shared tumor antigens + class II molecules present mostly extracellular peptides to CD4 T cells expressed by many different patients’ tumors. The earli- MHC restricted epitope: A short, linear string of amino acids from a protein that is digested est tumor associated antigens (TAAs; see Glossary) identi- through a series of steps involving several intracellular proteases that fits into the peptide- fied were proteins that were overexpressed in tumor cells binding groove of an MHC molecule expressed by the individual but minimally expressed in untransformed normal tis- Oncolytic : Viruses that lyse host tumor cells during viral replication sues.11‑14 Antigens were also identified after the cloning Prime boost: To start, or “prime,” an immune response with one type of vaccine and of genes that encoded proteins that make up (see enhance, or “boost,” the response with a different type of vaccine Glossary) recognized by tumor reactive TILs. PolyIC: a string of double stranded RNA of inosine-cytosine molecules; polyICLC: a string The initial classes of antigens used in cancer vaccines of double stranded RNA that includes inosine and cytosine molecules stabilized with polylysine, and that is meant to mimic viral infection included overexpressed antigens, cancer-testis antigens, oncofetal antigens, and mutated antigens (or tumor spe- Small molecule signaling pathway inhibitors: Small molecules that are used as drugs to 15 inhibit intracellular signaling pathways cific (private) antigens) (table). Transactivator early genes: Viral genes expressed early after infection that turn on other viral genes Overexpressed antigens Transfection: Transfer of DNA or RNA into a cell Overexpressed antigens are proteins that are amplified Tumor infiltrating lymphocytes (TILs): Generally CD8+ and CD4+ T cells that spontaneously at the DNA, mRNA, or protein level and are therefore infiltrate tumor deposits. TILs may also include B, natural killer, or suppressive cells expressed at a much higher level in tumor cells than in Tumor associated antigen (TAA): A protein expressed by a tumor that can be immunogenic adjacent normal tissue. They include carcinoembryonic WT-1: Wilms’s tumor 1—a shared tumor associated antigen antigen (CEA; colorectal cancer and others); prostate specific antigen (PSA; ); Her2/neu (breast

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Strengths and weaknesses of different types of tumor antigens MHC class I or II molecules (see Glossary), and that this would be difficult to predict and virtually impossible to Antigens Examples Strengths Weaknesses 25 Tumor associated MART-1, gp100, Highly upregulated in many tumors; Activated T cell clones may be target by vaccination in a clinical trial. But—as sequenc- antigens CEA, PSA low level expression in some normal weak; antigens are not drivers of ing technology has improved, and software capable of tissues; immunogenic oncogenesis predicting processed, presented, and properly binding Mutated, tumor p53, RAS, unique Activate high avidity and effective T Difficult to identify and use for peptide epitopes has improved—highly therapeutic T cells specific antigens mutations cells; may be tumor drivers vaccination that target these mutated patient specific mutations have Cancer-testis NY-ESO-1, MAGE-A3 Expressed by many tumor types Activated T cell clones may be 26 antigens and in immunoprivileged sites, weak; antigens are not drivers of begun to be identified. Currently, it takes a long time immunogenic oncogenesis to identify targetable, patient specific mutations, which Oncofetal antigens α fetoprotein Highly upregulated in many tumors; Activated T cell clones may be results in treatment delay; however, several investigators not expressed in normal adult weak; antigens are not drivers of are focusing on ways to identify such tumor specific tar- tissues; immunogenic oncogenesis CEA=carcinoembryonic antigen; PSA=prostate specific antigen. gets more quickly.

cancer); melanoma lineage antigens such as MART-1/ Vaccination with autologous tumor cells Melan-A, tyrosinase, and gp100 (see Glossary); and This technique involves a therapeutic agent that is pro- mucin 1 (several cancers including colorectal and pan- duced by isolating tumor cells from a patient and process- creatic cancer). All have shown efficacy as targets in vitro ing them into a vaccine in vitro; the vaccine is then given and in mouse models, and have been tested in clinical to the same patient. The vaccine would include all known trials with some objective RECIST (response evaluation tumor specific mutations and could take the form of killed criteria in solid tumors) clinical responses.168 ‑1 A concern tumor cells; tumor cells engineered with a such about targeting such TAAs is that the highest avidity (see as granulocyte-macrophage colony stimulating factor Glossary) T cells specific to these normal self antigens (GM-CSF) to improve immunogenicity; tumor lysates, may be deleted, leaving only less effective, lower avidity with or without adjuvants (see Glossary); or a tumor T cells to stimulate. lysate pulsed with APCs, such as dendritic cells. Tumors also express mostly normal self proteins, Cancer-testis antigens which could promote autoimmunity if presented in the Cancer-testis antigens are a class of proteins that are environment of an ongoing immune response. It is not expressed in a proportion of most tumor tissue types and necessary for the tumor specific mutations that could be in germ cells, which because of their physiologic loca- used in tumor vaccination approaches to be identified tion are ignored by the immune system. Such antigens for their role in antitumor responses to be tested. Despite include the large MAGE-A, MAGE-B, and MAGE-C fami- remaining technical hurdles in identifying patient spe- lies, and NY-ESO-1. These antigens have been tested in cific targetable mutations, many investigators are focus- human clinical trials (because of the lack of expression in ing on utilizing these mutated antigens, which have mice, the ability to model therapeutic strategies in mouse been shown to be capable of inducing a potent and avid models is limited) and implicated in some therapeutic immune response.27 responses.19 Determinant spreading Oncofetal antigens Although the identification of an optimal antigen is Oncofetal antigens are normal fetal antigens that are important for directing antitumor immunity to the tumor, turned off during development but turned back on in the spread of the immune response from one antigen to some transformed cells; they include oncofetal antigen another antigen expressed in the same tissue (“deter- and α fetoprotein. These antigens have been tested in minant spreading”28 or “epitope spreading”) has been vitro, in murine models, and in clinical trials and have linked to superior clinical outcome.29‑35 This spontane- shown immunogenicity and some efficacy as targets.20‑23 ous phenomenon has been studied in autoimmune dis- In 2008 the National Cancer Institute (NCI) organized eases and has also been noted in cancer immunotherapy a workshop to rank and prioritize the antigens identified studies. at that time, publishing the highest priority, most experi- The phenomenon of in vivo cross presentation of mentally confirmed tumor rejection antigens.24 Most of tumor derived antigens released in one wave of T cell the antigens were non-mutated shared antigens, and they attack to promote subsequent waves of antitumor T cells were ranked according to agreed criteria, including ther- directed against different antigens may be an important apeutic function, immunogenicity, oncogenicity, tumor mechanism for tumor rejection (fig 1).33 A vaccine that specificity, frequency of overexpression (in tumors and targets shared antigens can facilitate subsequent rounds in patients), and expression in cancer stem cells. None of immunity to unidentified, patient specific mutated of the classes of described above is truly antigens and may induce clinically significant tumor tumor specific. rejection. The observation from many clinical trials that Tumor specific mutations have been known for dec- the immune response to vaccine delivered antigens does ades and common mutations in the RAS oncogene and not correlate with clinical outcome may be related to P53 tumor suppressor gene have been identified. How- this mechanism.29 The most important role of vaccines ever, it was thought unlikely that such mutations would containing TAAs may be to induce determinant spread result in a processed, presented, and immunogenic MHC to tumor specific antigens that activate higher avidity T restricted epitope (see Glossary) in sufficiently common cells, which more effectively mediate tumor rejection. The

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Fig 1 | Determinant, or epitope, spreading. Central to this phenomenon is the activation of specific CD8+ T cells that recognize a particular MHC class I restricted peptide (derived from a tumor antigen) expressed on the surface of a tumor cell. These activated T cells kill and lyse the tumor cell, resulting in the release of a variety of tumor antigens. Endogenous antigen presenting cells (APCs) take up and present these newly released antigens to additional T cells that specifically recognize the newly released antigens, thereby broadening and spreading the response from one to multiple antigens

in vivo mechanism of cross priming (see Glossary) may Another common approach to activating TAA specific­ also result in autoimmunity,36 which has been found to be CD8+ T cells is to include autologous APCs, such as a biomarker of clinical response to interferon in patients dendritic cells, in TAA based vaccines. This approach with melanoma.37 takes into account the observation that tumors can have Many antigens have been identified as suitable for negative effects on endogenous APCs.39 Antitumor T cell cancer vaccination, but the most important step may responses can be triggered more effectively by preparing be the approach taken and the vehicle used for immune optimized APCs ex vivo, without the presence of tumor a­ctivation.38 derived factors but with specific positive growth factor and immune signals. Types of cancer vaccines A third strategy makes use of tumor cells (and, there- Most cancer vaccines aim to activate tumor specific CD8+ fore, a complex and incompletely characterized array of cytotoxic T cells because studies in mice support the key antigens including tumor specific mutated antigens), often therapeutic role played by these cells. engineered with cytokines such as GM-CSF or formulated The most common vaccination strategies used to with adjuvants (or both). These cells carry the full array of activate CD8+ T cells have been based on MHC class I tumor specific mutations and all of the patient’s MHC class restricted peptide epitopes on TAAs. These have been I and II molecules. Another strategy uses the naturally delivered in a variety of adjuvant formulations (including efficient infectivity of viruses to infect cells in vivo with cytokines and toll-like receptor (TLR) ligands) to promote encoded tumor antigens. Viral strategies also include the in vivo presentation by endogenous APCs. use of oncolytic viruses (see Glossary) that are engineered Peptide based vaccines take advantage of the ability to replicate specifically in tumor cells (fig 2). of computer algorithms to screen protein amino acid One therapeutic cancer vaccine—Sipuleucel-T manu- sequences for candidate MHC class I restricted pep- factured by Dendreon—has been approved by the Food tide epitopes derived from TAAs. Candidate epitopes and Drug Administration. It consists of autologous anti- are then tested experimentally for those that bind gen presenting cells loaded with the TAA prostatic acid commonly expressed HLA molecules, are naturally phosphatase and GM-CSF. It is approved for metastatic processed and presented by tumor cells, and are immu- prostate cancer on the basis of a 4.1 month improvement nogenic (capable of activating CD8+ cells). Many have in overall survival seen in data from large scale phase III also been tested in mouse models (to either mouse self clinical trials.40 antigen homologs, highly similar human antigens, or transfected (see Glossary)­ or transgenic models), and Peptide based strategies were found to have the therapeutic properties of a tumor One of the most common approaches for cancer vacci- rejection antigen. nation is the delivery of MHC class I restricted peptide

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Fig 2 | Cancer vaccine 9$&&,1(6 approaches. Vaccines 27+(5675$7(*,(6:,7+ include short peptides, 9$&&,1(/,.(())(&76 full length proteins (with 7XPRUDEODWLRQ and without adjuvants), &KHPRWKHUDS\ viruses, DNA (or plus 3HSWLGHV 5DGLRWKHUDS\ DNA in sequence), dendritic 6PDOOPROHFXOHV 2QFRO\WLFYLUXVHV cells, tumor cells (killed), and tumor lysates. These $GMXYDQWV elements can be modified, 3URWHLQV added to adjuvants, or combined together. Standard of care approaches 9LUXV such as tumor ablation, certain chemotherapies, %RRVWRUHOHFWURSRUDWLRQ %ORRG and radiation can also ,PPXQRORJLF have vaccine-like effects, '1$ PRQLWRULQJ 7XPRU promoting tumor specific %ORRG immunity 'HQGULWLFFHOOV

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epitopes derived from shared TAAs with the aim of acti- promoting systemic immunity.52 Hence, as peptide based vating rare specific CD8+ T cell clones that react against vaccines are tested, optimal adjuvants and formulations self antigens. Data from animal models support the of these vaccines are still being identified. Recent clinical potential for such vaccines to have a substantial thera- trials of peptide based vaccines were recently reviewed.53 peutic effect.41‑43 A benefit of peptide based approaches is that nine to Peptides formulated in adjuvants (such as Montanide, 10 amino acid peptides are simple and cheap to manufac- which is analogous to incomplete Freund’s adjuvant ture. Large scale manufacture is possible and the peptides (IFA)) with or without cytokines, such as GM-CSF and are stable when stored and shipped. interferon γ, or TLR agonists, have shown clinical ben- Unfortunately, however, because of HLA restriction, efit (partial responses, complete responses, and durable people who do not express common HLA types cannot disease stabilization) in small and large scale clinical tri- be treated with this type of vaccine. In addition, the usual als.44‑46 In smaller trials, peptides on APCs such as den- MHC class I binding short peptides do not activate CD4+ dritic cells have also resulted in positive immune and helper T cells, which can limit the functionality of CD8+ clinical effects.29 47 cytotoxic T cells. This problem has been overcome by the Vaccines based on one or more peptides can be injected addition of non-tumor specific help (inclusion of keyhole alone or with the simple adjuvant Montanide ISA-51 com- limpet hemocyanin (KLH), tetanus, or (pan-DR binding bined with a cytokine (such as GM-CSF to activate APCs), synthetic helper (PADRE) peptides), although data are with other adjuvants (such as a specific TLR ligand to acti- limited over the nature of the “help” provided by heter- vate and mature APCs), or with the peptides pulsed on to ologous helper peptides (see Glossary). autologous antigen presenting cells (or a combination of Another strategy that has shown significant clini- these tactics). Montanide ISA-51, an oil in water emulsion cal efficacy is the use of synthetic peptides that are similar to IFA that is used in mouse models, has led to long enough to include multiple MHC class I and II activation of TAA specific cytotoxic T cells.48‑50 Data sug- epitopes.54 55 These 23-45 amino acid long peptides, gested that altering the production of Montanide from a delivered subcutaneously, have been shown to be espe- beef source to an olive oil source changed its adjuvantic- cially effective, possibly because of a more efficient ity.51 A recently identified concern is that IFA can result in processing and presentation pathway, which leads to the accumulation of T cells at vaccination sites instead of superior T cell activation.56

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By contrast, a whole tumor antigen protein approach, vaccines are safe, feasible, and immunogenic, and that which also allows for uptake, processing, and presenta- they can promote clinically significant tumor regression tion of multiple MHC class II and MHC class I antigen in some patients.66‑68 peptides (with perhaps less efficiency), has been tested in Several important clinical trials of dendritic cell vac- phase III clinical trials. Despite formulation with an opti- cines have been published more recently (2004-12). mized adjuvant, thus far, this full length protein vaccine Objective clinical responses and immunologic responses has not met its primary clinical endpoints,57 although were seen in a trial of dendritic cells that had been pulsed trial analysis is ongoing. with mucin 1 derived peptide plus heterologous PADRE Multiple peptides can be given at the same time, target- peptides (delivered subcutaneously) in patients with ing several T cell clones and antigens at once.58‑60 A trial renal cell carcinoma.34 Mucin 1 was a highly ranked anti- combining pre-vaccine cyclophosphamide with multiple gen in the NCI prioritization project.24 These dendritic cell peptides and GM-CSF showed that improved survival vaccines were combined with low dose IL-2. In another was associated with antigenic breadth of response and study, patients with acute myeloid leukemia who were reduced suppressive circulating regulatory T cells (Tregs) in remission after standard treatment were given vac- and myeloid derived suppressor cells (MDSCs).60 cines in which dendritic cells were loaded with WT-1 (see Mouse models support combinations of multi-antigen Glossary). TAA mRNA and these patients showed both peptide vaccines and chemotherapy.61 Peptide vaccines immune activation and improved clinical outcomes.69 may also be useful for preventing the progression of WT-1 was also a highly ranked antigen in the NCI pri- premalignant lesions to cancer. A recent human clini- oritization project.24 Another trial that tested dendritic cal trial of the prevention of progression of colon ade- cell-tumor fusions in patients before and after autologous noma to colorectal cancer tested a mucin 1 TAA peptide stem cell transplantation found both antitumor immune based approach.62 The vaccine was highly immunogenic activation and a reduction in disease.70 Interestingly, in almost half of the 39 patients who were evaluated. these trials all used a dendritic cell vaccine combination Importantly, high numbers of immunosuppressive MDSCs strategy, where the antigen loaded vaccines were added were already present in more than half of patients with to standard of care treatments and systemic cytokine advanced colonic adenoma. This indicates that these therapy. Recent dendritic cell based vaccine trials have cells might provide a biomarker of vaccine response (cir- been summarized.71 culating numbers of MDSCs) and that earlier vaccination should be tested, because even premalignant lesions may Tumor based strategies induce systemic immunosuppression. Early cancer vaccine studies found that mice could be immunized with tumor cells that were killed and engi- APC based strategies neered to express immune stimulatory cytokines,72 73 Many types of APCs have been investigated, including including GM-CSF. The data supporting syngeneic, autol- peripheral blood mononuclear cells, activated B cells, ogous, or allogeneic tumor cells transfected to express and, more commonly, dendritic cells. Dendritic cells are high amounts of GM-CSF (G-Vax; see Glossary) sup- a heterogeneous population of APCs that can efficiently ported clinical testing, with some immune and clinical take up antigens and sample their environment. They responses.74‑77 Preparation of vaccines based on autolo- then process and present these antigens to CD4+ and CD8+ gous tumor cells was feasible but complex. T cells and incorporate immune response modulating cues (including the secretion of cytokines such as inter- Cell lines leukin 12 (IL-12) p70, which skews the immune response Allogeneic cell lines (see Glossary) were also tested, with to a type 1 response) to determine the type of response. or without autologous tumor cells. The G-Vax platform A type 1 response involves interferon γ, IL-2, and tumor continues to be tested and is part of a “prime boost” (see necrosis factor and it promotes the activation of cytotoxic Glossary) combination vaccine study in which patients CD8+ T cells. Several recent reviews summarize the his- with pancreatic cancer receive recombinant listeria bac- tory, biology, and clinical application of these cells.63‑65 teria expressing the TAA mesothelin, with or without a G-Vax composed of two allogeneic pancreatic cancer cell Dendritic cells lines.78 79 Importantly, multiple injections are possible Clinical trials of dendritic cell vaccines are usually without inhibition from induced antibody neutraliza- unique, involving individualized patient vaccination tion (see Glossary), and the inclusion of serves approaches and single clinical trial arms. It is therefore to mimic many aspects of a natural infection by triggering difficult to compare trials and draw firm conclusions TLRs and foreign pathogen pattern recognition receptors about the efficacy or different approaches. Monocytes (see Glossary). and CD34+ progenitor cells have been tested, and anti- Other strategies that use the personalized approach gens including complex tumor lysates that contain nor- of harnessing autologous tumor antigens include using mal, tumor associated, and tumor specific antigens, or tumor lysates to load APCs ex vivo and fusion of tumor synthetic MHC class I restricted peptides, have all been cells and autologous APCs. These have been tested in used. Vaccines have been injected into the blood, skin early phase clinical trials and several have shown prom- (subcutaneously or intradermally), and lymph nodes. All ising results. Immunity to undefined tumor lysates and these parameters could affect the clinical responses seen. foreign helper proteins (see Glossary) has been demon- The initial lessons learnt were that dendritic cell based strated in some cases.80‑82

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Autologous tumor cells Herpesviruses have also been used as oncolytic viruses Autologous tumor cells can also be used to transfect for cancer vaccination. A promising strategy has tested APCs (autologous or derived from allogeneic cell lines) GM-CSF as an adjuvant or APC growth factor engineered with tumor genomic DNA.83 This allows uncharacterized into replicating herpesvirus vectors. One such vector, mutated gene products specific to the tumor to be pro- T-VEC, was recently tested in patients with melanoma in cessed and presented for immune activation. a randomized phase III trial.99 The trial found an objective response rate of 26% and a complete clinical response Virus based strategies in 11% of patients with stage IIIB-IV melanoma.100 The As mentioned above, the inclusion of pathogens in can- immune mechanisms of response will be important to cer vaccines can greatly increase immune stimulation investigate. in the context of presenting tumor antigens. Although peptide based vaccines have sometimes included TLR What else can be considered a “cancer vaccine”? ligands such as CpG molecules (see Glossary) or polyIC/ Tumor ablation polyICLC (see Glossary), pathogens have complex arrays Several tumor ablative techniques can remove large and of molecules that can trigger multiple immune activation small tumors, and this process can reduce both systemic pathways. and intratumoral suppressive environments. Elimination The human papillomavirus vaccines and Gar- or reduction of the tumor mass can eliminate a broad dasil are licensed to prevent human papillomavirus (HPV) array of tumor derived suppressive factors while simulta- mediated cervical cancers in uninfected adolescents. neously releasing tumor antigens from dying tumor cells. They work by activating humoral immunity against viral capsid proteins assembled into non-infectious viral-like Radiofrequency ablation particles. They are not, however, effective against cancers This localized heating technique causes necrosis and that develop in infected patients. inflammation and transiently allows the re-emergence Viruses, including adenovirus, have been used as of circulating antitumor effector cells that recognize the vectors to directly immunize with tumor antigens by TAA α fetoprotein.7 Although these memory cells are injection into muscle tissue, which is relatively easily functional they are not potent enough to be therapeutic transfected,84 85 taking advantage of their natural infec- alone. In a larger scale study in patients with hepatocel- tivity. Viruses have also been used ex vivo to transduce lular carcinoma, this technique enhanced both a memory antigens into APCs,86‑91 and each virus has unique effects cell response and the development of new effector cells on these transduced cells, from activation to suppres- against multiple TAAs. The immune responses correlated sion. Direct administration of viral vectors can induce positively with the prevention of disease recurrence and neutralizing antibody responses that block repeated negatively with the numbers of MDSCs.101 Radiofrequency use, whereas the induction of neutralizing antibodies is ablation has also been shown to promote the activation minimal after vaccination with ex vivo virally transduced of natural killer cells.102 APCs. However, clinical use of viral vectors can involve complex logistics, including the requirements of clinical High intensity focused ultrasound grade virus production. This technique is being investigated for its immune stimu- A strategy that resolves some of these limitations latory effects alone and combined with other therapeu- involves virus based prime boost (see Glossary) with het- tic strategies. It has been shown to affect STAT5 (signal erologous viral backbones expressing tumor antigens. This transducer and activator of transcription 5) signaling,103 approach is exemplified by the vaccinia virus and fowl pox increase cytotoxic T cell responses,104 and alter tissue virus prime boost for use in patients with prostate cancer, architecture.105 Embolization (therapeutic blood vessel which expresses the TAA, PSA, as well as the costimulatory blockade) of tumors has also been shown to allow re- molecules B7-1 (CD80), intercellular adhesion Molecule emergence of circulating TAA specific CD4+ T cells.106 1 (CD54), and lymphocyte function-associated antigen 3 The frequency and function of these cells correlated with (CD58).92 This promising approach has improved survival improved clinical outcome. in patients with prostate cancer,93 94 and it continues to be tested in late phase clinical trials. The same group is also Cryoablation developing viruses encoding CEA and mucin 1 instead of Cryoablation of tumors can also result in the release of PSA to use against other carcinomas. TAAs, thereby activating antitumor immunity.107 Oncolytic viruses have been used for decades. They include adenoviruses that drive the transactivator early Chemotherapy genes (see Glossary) E1a and E1b and viral replication Data from mouse models from the past decade show from a tumor specific promoter (including promoters that that different classes of chemotherapeutic agents have drive TAAs such as α fetoprotein, PSA, and human telomer- very different effects on the tumor in terms of the type ase reverse transcriptase (hTERT).95 Vaccinia viruses have of death induced (for example, necrosis or apoptosis). also been used. One strategy has created mutations in viral The specific death signals induced also have an impact serpin (serine peptidase inhibitor) genes to improve tumor on immunity. “Immunogenic” death can be induced selectivity for viral replication and killing,96 and additional by the upregulation of tumor cell surface calreticulin engineering with chemokine genes or combinations with and release of ATP, HMGB1 (high mobility group B1), costimulation are being pur­ sued.97 98 and tumor antigens.8 It had previously been assumed

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that chemotherapy in g­eneral is immunosuppressive variability over and above the requirements for platform because it results in the depletion of white blood cells. development.122 However, the loss of these cells also removes suppressive The development of chimeric antigen receptor (CAR) Tregs and MDSCs,108‑110 and reduces tumor secretion of therapeutics (see Glossary) is a good example of the immune inhibiting cytokines and growth factors.111 With optimization of a cancer vaccination strategy. The geneti- the additional benefit of the release of tumor antigens cally engineered CAR has undergone three generations for uptake by endogenous APCs and reduction in tumor of development, from CD3 zeta chains, through the burden, specific chemotherapy drugs are thought to work addition of CD28 or 4-1BB regions, to multiple signal- with and promote antitumor immunity in certain settings. ing domain constructs using CD27, CD28, ICOS, 4-1BB, Examples of the most recent clinical trials in this area and OX40.123‑125 Electroporation of constructs and the have recently been summarized.112 use of coding cassettes in recombinant retroviruses and lentiviruses have also been used to introduce the recep- Radiotherapy tor into cells. Since the initial description of the CAR Radiotherapy induces cell death in the irradiated tis- approach, immune depleting regimens and cytokine sues by causing genomic DNA damage. In addition, support procedures have been developed to allow the irradiation of a tumor can sometimes cause shrink- persistence of CAR bearing cells.126 The success of CAR age not only of the treated tumor but also of unirradi- therapy is based on decades of painstaking work by ated lesions, a phenomenon known as the “abscopal many groups of dedicated investigators to identify con- effect.” This effect has been shown to be mediated by the structs, domains, mechanisms, targets, and combina- immune system.113‑115 In one recent clinical case report tion treatments that enable the basic CAR bearing cell with extensive immunologic monitoring, the radia- to be effective. Similarly, the field of “cancer vaccines” tion induced abscopal effect was shown to induce both continues to refine technical aspects of multiple vaccine a strong antibody response to TAAs and potent T cell platforms to improve efficacy. activation.116 Tumor reactive T cell activation has also been shown to be induced by radiotherapy in mouse Animal models do not always predict outcomes in humans models.117 Immune effects in radiotherapy studies were Several recent commentaries have discussed the role of recently reviewed.118 animal models and the need for genetically engineered mouse models with mutations that recapitulate human Targeted therapy tumors and which spontaneously develop tumors with The ability to design small molecules that can bind to the homologous histology and metastatic spread.127 128 active sites of signal transduction molecules that drive the Results of simple and short timeframe studies of in vitro proliferation of tumor cells and block proliferation has cultured tumors that are implanted subcutaneously have been a major advance in the treatment of cancer. How- predicted the success of some immune therapies but ever, many of the molecules are not specific and have off many have proved to have no significant clinical impact target effects on normal tissues and other signaling path- in human clinical trials. ways, and they also lead to compensatory mutations that For example, DNA vaccines have had very different limit the duration of their clinical effects.119 effects in mouse models and human studies. This sim- Such targeted therapy can also have immunologic ple, safe, and cost effective approach showed potent effects. The BRAF inhibitor vemurafenib increased the immunogenicity and intriguing therapeutic effects tumor cell expression of TAAs in and, there- in several mouse models.20 129 ‑ 131 Part of the efficacy fore, improved the immune recognition of tumor cells.120 in mice was related to CpG dinucleotides in bacteri- In melanoma biopsies from patients treated with a BRAF ally derived plasmid backbones and recognition by inhibitor, plus or minus a MEK (mitogen activated pro- TLR9 expressing myeloid and plasmacytoid dendritic tein kinase) inhibitor, increased TAA expression was cells.132 When this approach was tested in human tri- accompanied by increased CD8+ T cell infiltration and als the naked DNA injections were mostly ineffective reduced cell surface and soluble markers of immuno- and minimally immunogenic.133 134 Subsequent stud- suppression.119 Recently, an increase in tumor infiltration ies that have tested the addition of more potent adju- by adoptively transferred tumor specific T cells was also vants; improved delivery approaches, including in vivo shown in mice treated with a BRAF inhibitor.121 electroporation135; and priming with DNA, followed by boosting with a viral vector based vaccine, have shown Methodological optimization of cancer vaccination promising results.136 137 strategies Cancer vaccines still show only modest success in clini- Controversies cal trials. Many trials have shown potent therapeutic In 2004 a high profile review that summarized many responses in a proportion of patients with late stage can- clinical trials of cancer vaccines concluded that cancer cer, but it has been rare for trials to obtain more than a vaccine trials had shown minimal efficacy in patients 5-10% partial or complete response. One reason is the with cancer (3.8% objective response rate, with the broad range of platforms that are being developed. Some highest (7.1%) response rate for dendritic cell based are “off the shelf” allogeneic, synthetic peptide, protein, trials).138 Subsequent correspondence pointed out that or pathogen based vaccines. Others are autologous tumor many variables in cancer vaccination (certainly for den- or APC based vaccines that have a high level of inherent dritic cell based cancer vaccines) remain to be tested,

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and that biomarkers that might identify optimal vac- for Immunotherapy of Cancer, with the NCI and FDA, cine characteristics and patient variables have yet to be formed a task force that considered several questions validated.139 and made recommendations to the field.142 This report Another controversial review covered antigenic targets updated previous work from the society,143 and incorpo- for immunotherapy.122 As discussed above, most of the rated important recommendations from other groups,144 antigens targeted to date are non-mutated shared anti- as well as results of worldwide immunologic monitoring gens that are overexpressed in tumor tissues. The review proficiency panels and harmonization efforts.145‑148 discusses several instances of unexpected adverse events, Specifically, to determine key aspects of the biology severe toxicities, and death from adoptive transfer of of antitumor T cells, functional assessments are needed very high avidity lymphocytes bearing genetically engi- to determine not only the prevalence and phenotype of neered T cell receptors or CARs specific for non-mutated tumor reactive T cells, but also the cytokines, effector mol- self antigens. The review’s authors support a focus on ecules, and chemokines produced. Many trials have deter- viral antigens such as those found on HPV (implicated mined the prevalence of circulating peptide specific CD8+ in , as well as head and neck cancer) and T cells to an immunizing TAA epitope, but such measures Epstein-Barr virus (important for nasopharyngeal can- have rarely correlated significantly with clinical outcome. cers and lymphoproliferative diseases), mutated antigens This type of measure is more likely to be a reflection of (KRAS mutations in HLA-A2+ patients), and antigens like successful vaccination. CD19, where complete elimination of all normal cells and An exception to this is when vaccines include mul- cancer expressing cells is safe or has an acceptable level tiple peptides that are found in several antigens. The of toxicity. breadth of response to multiple peptides has correlated Current technologies and mouse models cannot com- with clinical outcome in several trials. In the past 10 pletely mimic the biology of each of these target antigens years an increasing number of trials have included well or predict the level of antigen expression in normal tis- designed and carefully performed immunologic moni- sue, the expression of T cell receptors or CARs, or cross- toring, including multiple functional assessments of reactivity with homologous antigens, which can lead to CD8+ and CD4+ T cells, natural killer cells, and antibody toxicity. Shared antigens may be “safe” targets for cancer responses. vaccines that harness the naturally positively and nega- tively selected endogenous T cell repertoire. However, Examples of immunologic measures correlating with they are not necessarily safe targets in situations where clinical response large numbers of T cells, engineered to be of high affin- A study of patients with vulvar intraepithelial neoplasia ity, are adoptively transferred, and where prolonged or who were vaccinated with long peptides from HPV-16 permanent deletion of any cell that expresses the target found a correlation between immunologic measures and antigen may occur. Elimination of the CD19+ B cell popu- clinical outcome.54 Investigators tested lymphocyte pro- lation by CAR T cells is considered to be an acceptable liferation and cytokine production to immunizing anti- toxicity.140 141 gens as well as circulating Tregs. Patients with a clinical response to treatment showed the highest levels of lym- Lessons learnt from immune monitoring of cancer vaccine phocyte proliferation, interferon γ, and IL-5 as well as the clinical trials lowest numbers of Tregs. Many cancer therapeutics with an incompletely charac- A trial testing vaccination with the TAA WT-1 in terized mechanism of action have been used suc­cessfully patients with acute myeloid leukemia identified signifi- for decades. Some of these mechanisms of action have cant changes in numbers of WT-1 specific CD8+ T cells, subsequently been identified and are important for and more dramatic activation of circulating natural killer patient enrollment and stratification, outcome prediction, cells in patients with a clinical response.69 and identification of suitable combination treatments to In another example, from a large multicenter clinical improve patient outcomes. in patients with melanoma, immunity to Regardless of platform, the primary mechanism of multiple vaccine peptide epitopes correlated with clini- action of all cancer vaccines is the same—activation of cal outcome. The trial used two assays to measure specific tumor specific T cells. Because cancer vaccines have immunity: MHC tetramer flow cytometry to measure the passed the hurdles of feasibility, safety, immunogenic- numbers of vaccine antigen specific T cells and ELIS- ity, biologic activity, and therapeutic efficacy (albeit in POT (enzyme linked immunospot) assays of interferon a small minority of patients), the crucial questions are: γ release by peripheral blood mononuclear cells. The • What qualities in vaccine activated T cells lead to functional ELISPOT assay correlated with overall sur- therapeutic tumor destruction? vival,44 but although the phenotypic MHC tetramer assay • How can vaccines be formulated and delivered to detected increased numbers of vaccine specific T cells, activate antitumor T cells effectively? this did not correlate with clinical outcome.149 • Which patients are the most likely to respond to A study that tested a multi- in patients cancer vaccines? with renal cancer found that inhibition of Tregs strength- • Is prevention the best clinical outcome for cancer ened antitumor immunity. The number of specific subsets vaccines? of MDSCs at baseline was crucial, and the improvement in Immunologic monitoring and detailed vaccine analysis clinical outcome correlated with the number of peptides are needed to answer these questions (fig 3). The Society responded to.60

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Fig 3 | Immunologic monitoring approaches. Summary of the processing of patient specimens and the immune monitoring assays. Tumors can be frozen or formalin fixed and paraffin embedded and slices tested by immunohistochemistry (IHC). They can also be enzymatically digested into viable single cell suspensions. Blood can be separated using density gradient centrifugation (Ficoll-Paque) and a variety of tests performed; TIL=tumor infiltrating lymphocyte

Prognostic markers Investigation of baseline circulating suppressor cells Other potential prognostic markers include “polyfunc- could identify those who are unlikely to respond owing tionality,” which includes simultaneous secretion of to high numbers of Tregs and MDSCs,155‑157 and those who cytokines, lytic granules, and chemokines in peripheral would benefit from a combination treatment that reduces blood cells.150 immunosuppression. Another important parameter is tumor infiltration. Tests for a wide range of immunomodulating factors in A strong or “brisk” lymphocytic infiltrate strongly cor- plasma or serum can also indicate immune skewing (to relates with a positive outcome in melanoma,151 and a regulatory or suppressive (type 2) response involving recently, the infiltrate in pretreatment colorectal cancers IL-4, IL-5, IL-13, and other molecules that do not sup- has been shown to be an important biomarker of T cells. port cytotoxic CD8+ T cells) and could indicate cytokines Although the antigen specificity is not known, the cells that need to be blocked or augmented. Genetic analysis are CD3+/CD8+/CD45RO+ and thoroughly infiltrate tumor of patient specific small nucleotide polymorphisms can tissue.4 152 identify subpopulations with altered gene expression Predictive and prognostic tissue biomarkers in mela- patterns. noma, including type 1 interferon signatures, have Lastly, as described above, identification of patients recently been identified by tissue analysis,153 and by the with infiltrated or “inflamed” tumors could pinpoint use of molecular approaches instead of immunohisto- those with an ongoing immune response that needs to chemistry in formalin fixed tissues.154 be boosted or to have checkpoint blockade (anti-CTLA-4, anti-PD-1; see Glossary) used to amplify or de-repress the Patient specific factors immune response. By contrast, patients with non-infil- Patient specific parameters that affect the antitumor trated tumors would be good candidates for a vaccina- response can be identified at several levels. Analysis tion strategy to initiate an antitumor immune response. of baseline tumor specific T cells can identify patients Approaches to test these different immunologic in whom vaccination will boost an existing response. parameters have recently been reviewed.158

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self regulates, activated T cells upregulate CTLA-4, PD-1, 9$&&,1(6 27+(575($70(176 and other cell surface molecules that can be triggered to inhibit T cell activity. Blockade of CTLA-4 and PD-1 bind- 3HSWLGHV 67$1'$5'2)&$5( ing through antibodies alone has led to highly significant $EODWLRQFKHPRWKHUDS\ clinical responses, and combining these antibodies with 3URWHLQV 5DGLDWLRQVPDOOPROHFXOHV a vaccine might strengthen the antitumor effects of either alone. 9LUXVHV &+(&.32,17%/2&.$'( &7/$3'3'/ Conclusion '1$ + The field of cancer vaccination encompasses a broad ,008127+(5$3< array of strategies that can promote tumor specific 3ULPHERRVW &\WRNLQHV ,/,)1_*0&6)  immune responses. TAAs have been shown to be safe and &RVWLPXODWLRQDGRSWLYHWUDQVIHU immunogenic, and several trials have produced objective 'HQGULWLFFHOOV RIHƷHFWRUV clinical responses. To improve responses, multiple anti- gens, patient specific mutated antigens, viral vectors, 7XPRUO\VDWHV 68335(66,215('8&7,21 prime boost strategies, and combinations with standards /\PSKRGHSOHWLRQ of care are being tested in new clinical trials. 7XPRUFHOOV 7UHJV0'6&UHGXFWLRQLQKLELWLRQ Thanks to Robert Vonderheide (University of Pennsylvania) for helpful Fig 4 | Cancer vaccines can be combined with various other treatments such as standard of care discussions. approaches, checkpoint blockade, immunotherapy, and strategies to reduce suppression. Contributors: As sole author I accept responsibility for all aspects of this CTLA-4=cytotoxic T lymphocyte associated protein 4; GM-CSF=granulocyte-macrophage colony review and act as guarantor. stimulating factor; IFN=interferon; IL-2=interleukin 2; MDSC=myeloid derived suppressor cell; Funding: LHB is supported by NIH/NCI RO1 CA138635, NIH P50 PD-1/L1=programmed death 1/L1; Tregs=circulating regulatory T cells CA121973, and NIH P30 CA047904. Competing interests: I have read and understood BMJ policy on Emerging treatments: cancer vaccine combinations declaration of interests and have none to declare. As noted above, some recent and relatively successful Provenance and peer review: Commissioned; externally peer reviewed. vaccination approaches have included combinations of 1 Rahib L, Smith BD, Aizenberg R, et al. Projecting cancer incidence and vaccine elements and vaccines combined with standard deaths to 2030: the unexpected burden of thyroid, liver, and pancreas of care treatments. On the basis of preclinical mouse cancers in the United States. Cancer Res 2014;74:2913-21. 2 Lawrence MS, Stojanov P, Polak P, et al. Mutational heterogeneity models, combinations of adjuvant cocktails that target in cancer and the search for new cancer-associated genes. Nature different TLRs are being investigated and are showing 2013;499:214-8. 159 3 Nordlund JJ, Kirkwood JM, Forget BM, et al. Vitiligo in patients with promise. metastatic melanoma: a good prognostic sign. J Am Acad Dermatol Prime boost vaccines are also inherently combination 1983;9:689-96. vaccines. Cancer vaccines aimed at supporting the sur- 4 Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. vival and function of adoptively transferred T cells (by the Science 2006;313:1960-4. optimal presentation of tumor antigens) have developed 5 Salgado R, Denkert C, Demaria S, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International from mouse models and are being tested clinically. TILs Working Group 2014. Ann Oncol 2015;26:259-71. The use of multiple antigens has also become more 6 Townsend KN, Spowart JE, Huwait H, et al. Markers of T cell infiltration and function associate with favorable outcome in vascularized high-grade common because so many antigens have been shown serous ovarian carcinoma. PLoS One 2013;8:e82406. to be immunogenic and safe to use. Strategies to reduce 7 Zerbini A, Pilli M, Penna A, et al. Radiofrequency thermal ablation of liver nodules can activate and enhance tumor- tumor induced immunosuppressive Tregs and MDSCs specific T-cell responses. Cancer Res 2006;66:1139-46. after vaccination are also being tested. 8 Zitvogel L, Kepp O, Kroemer G. Immune parameters affecting the efficacy Lastly, the combination of cancer vaccines with check- of chemotherapeutic regimens. Nat Rev Clin Oncol 2011;8:151-60. 9 WHO. Cancer fact sheet. 2015. www.who.int/mediacentre/factsheets/ point blockade (anti-CTLA-4, anti-PD-1) is an obvious fs297/en/. area for investigation (fig 4). Because the immune system 10 American Cancer Society. Cancer facts and figures 2014. www.cancer.org/ research/cancerfactsstatistics/cancerfactsfigures2014/. 11 Kawakami Y, Eliyahu S, Delgado CH, et al. Identification of a human RESEARCH QUESTIONS melanoma antigen recognized by tumor-infiltrating lymphocytes associated with in vivo tumor rejection. Proc Natl Acad Sci U S A Recent studies have investigated cancer vaccination to 1994;91:6458-62. prevent progression from premalignant lesions to a fully 12 Kawakami Y, Eliyahu S, Delgado CH, et al. Cloning of the gene coding for malignant state. Should they be further investigated with a shared human melanoma antigen recognized by autologous T cells multiple cancer vaccine platforms? infiltrating into tumor. Proc Natl Acad Sci U S A 1994;91:3515-9. 13 Coulie PG, Brichard V, Van Pel A, et al. A new gene coding for a Investigation of immunologic biomarkers seems to be differentiation antigen recognized by autologous cytolytic T lymphocytes crucial to providing standardized benchmarks of immune on HLA-A2 melanomas. J Exp Med 1994;180:35-42. response, levels of immune suppression, and to identify 14 Traversari C, van der Bruggen P, Luescher IF, et al. A nonapeptide encoded by human gene MAGE-1 is recognized on HLA-A1 by cytolytic predictive and prognostic biomarkers of clinical outcome. T lymphocytes directed against tumor antigen MZ2-E. J Exp Med Should this be emphasized in clinical studies, particularly 1992;176:1453-7. rigorous banking of blood and tumor samples? 15 Finn, OJ, Binder, RJ, Brickner, AG, et al. Human tumor antigens as targets of immunosurveillance and candidates for cancer vaccines. In: Gires O, Autologous, personalized therapies based on patient Seliger B, eds. Tumor-associated antigens: identification, characterization specific cellular vaccines, tumors, and peptide epitopes and clinical applications. Wiley-VCH Verlag, GmbH & Co, 2009:23-43. are potentially potent immunogens capable of activating 16 Topalian SL, Rivoltini L, Mancini M, et al. Human CD4+ T cells specifically recognize a shared melanoma-associated antigen encoded by the tumor specific and high avidity T cell responses. Should tyrosinase gene. Proc Natl Acad Sci U S A 1994;91:9461-5. such approaches be prioritized? 17 Finn OJ, Jerome KR, Henderson RA, et al. MUC-1 epithelial tumor mucin- based immunity and cancer vaccines. Immunol Rev 1995;145:61-89.

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