Introduction: Therapeutic Cancer Vaccines

CANCER VACCINES

Introduction: Therapeutic Cancer Vaccines

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his issue of Seminars in Oncology is aimed at defining the current state of research, development, and clinical evaluation of therapeutic cancer vaccines. The various chapters review potential reasons for past failures, the US Food and Drug Administration (FDA) approval of Sipuleucel-T for prostate cancer therapy, promising randomized phase II and phase III results with several other therapeutic vaccines in different cancer types, and the broad range of cancer vaccines and vaccine strategies currently being evaluated in preclinical settings and in phase I and phase II trials. This issue is comprised of three sections based on major areas of investigation: Section I, Clinical investigations in a specific cancer type, ie, prostate carcinoma, lymphoma, melanoma, and renal cell carcinoma; Section II, diverse vaccine platforms, including peptides and proteins, recombinant viral vectors (poxviral, adenoviral, and alphavirus), recombinant bacterial vectors (Listeria), whole tumor cell vaccines, dendritic cell vaccines, and dendritic cell/tumor cell fusions; and Section III, novel vaccines and vaccine strategies. The last section includes the combined use of vaccines with (1) immune enhancers and modulators such as cytokines, chemokines, Toll-like receptor (TLR) agonists, immunomodulatory drugs (IMiDs), and T-cell co-stimulators; (2) immune checkpoint inhibitors such as monoclonals anti-CTLA4 and anti-PD1, and transforming growth factor-beta (TGF-␤) inhibitors; and (3) standardof-care chemotherapeutics, radiation, and small molecule–targeted therapeutics, as well as novel experimental small molecule targeted therapeutics. This section also will deal with potential new vaccine targets such as products that drive the “epithelial-to-mesenchymal transition” (EMT) process, which is involved in cancer invasion, metastasis, and drug resistance. There are several themes that weave through virtually all the chapters in this issue. These include: A. Clinical trial design. Numerous clinical studies are now demonstrating the importance of appropriate patient selection. Due to the mode of action of therapeutic cancer vaccines, patients most likely to benefit from this modality are those with low tumor burden metastatic disease and those whose treatment is initiated earlier in the disease process. Numerous clinical studies are demonstrating increases in patient survival with limited decreases in Seminars in Oncology, Vol 39, No 3, June 2012, pp 243-244

tumor volume employing strict Response Evaluation Criteria in Solid Tumors (RECIST) and time to progression. Evaluation of clinical results is demonstrating, in many cases, a delayed clinical response and reduction in tumor growth rate kinetics. One is also struck with the relative safety of therapeutic vaccines, in most cases adverse events being restricted to grade 1 and grade 2 toxicities with little evidence of autoimmunity. B. Combining vaccines with immune modulators. Numerous preclinical studies have demonstrated the influence of the tumor microenvironment in reducing the efficacy of vaccine monotherapy. In addition to issues in vascular permeability, the tumor microenvironment will in many cases include regulatory T cells (Tregs), myeloid derived-suppressor cells (MDSCs), and soluble factors such as TGF-␤ and interleukin (IL)-10, which are also capable of inhibiting immune-mediated tumor destruction. These immune-suppressive entities are being attacked by numerous strategies, including the use of several immune checkpoint inhibitors, as discussed above, and the use of other therapeutic modalities that can lead to potential therapeutic benefit. C. Vaccine combinatorial therapies. The use of certain chemotherapeutic agents, local radiation of tumor, and small molecule targeted therapeutics have all been shown in preclinical studies to be capable of enhancing vaccine efficacy, and evidence is emerging in clinical studies how to best employ these therapeutics in combination with vaccine. Certain chemotherapeutic agents have demonstrated the ability to induce “immunologic cell death” in which dying tumor cells are presented to the immune system via dendritic cell “cross-priming” to enhance T-cell responses. Local radiation of tumor via external beam radiation, chelated radiopharmaceuticals and radiolabeled monoclonal antibodies administered systemically, as well as certain chemotherapeutic agents have been shown to alter the phenotype of the tumor cell to render them more susceptible to vaccine-mediated T-cell lysis; this phenomenon has been observed via upregulation of tumor-antigen expression, major histocompatibility complex (MHC) peptide complexes, death receptors such as Fas, and other accessory molecules. Certain small molecule–targeted therapeutics such as a BCL-2 inhibitor and 243

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tyrosine kinase inhibitors (TKIs) have been shown to differentially inhibit Tregs and MDSCs compared to effector T cells, resulting in greater effector T-cell–to–Treg ratios and greater anti-tumor effects. The homeostatic proliferation that results following the use of chemotherapy has been shown to also be exploited by the differential rebound of effector T cells versus Tregs, again resulting in greater effector T-cell–to–Treg ratios and greater anti-tumor effects. Homeostatic proliferation also has been shown to be accompanied by the production of IL-15 and IL-7, both cytokines which drive Th1 T-cell responses. D. Diversity of immune responses. Numerous preclinical and clinical studies have demonstrated the diversity of immune responses that can be elicited resulting in anti-tumor responses with the use of therapeutic cancer vaccines. These include the generation of CD8 and CD4 T-cell responses, natural killer (NK) cell and macrophage responses, cytokine responses, and various types of antibody responses. Preclinical studies have demonstrated that one of these compartments, such as CD8 or CD4 responses, can be essential for anti-tumor activity, but for the most part most studies have demonstrated that more than one of these immune compartments contribute to the anti-tumor response. Due to limitations in the amount of peripheral blood available for assay, and the difficulty in obtaining biopsy specimens pre- and post-therapy, evaluation of the range of immune responses in vaccine clinical trials continues to be difficult in defining the mode of action of anti-tumor responses. E. Biomarkers. For the most part, patient immune responses in vaccine clinical trials are being monitored for vaccine-induced CD8 T cells via ELISPOT or by fluorescence-activated cell sorting (FACS)-based assays. These assays traditionally measure the amount of cytokine, such as interferon, being induced by CD8 T cells when presented with a single tumor antigen peptide epitope. This of course does not measure the lytic activity of these T cells, the avidity of T cells, nor the breadth of CD8 T-cell response to other epitopes of the antigen in the vaccine; this evaluation also does not measure the contribution of CD4 T cells, NK cells, and the inhibitory aspects of regulatory cells that may be present. It should be pointed out that preclinical studies also have demonstrated the importance of “antigen cascade” or “epitope spreading” in anti-tumor immune responses; it has been demonstrated that the principal antitumor response can be due to T cells directed against antigens not found in the vaccine itself, but by T cells that have been generated by an initial level of tumor destruction employing the vaccine,

J. Schlom and J.W. Hodge

and then cross-priming of other antigens in the tumor by dendritic cells. Numerous reports evaluating immune cell infiltrates of tumor biopsies prior to therapy also have demonstrated a strong link between these immune infiltrates and favorable prognosis following response to conventional therapies. This and other markers within tumor biopsies have yet to be exploited in vaccine clinical studies but represent the fertile area of future investigation. In the review of the various chapters in this issue one is struck by the great potential of therapeutic cancer vaccines in cancer management. With the FDA approval of the first therapeutic cancer vaccine in Sipuleucel-T, one can thus envision a new era in cancer vaccine therapy. It is clear that the interest in and development of cancer vaccines is now moving from the purview of biotechnology to pharmaceutical companies. Factors that have led to this transition are: (1) the now “proof of concept” that cancer vaccines “work”; (2) the minimal toxicity observed with the vast majority of cancer vaccines in numerous settings; (3) the demonstration that these vaccines can be used in combination with a range of other therapeutic modalities; (4) the realization of the appropriate settings for vaccine therapy; and (5) the demonstration that vaccines can improve survival with good quality of life, without necessarily demonstrating adherence to strict RECIST criteria or increased time to progression. Just as chemotherapeutics and small molecule targeted therapeutics are seldom employed as monotherapies, one can envision the use of combinations of various types of therapeutic vaccines, either in prime-boost strategies or concurrently, to take advantage of the unique effects of each vaccine mode of action. The safety demonstrated with therapeutic cancer vaccines also renders them potentially ideal for use with other therapeutic modalities in the neo-adjuvant and adjuvant settings, and perhaps in patients with pre-neoplastic conditions.

Jeffrey Schlom, PhD Laboratory Chief Laboratory of Tumor Immunology and Biology Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda, MD James W. Hodge, PhD, MBA Principal Investigator Laboratory of Tumor Immunology and Biology Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda, MD Guest Editors