Tumor immunology and cancer immunotherapy: summary of the 2013 SITC primer

Raval et al. Journal for ImmunoTherapy of Cancer 2014, 2:14 http://www.immunotherapyofcancer.org/content/2/1/14 REVIEW Open Access Tumor immunology and cancer immunotherapy: summary of the 2013 SITC primer Raju R Raval1, Andrew B Sharabi1, Amanda J Walker1, Charles G Drake2,3 and Padmanee Sharma4,5* Abstract Knowledge of the basic mechanisms of the immune system as it relates to cancer has been increasing rapidly. These developments have accelerated the translation of these advancements into medical breakthroughs for many cancer patients. The immune system is designed to discriminate between self and non-self, and through genetic recombination there is virtually no limit to the number of antigens it can recognize. Thus, mutational events, translocations, and other genetic abnormalities within cancer cells may be distinguished as “altered-self” and these differences may play an important role in preventing the development or progression of cancer. However, tumors may utilize a variety of mechanisms to evade the immune system as well. Cancer biologists are aiming to both better understand the relationship between tumors and the normal immune system, and to look for ways to alter the playing field for cancer immunotherapy. Summarized in this review are discussions from the 2013 SITC Primer, which focused on reviewing current knowledge and future directions of research related to tumor immunology and cancer immunotherapy, including sessions on innate immunity, adaptive immunity, therapeutic approaches (dendritic cells, adoptive T cell therapy, anti-tumor antibodies, cancer vaccines, and immune checkpoint blockade), challenges to driving an anti-tumor immune response, monitoring immune responses, and the future of immunotherapy clinical trial design. Keywords: CTLA-4, PD-1, Melanoma, Prostate cancer, Kidney cancer, Bladder cancer, PD-L1, LAG-3 Introduction The innate and adaptive immune systems function to protect the host from foreign pathogens, and are generally tolerant toward host tissues – adequately differentiating between “self” and “non-self” antigens. In the setting of an evolving tumor, the immune system is likely exposed to numerous, previously unseen, antigens arising from genetic abnormalities. Interestingly, it is thought that the immune system is able to perceive and eliminate some tumors early on in their development. However, the theory of immunoediting, which involves the process of immunosurveillance, suggests that certain tumors escape from an equilibrium state previously held in check by the immune system, and become clinically significant [1]. Oncologists and cancer researchers are focused on understanding these mechanisms, and in finding novel (often combinatorial) approaches to * Correspondence: 4 Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 5 Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Full list of author information is available at the end of the article cancer immunotherapy. There are a variety of approaches to eliciting an anti-tumor immune response, with advancements in techniques involving therapeutic cancer vaccines, adoptive T cell therapy, anti-tumor antibodies, and immune checkpoint blockade. In addition, combining these approaches with other therapies such as immunomodulators (cytokines, cyclic dinucleotides, IDO inhibitors), cytotoxic chemotherapy, radiation therapy, or molecularly targeted therapies may hold the key to the true potential of immunotherapy in the future management of cancer patients. In its desire to further explore and educate the broader scientific community on these advancements, the Society for Immunotherapy of Cancer (SITC) convened a Primer on Tumor Immunology and Cancer Immunotherapy, which was organized by Padmanee Sharma, MD, PhD and Charles Drake, MD, PhD. Experts in the fields of tumor immunology led lectures and discussions on a variety of topics including Innate Immunity (Vincenzo Bronte, MD), Dendritic Cells (A. Karolina Paluka, MD, PhD), Adoptive Immunity (Jonathan Powell, MD, PhD), Adoptive T cell Therapy (Cassian Yee, MD), Anti-tumor © 2014 Raval et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Raval et al. Journal for ImmunoTherapy of Cancer 2014, 2:14 http://www.immunotherapyofcancer.org/content/2/1/14 Antibodies (Charles Drake, MD, PhD), Challenges to Driving an Immune Response (Jedd Wolchok, MD, PhD), Cancer Vaccines (Nina Bhardwaj, MD, PhD), Immune Checkpoint Blockade (James Allison, PhD), Monitoring Immune Responses (Sacha Gnjatic, PhD), and Immunotherapy Clinical Trial Design (Padmanee Sharma, MD, PhD). Review Innate immunity The innate immune system acts as a first line of defense against foreign pathogens, responds over a short period of time within minutes to hours, has a variety of effector mechanisms, and is both phylogenetically older than and can shape the adaptive immune response. There are a multitude of diverse components of innate immunity including physical barriers (skin epithelium and mucosal membranes), effector cells (macrophages, NK cells, innate lymphoid cells, dendritic cells, mast cells, neutrophils, and eosinophils among others), mechanisms of pattern recognition (Toll-like receptors), and humoral mechanisms (complement proteins or cytokines). In contrast to the more specific, but slower adaptive immune response consisting primarily of B and T cells, the more rapid innate immune response is usually characterized by tissue inflammation (with physical characteristics manifested usually by heat, pain, swelling, and erythema). Tissue inflammation as part of the innate immune response serves to help eliminate invasive foreign pathogens, initiate tissue repair, and can serve to stimulate the adaptive immune response through B and T cells. However, there is a significant amount of evidence that both acute and chronic inflammation may promote genetic abnormalities and cancer progression. In an environment of chronic inflammation, myeloid cell differentiation can be skewed toward the expansion of myeloid-derived suppressor cells (MDSCs). MDSCs are a heterogeneous population of myeloid derived immune cells (including macrophages, neutrophils, and dendritic cells) that can have potent immunosuppressive activities [2]. Among these effects, MDSCs can inhibit T cell proliferation and activation. In regions of inflammation such as tumors, these cells can inhibit anti-tumor immune responses through suppression of both T cells (...truncated)