Cancer immunotherapy: the beginning of the end of cancer?

Farkona et al. BMC Medicine (2016) 14:73 DOI 10.1186/s12916-016-0623-5 REVIEW Open Access Cancer immunotherapy: the beginning of the end of cancer? Sofia Farkona1,2, Eleftherios P. Diamandis1,2,3 and Ivan M. Blasutig1,3,4* Abstract These are exciting times for cancer immunotherapy. After many years of disappointing results, the tide has finally changed and immunotherapy has become a clinically validated treatment for many cancers. Immunotherapeutic strategies include cancer vaccines, oncolytic viruses, adoptive transfer of ex vivo activated T and natural killer cells, and administration of antibodies or recombinant proteins that either costimulate cells or block the so-called immune checkpoint pathways. The recent success of several immunotherapeutic regimes, such as monoclonal antibody blocking of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD1), has boosted the development of this treatment modality, with the consequence that new therapeutic targets and schemes which combine various immunological agents are now being described at a breathtaking pace. In this review, we outline some of the main strategies in cancer immunotherapy (cancer vaccines, adoptive cellular immunotherapy, immune checkpoint blockade, and oncolytic viruses) and discuss the progress in the synergistic design of immune-targeting combination therapies. Keywords: Cancer, Immunotherapy, T cells, Adoptive cellular therapy, Cytotoxic T lymphocyte-associated protein 4, Programmed cell death protein 1, Immune checkpoint blockade Background The idea of exploiting the host’s immune system to treat cancer dates back decades and relies on the insight that the immune system can eliminate malignant cells during initial transformation in a process termed immune surveillance [1]. Individual human tumors arise through a combination of genetic and epigenetic changes that facilitate immortality, but at the same time create foreign antigens, the so-called neo-antigens, which should render neoplastic cells detectable by the immune system and target them for destruction. Nevertheless, although the immune system is capable of noticing differences in protein structure at the atomic level, cancer cells manage to escape immune recognition and subsequent destruction. To achieve this, tumors develop multiple resistance mechanisms, including local immune evasion, induction of tolerance, and systemic disruption of T cell signaling. Moreover, in a process termed immune editing, immune * Correspondence: 1 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada 3 Department of Clinical Biochemistry, University Health Network, Toronto, ON, Canada Full list of author information is available at the end of the article recognition of malignant cells imposes a selective pressure on developing neoplasms, resulting in the outgrowth of less immunogenic and more apoptosis-resistant neoplastic cells [2]. Scientists have known for decades that cancer cells are particularly efficient at suppressing the body’s natural immune response, which is why most treatments exploit other means, such as surgery, radiation therapy and chemotherapy, to eliminate neoplastic cells. It is now established that various components of the immune system play pivotal roles in protecting humans from cancer. Following numerous disappointing efforts and unequivocal clinical failures, the field of cancer immunotherapy has recently received a significant boost, encouraged primarily by the approval of the autologous cellular immunotherapy, sipuleucel-T, for the treatment of prostate cancer in 2010 [3] and the approval of the anti-cytotoxic T lymphocyteassociated protein 4 (CTLA-4) antibody, ipilimumab, and of anti-programmed cell death protein 1 (PD1) antibodies for the treatment of melanoma in 2011 and 2014, [4] respectively. These successes have revitalized the field and brought attention to the opportunities that immunotherapeutic approaches can offer [5]. © 2016 Farkona et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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. Farkona et al. BMC Medicine (2016) 14:73 Page 2 of 18 Immunotherapies against existing cancers include various approaches, ranging from stimulating effector mechanisms to counteracting inhibitory and suppressive mechanisms (Table 1). Strategies to activate effector immune cells include vaccination with tumor antigens or augmentation of antigen presentations to increase the ability of the patient’s own immune system to mount an immune response against neoplastic cells [6]. Additional stimulatory strategies encompass adoptive cellular therapy (ACT) in an attempt to administer immune cells directly to patients, the administration of oncolytic viruses (OVs) for the initiation of systemic antitumor immunity, and the use of antibodies targeting members of the tumor necrosis factor receptor superfamily so as to supply co-stimulatory signals to enhance T cell activity. Strategies to neutralize immunosuppressor mechanisms include chemotherapy (cyclophosphamide), the use of antibodies as a means to diminish regulatory T cells (CD25-targeted antibodies), and the use of antibodies against immune-checkpoint molecules such as CTLA-4 and PD1. This review summarizes the main strategies in cancer immunotherapy and discusses recent advances in the design of synergistic combination strategies [1]. Vaccines Historically, the primary approach to specifically activate host T cells against tumor antigens has been therapeutic cancer vaccination. In addition to the successful use of preventative vaccines used in the defense against cancercausing infectious diseases, including hepatitis B virus and human papillomavirus, the knowledge that patients can harbor CD8+ and CD4+ T cells capable of recognizing tumor expressed antigens hinted at the possibility of developing cancer vaccines [5, 7]. Unfortunately, the general lack of understanding of the mechanisms of immunization, and particularly of the role of dendritic cells (DCs), has led to a series of failures of therapeutic cancer vaccines in initial randomized trials [5, 8]. Early on, it was not appreciated that, by creating an environment that disables the immune response, cancer is able to induce tolerance. Therefore, in contrast to conventional prophylactic vaccines for infectious agents, in Table 1 The spectrum of available immunotherapies Strategy Basic mechanism and major advantages Major (...truncated)