Emerging Opportunities and Challenges in Cancer Immunotherapy

Abstract

Immunotherapy strategies against cancer are emerging as powerful weapons for treatment of this disease. The success of checkpoint inhibitors against metastatic melanoma and adoptive T-cell therapy with chimeric antigen receptor T cells against B-cell-derived leukemias and lymphomas are only two examples of developments that are changing the paradigms of clinical cancer management. These changes are a result of many years of intense research into complex and interrelated cellular and molecular mechanisms controling immune responses. Promising advances come from the discovery of cancer mutation-encoded neoantigens, improvements in vaccine development, progress in delivery of cellular therapies, and impressive achievements in biotechnology. As a result, radical transformation of cancer treatment is taking place in which conventional cancer treatments are being integrated with immunotherapeutic agents. Many clinical trials are in progress testing potential synergistic effects of treatments combining immunotherapy with other therapies. Much remains to be learned about the selection, delivery, and off-target effects of immunotherapy used alone or in combination. The existence of numerous escape mechanisms from the host immune system that human tumors have evolved still is a barrier to success. Efforts to understand the rules of immune cell dysfunction and of cancer-associated local and systemic immune suppression are providing new insights and fuel the enthusiasm for new therapeutic strategies. In the future, it might be possible to tailor immune therapy for each cancer patient. The use of new immune biomarkers and the ability to assess responses to therapy by noninvasive monitoring promise to improve early cancer diagnosis and prognosis. Personalized immunotherapy based on individual genetic, molecular, and immune profiling is a potentially achievable future goal. The current excitement for immunotherapy is justified in view of many existing opportunities for harnessing the immune system to treat cancer.

Conflict of interest statement

Disclosure of Potential Conflicts of Interest

S. Demaria is a consultant/advisory board member for Eisai, Lytix Biopharma, and Nanobiotix. H.M. Zarour reports receiving commercial research grants from Bristol-Myers Squibb and Merck. I. Melero reports receiving commercial research grants from Bristol-Myers Squibb and Pfizer and is a consultant/advisory board member for Alligator Bioscience, AstraZeneca, BiOncoTech Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Incyte, and Novartis. No potential conflicts of interest were disclosed by the other authors.

©2016 American Association for Cancer Research.

Figures

Figure 1. A conceptual palette of immune interventions designed to mix potentially effective combined immunotherapies

For immunomodulatory interventions to be effective a baseline immune response must be available. Such antitumor responses can be built up by means of vaccines, adoptive cell transfers or by enhancing tumor tissue immunogenicity using one or more of the f listed strategies. Manipulation of the tumor microenvironment appears to be most important to achieve the goal. Adapted from Meleroand colelagues (35).

Figure 2. Concept of immune mediated abscopal effects

Schematic representation of immune mediated effects. The scheme describes the systemic pro-inflamatory effects of gamma irradiation of the irradiated tumor lesion well that become hot and acts as an in situ tumor-attenuated vaccine against distant non-irradiated tumors. Such local response can be enhanced by immunostimulatory monoclonal antibodies to attain a systemic effect. Exploiting the systemic immune-mediated effects of radiotherapy offers opportunity to maximize the effect of novel immunotherapies. DC, dendritic cell; CTL, cytotoxic T cell.