Strengthening the pillars of cancer immunotherapy

Abstract

The treatment of disease in cancer patients by harnessing the potent mechanisms that exist within the immune system is not a novel approach, and has been first attempted more than a century ago. During the major part of this century cancer immunotherapy has been relegated to the periphery of standard care for patients. Within the last few years a dramatic shift has occurred in the treatment of cancer, and patients are now the recipients of drugs and therapies that aim to modulate and modify their immunity towards cancer. These treatments fall into one of two categories; either the therapy is passive immunotherapy or active immunotherapy. The first is based on the premise of introducing specific immunity in the form of cytokines, monoclonal antibodies or tumor specific T cells into the tumor-bearing patient. Active immunotherapy aims at inducing an in vivo tumor specific response, typically through various means of vaccination to activate specific immunity. We have directed our efforts at strengthening the pillar of passive immunotherapy through harnessing our understanding of the tumor microenvironment. Tumors generate large amounts of reactive oxygen species which adversely effect anti-tumor effector T cells. One approach to mitigate the effects of reactive oxygen intermediates is by co-expressing high levels of catalase in tumor-redirected T cells that express chimeric antigen receptors. Increased levels of catalase neutralize the negative effects of oxidative stress on T cells and allows them to survive, proliferative and perform their cytolytic functions whereas typically they would become anergic. In addition, these cells are able to protect bystander T and NK cells from oxidative stress mediated dysfunction. This strategy of attenuating the negative effects derived from the tumor microenvironment can potentially increase the efficacy of chimeric antigen receptor based passive immunotherapy. To strengthen the pillar of active immunotherapy we attempted to identify, enhance and broaden the potential targets of DNA based vaccine delivery. Vaccines, that activate immunity against tumor antigens, have the potential to revolutionize the field of cancer treatment. DNA vaccines in particular remain an interesting platform for activating tumor specific immunity. The delivery of DNA vaccines into the skin, where professional antigen presenting cells that can be readily primed are present, can induce recruitment of tumor specific T cells as well as antibody producing B cells. We found that dermal DNA vaccination relies heavily on NF-κB activation but surprisingly not on the IRF. IRF induces the production of type I interferon which are strong activators of antiviral activity in immune cells. This is particularly relevant for inducing anti-tumor responses, which are mediated in large part by cytotoxic T lymphocytes. To harness this mechanism we delivered a genetically encoded intracellular DNA sensing molecule, DAI, which increased type I interferon molecule production as well as matured skin resident dendritic cells. This led to increased anti-tumor T cell activity as well as provided long-term protection from tumor re-challenge by generating more abundant tumor specific memory T cells. Generation of vaccine responses against cancer requires targeting antigens expressed by the tumor. To increase the potential targets available to cancer immunotherapists we explored the capacity of eliciting an immunological response against oncofetal tumor antigen Cripto-1. Delivery of DNA vaccine encoding full length Cripto-1 into the dermis of mice generated a cellular as well as humoral response that was able to inhibit the growth of transplanted tumors as well as decreased metastatic burden.

The pillars of cancer immunotherapy rest upon foundations laid by a myriad of immunologists and cancer biologists. By protecting adoptively transferred tumor specific lymphocytes and furthering the understanding, as well as boosting the immunogenicity of classical and novel tumor antigen encoding DNA vaccines, we hope to improve the outcomes of cancer immunotherapy.