Local Immunotherapies of Cancer

The past decade has seen clinical cancer research turn away from refining cytotoxic therapies to identifying immunomodulatory therapies that can harness the immune system to do the work of fighting cancer for us. The first revolution in cancer therapy brought us potent but toxic chemotherapies that were often initially good at controlling tumors; however, in the metastatic setting, recurrence was typically inevitable and more difficult to control. Immunotherapy has now emerged as among the most promising class of therapeutics for the treatment of cancer. These therapies harness the potent tumoricidal potential of cytotoxic effector cells of the patient’s own immune system. Although checkpoint-blocking antibodies approved in the past decade offer great promise, they non-specifically release the brakes on immune cells, and the majority of cancer patients are, so far, non-responders, while some patients experience toxic autoimmune adverse effects. One approach to improve on these limitations is with localized, in situ therapies, inducing a vaccinal response within the tumor microenvironment. These approaches alter the tumor microenvironment by inducing local immunogenic cell death to release tumor antigen, recruiting inflammatory leukocytes, priming of the adaptive immune response, and inhibiting tolerogenic mechanisms through which tumors dampen the immune response. Through a combined approach using some or all of these features, we are working to develop an in situ vaccine strategy that will result in systemic elimination of tumor cells as well as long-term remissions.