Combining cancer immunotherapy and targeted therapy

Abstract

The ability to pharmacologically modulate key signaling pathways that drive tumor growth and progression, but do not negatively impact the function of lymphocytes, provides avenues for rational combinatorial approaches to improve the antitumor activity of tumor immunotherapies. Novel targeted agents can very specifically block oncogenic events in cancer cells, leading to a pro-apoptotic milieu and a potential increase in sensitivity to recognition and attack by cytotoxic T lymphocytes (CTLs). Furthermore, targeted pathway modulation in lymphocytes may change their function and have activating effects in some instances. When tested together with recently developed powerful tumor immunotherapies, such combinations may exploit the highly specific targeting of oncogenes with small molecule inhibitors to lead to high frequency of tumor regressions, and merge this benefit with the durable responses achievable with effective tumor immunotherapies.

Figure 1

Potential mechanisms of immune sensitization by BRAF inhibition as an example of means by which targeted therapies could improve tumor immunotherapy. A) BRAF inhibitors may result in increased tumor antigen presentation directly to T cells through the increased expression of melanosomal antigens. B) The increased antigen presentation may be indirect through antigen cross-presentation by host dendritic cells taking up dying cells. C) BRAF inhibitors may have direct stimulatory effects on T cells through paradoxical MAPK activation in the setting of wild type BRAF. D) Inhibition of oncogenic BRAF with BRAF inhibitors may decrease the release of immune suppressive factors, which indirectly would result in a more permissive intratumoral milieu for T cell infiltration.