Targeted Therapy and Checkpoint Immunotherapy Combinations for the Treatment of Cancer

Many advances in the treatment of cancer have been driven by the development of targeted therapies that inhibit oncogenic signaling pathways and tumor-associated angiogenesis, as well as by the recent development of therapies that activate a patient's immune system to unleash antitumor immunity. Some targeted therapies can have effects on host immune responses, in addition to their effects on tumor biology. These immune-modulating effects, such as increasing tumor antigenicity or promoting intratumoral T cell infiltration, provide a rationale for combining these targeted therapies with immunotherapies. Here, we discuss the immune-modulating effects of targeted therapies against the MAPK and VEGF signaling pathways, and how they may synergize with immunomodulatory antibodies that target PD1/PDL1 and CTLA4. We critically examine the rationale in support of these combinations in light of the current understanding of the underlying mechanisms of action of these therapies. We also discuss the available preclinical and clinical data for these combination approaches and their implications regarding mechanisms of action. Insights from these studies provide a framework for considering additional combinations of targeted therapies and immunotherapies for the treatment of cancer.

TrendsTargeted therapies inhibit tumor-intrinsic drivers of growth and can elicit significant but transient clinical responses.Immunotherapies enhance host antitumor immunity and can elicit durable responses in subsets of patients across multiple tumor types. Checkpoint inhibitors are immunotherapies that relieve suppressive signals acting on host T cells to unleash antitumor T cell activity.In some cases, targeted therapies can enhance aspects of cancer immunity, such as tumor antigenicity, T cell trafficking, or T cell infiltration into tumors, which provides a rationale for combining them with checkpoint inhibitors or other cancer immunotherapies that may lead to synergistic efficacy.Considerations for the clinical development of combinations of targeted therapies and immunotherapies include optimizing dosing regimens, minimizing treatment related toxicities, and selecting appropriate biomarkers and endpoints to assess efficacy.