Harness the synergy between targeted therapy and immunotherapy: what have we learned and where are we headed?

Since the introduction of imatinib for the treatment of chronic myelogenous leukemia, several oncogenic mutations have been identified in various malignancies that can serve as targets for therapy. More recently, a deeper insight into the mechanism of antitumor immunity and tumor immunoevasion have facilitated the development of novel immunotherapy agents. Certain targeted agents have the ability of inhibiting tumor growth without causing severe lymphocytopenia and amplifying antitumor immune response by increasing tumor antigenicity, enhancing intratumoral T cell infiltration, and altering the tumor immune microenvironment, which provides a rationale for combining targeted therapy with immunotherapy. Targeted therapy can elicit dramatic responses in selected patients by interfering with the tumor-intrinsic driver mutations. But in most cases, resistance will occur over a relatively short period of time. In contrast, immunotherapy can yield durable, albeit generally mild, responses in several tumor types via unleashing host antitumor immunity. Thus, combination approaches might be able to induce a rapid tumor regression and a prolonged duration of response. We examine the available evidence regarding immune effects of targeted therapy, and review preclinical and clinical studies on the combination of targeted therapy and immunotherapy for cancer treatment. Furthermore, we discuss challenges of the combined therapy and highlight the need for continued translational research.