Immune checkpoint inhibitor combinations: Current efforts and important aspects for success.

Immune checkpoint inhibitors (ICI) have emerged as a remarkable treatment option for diverse cancer types. Currently, ICIs are approved for an expanding array of cancer indications. However, the majority of patients still do not demonstrate a durable long-term response following ICI therapy. In addition, many patients receiving ICI therapy develop immune-related adverse events (irAEs) affecting a wide variety of organs. To increase the percentage of patients who benefit from ICI therapy and to reduce the occurrence of irAEs, there is an ongoing effort to combine current ICIs with novel checkpoints inhibitors or other therapeutic approaches to achieve a synergistic effect which is larger than the sum of its parts. In this review we highlight the essential factors for more effective ICI combinations. We describe how the design of these strategies should be driven by the tumor's immunological context. We analyze current combination strategies and describe how they can be improved to unleash the immune system's full anti-cancer potential as well as convert immunologically "cold" tumors into "hot" ones. We examine the efforts to combine current ICIs (PD-1 and CTLA-4) with novel checkpoints (TIM-3, LAG-3, VISTA, TIGIT and others), immunotherapies (CAR-T cells and Cancer Vaccines) and delivery strategies (bispecific antibodies and other delivery platforms). Importantly, we outline how can one optimally combine ICIs with traditional pillars of cancer therapy such as radiation therapy (RT) and chemotherapy. We discuss the considerations regarding successful combination with RT and chemotherapy; these include fractionation schemes and selection of chemotherapeutics which can both directly eradicate cancer cells as well as increase the infiltration of immune cells into tumors. Finally, we critically assess these approaches and attempt to establish their strengths and weaknesses based on pre-clinical and clinical data.

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