LAUSR

Immune checkpoint therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1, have led to significant clinical responses in cancer patients. However, there are still substantial numbers of patients who do not respond to anti-CTLA-4 or anti-PD-1/PD-L1. We and others have demonstrated that treatment of patients with immune checkpoint therapies impacts immune responses to enhance effector T-cell responses but also leads to increased expression of compensatory pathways or development of adaptive resistance mechanisms that act to abrogate antitumor immune responses. Rational combination strategies to address these compensatory pathways and/or adaptive resistance mechanisms, including those that permit blockade of multiple T-cell inhibitory pathways or blockade of inhibitory pathways plus targeting of co-stimulatory pathways or intervention with agents, such as epigenetic agents, to promote differentiation of effector T cells and/or M1 macrophages, are at the forefront of preclinical and clinical studies as the field of immune checkpoint therapy aims to provide benefit to even more patients. Combination therapies with anti-CTLA-4 and anti-PD-1 have already shown improved patient benefit. The next promising combinations include those with ICOS, CD47, VISTA, oncolytic viruses, and EZH2-inhibitors, to name a few. Preclinical and clinical data regarding these targets will be discussed in greater detail. Citation Format: Padmanee Sharma. Immune checkpoint therapy: From CTLA-4 to PD-1/PD-L1 and beyond [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr PL01-02.