Antibody drugs which block engagement of the T cell co-inhibitory receptor programmed cell death-1 (PD-1) or its cognate ligand programmed death-1 ligand 1 (PD-L1) are the cornerstone of immunotherapy’s emergence as a key pillar of modern oncology. For patients with “hot”, immune infiltrated cancers, PD-1 blockade offers moderate to high frequencies of objective clinical responses and the chance of durable lifelong cures. The majority of cancer patients, however, present with “cold” tumors with low frequencies of immune-targetable mutations and little or no immune infiltration. In this setting, PD-1 blockade benefits less than 5% of patients and there are no FDA-approved indications excepting the small minority of patients with underlying mismatch-repair deficiencies. Even across the “hot” and “warm” cancers for which there are FDA-approved PD-(L)1 indications, the response rate to PD-1 blockade remains under 25%. Thus, a critical need exists for immunotherapies that both provide more consistent benefit for patients with immune-infiltrated tumors, and also mediate significant clinical responses against “cold” cancers.
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