PT-112 induces immunogenic cell death and synergizes with immune checkpoint blockers in mouse tumor models

Abstract

PT-112 is a novel platinum-pyrophosphate conjugate under clinical development for cancer therapy. PT-112 mediates cytostatic and cytotoxic effects against a variety of human and mouse cancer cell lines in vitro. The cytotoxic response to PT-112 is associated with the emission of danger signals underpinning the initiation of anticancer immunity, including calreticulin exposure on the surface of dying cells, as well as ATP and HMGB1 secretion. Consistently, mouse cancer cells succumbing to PT-112 in vitro can be used to provide syngeneic, immunocompetent mice with immunological protection against a subsequent challenge with living tumor cells of the same type. Moreover, PT-112 administration synergizes with PD-1 or PD-L1 blockade in the control of mouse cancers in immunologically competent settings, as it simultaneously recruits immune effector cells and depletes immunosuppressive cells in the tumor microenvironment. Finally, PT-112 employed intratumorally in the context of immune checkpoint inhibition initiates a robust immune response that has systemic outreach and limits the growth of untreated, distant lesions. Thus, PT-112 induces the immunogenic demise of cancer cells, and hence stands out as a promising combinatorial partner of immune checkpoint blockers, especially for the treatment of otherwise immunologically cold tumors.

A novel platinum-based chemotherapeutic inducing immunogenic cell death

“…Moreover, cells killed with PT-112 elicited a protective immune response in vivo, and tumors treated with PT-112 locally could enable at least some degree of systemic disease control in abscopal models. 12 Most importantly, in vivo, in mice, PT-112 sensitized tumors to subsequent treatment with PD-1 blocking antibodies, strongly supporting the rather anecdotic clinical evidence at the preclinical level. Finally, PT-112-treated tumor exhibited signs of improved local immune control with a major increase in the ratio of cytotoxic T lymphocytes over regulatory T cells that was particularly strong when PT-112 was combined with PD-1 blockade.…”

“…Finally, PT-112-treated tumor exhibited signs of improved local immune control with a major increase in the ratio of cytotoxic T lymphocytes over regulatory T cells that was particularly strong when PT-112 was combined with PD-1 blockade. 12 Altogether, these findings suggest the possibility that anticancer agents that favorably interact with PD-1/PD-L1targeting immunotherapy usually act as ICD inducers. Future studies should address this conjecture that, if true, would streamline mode of action studies from a serendipitous to a strongly hypothesis-driven strategy.…”

Trial watch: TLR3 agonists in cancer therapy

“…112 This effect appears to be orchestrated by multiple changes within the lymphoid compartment of the tumor microenvironment, encompassing an increased abundance of CD8 + CTLs expressing the effector molecule granzyme B (GZMB), 145 a reduction in the relative amount of tumor-infiltrating CD4 + CD25 + FOXP3 + regulatory T (T REG ) cells 105 (with respect to CD8 + cells), an improved proliferation of tumor-antigen specific CD8 + CTLs, as well as an enhanced expression of programmed cell death 1 (PDCD1, best known as PD-1) 146 and its main ligand CD274. These findings suggest that, similar to numerous chemotherapeutic agents that promote PD-L1 expression, 147,148 polyA:U might be advantageously combined with immunotherapies blocking the PD-1/ PD-L1 axis. 112,149,150 Ampligen™, an analogue of polyI:C Ampligen™ (also known polyI:C 12 U, AMP-516 or rintatolimod) was synthesized in the 1970 s by William A. Carter by adding unpaired uracil and guanine bases to the classical polyI:C structure.…”

Trial watch: IDO inhibitors in cancer therapy

“…The NCT02298153 ECHO-11O Phase Ib trial evaluated the efficacy, tolerability and safety of the epacadostat administered together with the PD-L1 blocker atezolizumab, [129][130][131] to 29 patients with stage IIIB/IV NSCLC previously treated with platinum derivatives [132][133][134][135][136] chemotherapy in conjunction with a folic acid analogue. [137][138][139] Seventy-nine percent of enrolled patients experienced TRAEs, 17% discontinued treatment due to such effects, one patient showed anticancer partial response, and the maximum tolerated dose (MTD) was not achieved.…”