Abstract
This study determined the influence of intravenous (i.v.) oncolytic vaccinia virus mpJX-594 (mpJX) on antitumor activity of anti-programmed death receptor-1 antibody (aPD1) in functional and metastatic pancreatic neuroendocrine tumors (PanNETs). One i.v. dose of mpJX, engineered for mice with the same plasmid design as clinical virus Pexa-Vec, was administered alone or with repeated dosing of aPD1 (mpJX+aPD1) to two contrasting genetic models of PanNET: one developing benign insulin-secreting tumors (RIP1-Tag2;C57BL/6J mice) and the other developing liver metastases (RIP1-Tag2;AB6F1 mice). Experiments revealed that aPD1 had synergistic actions with mpJX on CD8+ T cell and natural killer (NK) cell influx, apoptosis, and suppression of proliferation in PanNETs. After mpJX+aPD1, the 53-fold increase in apoptosis (5 days) and 85% reduction in proliferation (20 days) exceeded the sum of mpJX and aPD1 given separately. mpJX+aPD1 also stabilized blood insulin and glucose in mice with functional PanNETs, regressed liver metastases in mice with aggressive PanNETs, and prolonged survival of both. The findings revealed that mpJX+aPD1 converted “cold” PanNETs into immunogenic tumors with widespread cytotoxic T cell influx, tumor cell killing, and suppression of proliferation. Reduction of tumor insulin secretion from functional PanNETs prolonged survival, and anti-metastatic actions on aggressive PanNETs reduced the metastatic burden to less than before treatment. The findings support the efficacy of the vaccinia virus with aPD1 for functional and metastatic PanNETs.
Highlights
Immune checkpoint blockade, which promotes antitumor immunity by targeting programmed death receptor-1(PD-1), PD-ligand 1 (PDL1), or other immune checkpoints has promising efficacy in some cancers
The influence of i.v. administration of the vaccinia virus mpJX with concurrent checkpoint blockade by aPD1 was assessed by determining (1) the balance of tumor cell killing and growth suppression in spontaneous pancreatic neuroendocrine tumors (PanNETs) in RT2;B6 mice; (2) the time course of infection, types of immune cells recruited, and amount of vascular remodeling in tumors in RT2;B6 mice as factors contributing to antitumor activity; and (3) the effects on liver metastasis in RT2;AB6F1 mice
The foregoing data were from mouse cohorts balanced for sex, we evaluated metastasis number, size, and burden separately in both sexes because male RT2;AB6F1 mice are reported to have more aggressive liver metastasis.[28]
Summary
Immune checkpoint blockade, which promotes antitumor immunity by targeting programmed death receptor-1(PD-1), PD-ligand 1 (PDL1), or other immune checkpoints has promising efficacy in some cancers. Numerous studies have reported clinical responses to immune checkpoint inhibition in a subset of patients with immunogenic tumors with cytotoxic T cell infiltration.[1]. Neuroendocrine neoplasms (NENs), classified by the World Health Organization as pancreatic neuroendocrine tumors (PanNETs), poorly differentiated pancreatic neuroendocrine carcinomas (PanNECs), and other advanced NENs,[2] are among the cancers in which immune checkpoint inhibitors have been used.[3,4] limited efficacy in these patients[5] drives the search for combinations with other agents that increase responses by turning immunologically “cold” tumors into “hot” tumors.[1]. Oncolytic viruses that amplify antitumor responses are among the treatment combinations being assessed for increasing susceptibility to immune checkpoint blockade.[6,7,8,9,10,11,12] The approach is supported by preclinical and clinical studies showing that oncolytic viruses increase cytotoxic and memory T lymphocyte influx and promote antitumor immunity.[13,14]
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