Anti–Programmed Death-1 Synergizes with Granulocyte Macrophage Colony-Stimulating Factor–Secreting Tumor Cell Immunotherapy Providing Therapeutic Benefit to Mice with Established Tumors

Abstract

Purpose: The purpose of the present study was to evaluate granulocyte macrophage colonystimulating factor (GM-CSF)^secreting tumor cell immunotherapy, which is known to stimulate potent and long-lasting antigen-specific immune responses, in combination with PD-1blockade, which has been shown to augment cellular immune responses. Experimental Design: Survival studies were done in the B16 melanoma and CT26 colon carcinoma tumor models. Immune monitoring studies were done in the B16 model. GM-CSF^secret-ing tumor cell immunotherapy was administered s.c. and the anti^PD-1 antibody was administered i.p. Results:The studies reported here show that combining PD-1blockade with GM-CSF^secret-ing tumor cell immunotherapy prolonged the survival of tumor-bearing animals compared with animals treated with either therapy alone. Prolonged survival correlated with strong antigen-specific T-cell responses detected by tetramer staining and an in vivo CTL assay, higher secretion levels of proinflammatory cytokines by splenocytes, and the persistence of functional CD8 + T cells in the tumor microenvironment. Furthermore, in the biweekly multiple treatment setting, repeated antigen-specificT-cell expansion was only observed following administration of the cellular immunotherapy with the PD-1 blockade and not when the cellular immunotherapy or PD-1 blockade was used as monotherapy. Conclusion:The combination of PD-1 blockade with GM-CSF^secreting tumor cell immunotherapy leads to significantly improved antitumor responses by augmenting the tumor-reactive T-cell responses induced by the cellular immunotherapy. Readministration of the cellular immunotherapy with the anti^PD-1antibody in subsequent immunotherapy cycles was required to reactivate theseT-cell responses.

In VitroCharacterization of the Anti-PD-1 Antibody Nivolumab, BMS-936558, andIn VivoToxicology in Non-Human Primates

“…However, slightly higher antibody titers to a cellular vaccine directed, at least in part, against the HLA-A2404 antigen expressed on SK-MEL3 cells, were detected in monkeys treated with 10 mg/kg of nivolumab. In mice, anti-PD-1 antibody can promote T-cell responses to a GVAX cellular vaccine (44) and to peptide-loaded DC vaccination (K. Bahjat et al; unpublished data). Although not a vaccine study, it is noteworthy that simian immunodeficiency virus (SIV)-infected monkeys treated with an anti-PD-1 antibody showed increased humoral responses to SIV antigens (45).…”

Anti-SIRPα antibodies as a potential new tool for cancer immunotherapy

“…Immunotherapy with Abs against PD-1 that block the inhibitory PD-1/PD-L1 axis has recently been found to provide substantial clinical benefit in patients with a wide range of cancer types (5). Such Abs also exert antitumor activity in immunocompetent mice implanted with various types of mouse cancer cells including colon cancer cells (38,39). We therefore examined the impact of combination therapy with MY-1 and an Ab against PD-1 (4H2) that blocks the PD-1-PD-L1 interaction (39) on the growth of tumors formed by mouse CT26 colon cancer cells in BALB/c mice.…”

PD-1 blockade enhances elotuzumab efficacy in mouse tumor models

“…The generation of an antimouse PD-1 mAb, clone 4H2, has previously been described. 41 To generate non-FcgR-binding PD-1-mg1-D265A 42 and elotuzumab-mg1-D265A variants, V H and Vk sequences from the parental mAbs were grafted onto a murine IgG1 constant region containing the D265A mutation. Control antibodies included mIgG2a (clone C1.18.4, BioXCell) and mIgG1 (Bristol-Myers Squibb, Princeton, NJ).…”