Checkpoint inhibitor therapy in combination with the implantation of agarose encapsulated cancer cells inhibits tumor growth in a mouse model of osteosarcoma

Abstract We have previously shown that murine renal adenocarcinoma (RENCA) cells encapsulated in agarose macrobeads (MB) secrete factors that inhibit the proliferation of freely growing tumor cells outside the MB, both in vitro and in vivo. This effect is being investigated in ongoing clinical trials with colorectal patients who underwent laparoscopic intraperitoneal implantations of RENCA MBs (NCT01053013, NCT02046174). In the current study, we report the effect of immune checkpoint inhibitors (anti-PD-1 and anti-PD-L1 monoclonal antibodies) in combination with RENCA MBs on tumor burden in BALB/cJ mice induced with K7M2 murine osteosarcoma tumors. Mice that developed tumors (2-5 mm) on subcutaneous injection of K7M2 cells were randomly enrolled in the following study groups: sham, RENCA MBs only, anti-PD-1 only, RENCA MBs + anti-PD-1, anti-PD-L1 only, RENCA MBs + anti-PD-L1. Anti-PD-1 and anti-PD-L1 antibodies were administered ip bi-weekly for 3-6 weeks. RENCA MBs were implanted in the peritoneal cavity on the day of enrollment. Mean tumor volumes (mm3) throughout days 0-24 were: RENCA MB (199.17 ± 125.57), anti-PD-1 only (278.87 ± 180.34), anti-PD-L1 only (332.46 ± 185.13) and sham treated mice (512.61 ± 230.12). RENCA MB and anti-PD-L1 combination therapy did not inhibit tumor growth (375.00 ± 511.61). PD-L1 expression was absent in primary tumors as observed by immunostaining. Treatment with RENCA MBs plus anti-PD-1 treatment demonstrated an additive effect (116.94 ± 83.77) compared to RENCA MB only or anti-PD-1 alone. Moreover, tumors in 4 out of 16 mice from the RENCA MB plus anti-PD-1 group receded and were undetectable (3 in less than 1 week and 1 at 39 days) following treatment. Tumors also regressed and were not palpable in 1 mouse each in the anti-PD-1 and RENCA MB plus anti-PD-L1 groups at day 14 and 9, respectively. Discontinuation of anti-PD-1 and anti-PD-L1 treatment after 3 weeks of treatment resulted in loss of tumor growth regulation. Preliminary data suggests that continued treatment with these immune checkpoint inhibitors beyond 3 weeks prolongs the regulation of tumor growth in this model. These data support the use of anti-PD-1 in combination with the implantation of RENCA macrobeads in this mouse model of osteosarcoma, and the possibility of similar approaches in the clinic. Citation Format: Pradeep R. Dumpala, Prithy C. Martis, Melissa A. Bemrose, Atira Dudley, Barry H. Smith, Lawrence S. Gazda. Checkpoint inhibitor therapy in combination with the implantation of agarose encapsulated cancer cells inhibits tumor growth in a mouse model of osteosarcoma [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 2731.