The targeted delivery of interleukin-12 to the carcinoembryonic antigen increases the intratumoral density of NK and CD8+ T cell in an immunocompetent mouse model of colorectal cancer

J Gastrointest Oncol. 2020 Aug;11(4):803-811. doi: 10.21037/jgo.2020.04.02.


The recent success achieved by immune checkpoint inhibitors in the field of immuno-oncology has been less evident for the treatment of metastatic colorectal cancer (mCRC) patients. To date, cancer immunotherapy has been efficacious only in few patients bearing high mutational burden (less than 25%) mCRCs. In this Communication, we report the generation of a novel antibody cytokine fusion protein (termed Sm3E-mIL12) targeting the CRC-associated carcinoembryonic antigen (CEA). The antibody moiety bound avidly to CEA when immobilized on solid supports, and selectively stained C51 tumor cells transfected with the antigen (C51-CEA). The cytokine payload retained full activity in vitro, as compared to the parental recombinant interleukin-12 (IL12). Ex vivo microscopic analyses revealed a homogenous distribution of Sm3E-mIL12 in the neoplastic mass upon intravenous administration. In vivo, Sm3E-mIL12 was well tolerated up to 180 µg per mouse. The targeted delivery of IL12 to CEA-expressing C51 carcinomas led to durable complete responses in 60% of the treated mice. The intratumoral density of immune effector cells was markedly increased after the third injection of Sm3E-mIL12, in keeping with the progressive regression of the neoplastic mass. The data suggest that a fully human analogue may be considered for the treatment of patients with mCRC.

Keywords: Antibody-cytokine fusions; carcinoembryonic antigen; colorectal cancer; interleukin-12; tumor-infiltrating lymphocytes (TILs).