Safety of Autologous Infusion of CER T Cells in Nonhuman Primates.

Cellular immunotherapies have shown great promise in the treatment of various diseases. Chimeric engulfment receptor (CER)-engineered T cells were developed to utilize the extracellular T-cell immunoglobulin and mucin domain-containing 4 (TIM-4) domain and intracellular engulfment signaling domains to target and enhance phagocytosis and T-cell cytotoxic function. These processes are activated through TIM-4 binding with phosphatidylserine (PS), a pro-phagocytic "eat me" signal. HIV infection has been shown to induce extracellular PS exposure shortly after infection, and engineered CER T cells have been shown to kill CD4+ T cells infected with simian immunodeficiency virus (SIV) in vitro. In this study, we infused two rhesus macaques (RMs) with CER-1236 T cells (the iteration of CER T cells currently moving forward in human clinical trials for cancer) and evaluated safety, the tissue distribution of the CER-1236 T cells, and antiviral activity against SIV (SIVmac239). Prior to infusions, RMs underwent SIV infection, antiretroviral therapy (ART), and ART cessation. The infusions were well tolerated. Neither of the macaques exhibited clinical evidence of illness nor changes in vital signs, serum chemistry, hematology, or other evaluated physiological parameters beyond what is typically observed with SIV infection. Post-infusion proliferation of CER T cells in PBMC was limited and seen with cells manufactured by the Prodigy system. Histologic and flow cytometry evaluation from post-infusion tissue biopsies and necropsy revealed tissue detection of CER T cells in bronchoalveolar lavage fluid with intermittent detection of infused cells in lymphoid tissue in concert with the limited expansion of T cells in PBMC. No laboratory or clinical evidence of hepatic, splenic, bone marrow, or CNS alterations was noted, and no evidence of in vivo suppression of SIVmac239 was observed as a result of the infusions. The CER-1236 T cell infusions were not associated with any discernable histopathological toxicity. This safety profile of CER-1236 T cells in nonhuman primates portends well for its potential for clinical development, especially for tumors with high expression of the tissue damage receptor PS. Optimization of in vivo functionality will be required for CER T cells to be effective against HIV infection.