Abstract CT131: Initial preclinical and clinical experience of autologous engineered monocytes in T cell lymphoma patients
Authors: Gerber Michele , Prod'homme Thomas , Wang Yuxiao , Kieffer-Kwon Kyong-Rim , Diwanji Neha , D'Alessandro Josephine , Du Xing , Cochran Edward , Gorgievski Michael , Ling Zheng , King Nicholas , Mukherjee Siddhartha , Getts Daniel 
Published: April 2023

Abstract
For many patients with T cell lymphomas (TCL), sustained clinical benefit with standard treatment options is elusive. Myeloid cells, such as monocytes, dendritic cells and macrophages, readily accumulate in tumors, whereby they support tumor progression. The ability to harness the capability of myeloid cells to penetrate into tumors, and to subsequently program them to activate and elicit broad anti-tumor immunity has the potential to transform cancer therapies. With this goal we developed the first engineered monocyte cell product, by manipulating autologous monocytes to express a novel chimeric antigen receptor (CAR). This CAR contains a tumor recognition domain fused to a CD8 hinge domain, Fcγ and PI3K intracellular signaling domains. In addition to imparting tumor specificity, the Fcγ and PI3K signaling domains promote phagocytosis, cytokine production and antigen presentation upon activation. In a rodent model of melanoma (gp75+ B16/F10-OVA), Ly6C+ monocytes engineered with this receptor were able to phagocytose tumor cells and cross present antigen in vitro. In vivo infusion of engineered monocytes was associated with significant suppression of tumor growth. FACS analysis of tumor-infiltrates demonstrated that engineered monocytes preferentially infiltrated tumors and differentiated into antigen presenting cells. Adoptive T cell transfer of CFSE-labeled OT-I CD8+ T cells confirmed that treatment was also associated with increased accumulation of tumor specific T cells in tumor and spleen. Based on these promising data, MT-101 is being assessed in humans in the Phase 1, open-label, first-in-human trial in patients with refractory or relapsed T cell lymphoma, IMAGINE trial (NCT05138458). The primary objective is the assessment of safety and tolerability at Day 28, following 3 weekly cycles of 2 infusions. Secondary objectives include assessment of correlative markers of response, pharmacokinetics, and efficacy. In the first 3 subjects, MT-101 has been well-tolerated, with no evidence of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), or infusion reactions. Examination of biomarkers by CyTOF in one subject shows changes in circulating leukocytes, including B cells. In this subject, survival has been greater than 10 months, while the median overall survival of patients with R/R PTCL is 5.5 months. Continued patient enrollment and data collection is ongoing to confirm these observations.
Citation Format: Michele Gerber, Thomas Prod'homme, Yuxiao Wang, Kyong-Rim Kieffer-Kwon, Neha Diwanji, Josephine D'Alessandro, Xing Du, Edward Cochran, Michael Gorgievski, Zheng Ling, Nicholas King, Siddhartha Mukherjee, Daniel Getts. Initial preclinical and clinical experience of autologous engineered monocytes in T cell lymphoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT131.