IN8bio, Inc. announced new preclinical data from its non-signaling gamma-delta T cell based Chimeric Antigen Receptor-T cell (nsCAR) platform, known as INB-300, that demonstrated improved selectivity to target leukemia cells while preserving healthy ones. The data support the potential for nsCAR to have a wider therapeutic window and to be used to prevent on-target off-tumor killing of healthy tissue that may express the CAR-T target. The data was presented in a poster session at the American Association for Cancer Research (AACR) Annual Meeting 2024 on April 9, 2024.

IN8bio's nsCAR platform is based on the natural ability of gamma-delta T cells to distinguish between healthy and malignant tissue. By using a Chimeric Antigen Receptor that lacks a signaling domain, IN8bio believes it has created a technology that enables these cells to differentiate between tumor and healthy tissue, even when both express the CAR-targeted antigen. Approved CAR-T therapies have shown remarkable efficacy against B cell malignancies, offering hope to patients with limited treatment options.

However, extending this therapy to myeloid malignancies and solid tumors has proven challenging since the antigens they target are also often found on the surface of healthy blood cells and tissues. This unintended targeting of healthy cells and tissues has led to many of the toxicities, including patient deaths, observed in prior CAR-T therapies and has limited their utility. Unlike traditional CAR-T therapy, IN8Bio?s nsCAR is designed to direct the gamma delta T cell to its target while maintaining their unique gamma-delta T cell receptors, allowing them to identify and specifically eliminate heterogeneous tumor cells through recognition of tumor-associated stress antigens.

The new data presented at AACR included results from proprietary constructs targeting CD33 and/or CD123 for in vitro evaluation against various types of leukemia, including acute myeloid leukemia and chronic myeloid leukemia. The study results demonstrated notable differences between cells expressing traditional signaling CARs and those expressing the nsCAR constructs, which include a reduction in activation-induced cell death with nsCAR constructs. The nsIL3-33mb15 CAR (CD123+CD33+IL-15) enhancement of the gamma delta T cells against leukemia cells demonstrated an average 1.8x increase in tumor killing capability across three AML cell lines (HL-60, KG-1a and MOLM-13), compared to unmodified gamma-delta T cells as measured by a 24-hour cytotoxicity assay.

Importantly, the nsCAR cells did not lead to significant killing of healthy cells expressing the CD33 or CD123 target, demonstrating the selectivity of the nsCAR platform. Results were run in triplicate and on average the selectivity was increased by 5.5x. Across all runs, killing by the nsIL3-33mb15 construct against healthy CD34+ HPCs was below that of un-transduced control gamma-delta T cells.