Dual Receptor Modular CAR T-Cell Therapy Shows Preclinical Efficacy


A2 Biotherapeutics is developing CEA- and MSLN- targeted Tmod CAR T-cell therapies.

A2 Biotherapeutics has published preclinical data that demonstrate the selective efficacy against cancer cells of its chimeric antigen receptor (CAR) modular T-cell (Tmod) technology.1,2

The Tmod therapy has dual receptors towards human leukocyte antigen (HLA)–A*02 and a target such as carcinoembryonic antigen (CEA) or mesothelin (MSLN). The dual receptors cause the cells to target cancer cells with HLA loss of heterozygosity (LOH) expressing the target while sparing healthy, HLA-expressing tissue.

“These two papers present a large body of preclinical in vitro and in vivo evidence that supports the robust, highly selective function of the Tmod™ system, a new approach to cancer therapy that addresses head-on the central problem of oncology – the ability of cancer medicines to distinguish between tumor and normal cells,” Alexander Kamb, chief scientific officer, A2 Bio, said in a statement.3

The first paper was published in January 2022 in the Journal for ImmunoTherapy of Cancer by senior author Agi Hamburger, PhD, vice president, drug discovery, A2 Bio, and colleagues.1 The paper discusses the potential of MSLN as a target for Tmod therapy in lung cancer and other solid tumors. Hamburger and colleagues demonstrated similar specificity of MSLN-Tmod therapy to MSLN-CAR T-cell therapy without the toxicities.

“Our publication not only describes the properties of an exciting new prospect for lung cancer patients but also highlights the impressive modularity of our Tmod™ platform, a platform that we hope can be extended to create therapies for many other cancer patients in the future,” Hamburger added to the statement.3

The second paper was published in March 2022 in Science Translational Medicine by senior author Han Xu, PhD, vice president, therapeutic technology, A2 Bio, and colleagues.2 This paper explored CEA-targeted Tmod therapies for the potential treatment of solid tumors in the colon and other organs. Xu and colleagues found similar positive specificity data with CEA-Tmod therapies compared to CEA-CAR T-cell therapies. A2 Bio is planning to soon advance CEA-targeted Tmod therapies into phase 1 trials.

“Our preclinical data suggest that this cell-based medicine will have the potency of a clinically active CEA-targeted therapeutic benchmark, but without the toxicity,” Xu added to the statement.3

In addition to preclinical studies, A2 Bio is also conducting the observational BASECAMP-1 study, which is meant to identify patients with relapsed solid tumors with HLA LOH as a future target for MSLN- and CEA-targeted Tmod CAR T-cell therapies.

CGTLive previously spoke to Julian Molina, MD, PhD, professor, oncology, Mayo Clinic, and investigator on the BASECAMP-1 study, to learn more about the observational study and the potential of Tmod CAR T-cell therapies in this population. He discussed the benefit of targeting tumors with HLA LOH while sparing healthy, HLA-expressing tissue. Watch part of the conversation below.

1. Tokatlian T, Asuelime GE, Mock J, et al. Mesothelin-specific CAR-T cell therapy that incorporates an HLA-gated safety mechanism selectively kills tumor cells. JImmunother Cancer. 2022; 10: e003826. doi:10.1136/jitc-2021-003826
2. Sandberg ML, Wang X, Martin AD, et al. A carcinoembryonic antigen-specific cell therapy selectively targets tumor cells with HLA loss of heterozygosity in vitro and in vivo. SciTransl Med. 2022; 14(634). doi:10.1126/scitranslmed.abm0306/
3. A2 Bio publishes key preclinical findings demonstrating potential of its highly selective Tmod™ cell therapy platform to revolutionize the treatment of solid tumors in select patients. News release. A2 Biotherapeutics. March 2, 2022. https://www.a2bio.com/a2-bio-publishes-key-preclinical-findings-demonstrating-potential-of-its-highly-selective-tmod-cell-therapy-platform-to-revolutionize-the-treatment-of-solid-tumors-in-select-patients/
4. Molina J, Go W, Kopetz S, et al. BASECAMP-1: an observational study to identify relapsed solid tumor patients with human leukocyte antigen (HLA) loss of heterozygosity (LOH) and leukapheresis for future CAR T-cell therapy. Presented at: 2021 SITC Annual Meeting. November 10-14, 2021; Washington, DC. Abstract 491.
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