HLA LOH-Targeting Tmod Cell Therapies Demonstrate Selective Killing of Tumor Cells in Mice

Two of A2 Biotherapeutics’ autologous Tmod cell therapies, the carcinoembryonic antigen (CEA)-targeted A2B530 and the mesothelin (MSLN)-targeted A2B694, have demonstrated proof-of-concept in their abilities to target tumor cells in preclinical studies.^1,2

These data were presented at the Society for Immunotherapy of Cancer’s (SITC) 37th Annual Meeting, November 8-12, 2022, in Boston, Massachusetts. J. Randolph Hect, MD, professor, clinical medicine, David Geffen School of Medicine, University of California – Los Angeles (UCLA), and director, UCLA Gastrointestinal Oncology Program, gave the presentation on A2B530. Julian R. Molina, MD, PhD, oncologist, Mayo Clinic, gave the presentation on A2B694.

“Nearly all colorectal and more pancreatic and lung cancers express CEA. However, due to its expression in normal gut epithelial cells, CEA-targeted therapies have resulted in on-target, off-tumor toxicity. To overcome this, we have developed Tmod, a logic-gated T-cell therapy platform. Tmod constructs are composed of an activating chimeric antigen receptor (CAR) or T-cell receptor that targets a tumor antigen and an inhibitory receptor recognizing an antigen expressed on normal healthy tissues, but not on tumor cells due to loss of heterozygosity (LOH),” Hecht said during his presentation.¹

Both cell products are developed using T cells from HLA-A*02+ donors transduced with a lentivirus construct to express the CAR, the blocker, and a short-hairpin RNA targeting β2M. Cytotoxicity was measured in cultured cell lines that were CEA or MSLN+with LOH and no LOH. Mice were also treated intravenously with CEA/MSLN CAR Tmod cells or control T cells.

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“A2B530 is an autologous CEA Tmod cell product that exploits common loss of heterozygosity at the HLA locus in cancer cells, enabling these engineered T cells to distinguish between normal and tumor cells,” Molina said during his presentation.²

Both A2B530 and A2B694 exhibited on-target, off-tumor selectivity in vitro, as well as selective killing of tumor cells when mixed in culture with normal cells, with minimal off-target effects in vitro. This selective killing was also seen in vivo in mice models.

“BASECAMP-1 [NCT04981119], an observational study that will identify patients with somatic HLA LOH, is currently recruiting. Eligible patients with metastatic colorectal, pancreatic, ovarian, mesothelioma or non-small cell lung cancer will be apheresed for a future interventional study (EVEREST-2) [with A2B694],” Molina concluded his presentation.² Similarly, A2B530 will be evaluated in the future EVEREST-1 interventional study.

Another poster presented at the SITC meeting gave updates on the BASECAMP-1 trial, which has enrolled 4 participants so far. The trial is enrolling in sites across the US.

“The unmet medical need in lung, colorectal and particularly pancreatic cancer remains extremely high. BASECAMP-1 is a non-interventional pre-screening trial that identifies eligible patients and banks their T cells. If the patients have the misfortune to relapse or progress, A2 Bio will have their cells ready to be manufactured and dosed in our upcoming Phase 1 studies targeting CEA and MSLN,” William Go, MD, PhD, chief medical officer, A2 Bio, said in a statement.³

REFERENCES

1. Mardiros A, Patel S, Kamb A, et al. A2B530, an autologous CEA-directed Tmod T-cell therapy with an inhibitory receptor gated by HLA-A*02 to target colorectal, pancreatic, and lung cancer. Presented at: SITC 37th Annual Meeting, November 8-12, 2022, Boston, Massachusetts. Abstract #229.
2. Patel S, Kamb A, Morelli MP, et al. A2B694, an autologous logic-gated cell therapy targeting mesothelin. Presented at: SITC 37th Annual Meeting, November 8-12, 2022, Boston, Massachusetts. Abstract #263.
3. A2 Bio identifying solid tumor patients for possible inclusion in phase 1 studies targeting CEA and mesothelin expected to begin in 2023: Update at SITC 2022. News release. A2 Bio. November 7, 2022. https://www.businesswire.com/news/home/20221107005336/en/A2-Bio-Identifying-Solid-Tumor-Patients-for-Possible-Inclusion-in-Phase-1-Studies-Targeting-CEA-and-Mesothelin-Expected-to-Begin-in-2023-Update-at-SITC-2022