HLA LOH Prevalent in GI Cancers, Identifies Future Study Participants

Investigators have identified the prevalence of Human Leukocyte Antigen Loss of Heterozygosity (HLA LOH) in gastrointestinal (GI) tumors as part of the BASECAMP-1 study (NCT04981119) for future use of Tmod chimeric antigen receptor (CAR) T-cell therapy.¹

The BASECAMP-1 study used Tempus next-generation sequencing (NGS) to detect HLA LOH, which was detected in 830 (17.3%) of all solid tumor records and 17.0% of all GI cancer records. For GI cancer subtypes, 880 (13.5%) of colorectal cancer records, 325 (21.8%) of pancreatic cancer records, and 234 (23.1%) of gastroesophageal cancer records had HLA LOH.

These data were presented at the 2022 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers (GI) Symposium, January 20-22, 2022, by J. Randolph Hecht, MD, professor, clinical medicine, David Geffen School of Medicine, University of California Los Angeles.

“A2 Bio has developed Tmod CAR T, which targets clonal HLA LOH as a clear differentiator between normal versus tumor cells,” William Go, MD, PhD, chief medical officer, A2 Bio, said in a statement.² “The Tempus xT next generation sequencing assay will be utilized in BASECAMP-1. BASECAMP-1 is a study to identify HLA LOH solid tumor cancer patients and obtain their T cells earlier in their treatment paradigm who may benefit from future carcinoembryonic antigen (CEA) and mesothelin (MSLN) Tmod CAR T therapy. Novel therapies are sorely needed in GI malignancies, especially in pancreatic cancer, where limited therapeutic advances have been made in over two decades.”

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A2 Biotherapeutics previously presented an overview of the BASECAMP-1 study at the 36th Annual Meeting of the Society for Immunotherapy of Cancer (SITC), November 10-14, 2021, by Julian Molina, MD, PhD, professor, oncology, Mayo Clinic.³

“HLA LOH is the tool that is going to allow us to discriminate normal cells from cancer cells. It's going to allow the target construct to be able to be more specific and to prevent some of those off-target effects. We're starting with HLA-A*02 because this is the most prevalent allele. The key issue is going to be for us to identify this group of patients that have HLA loss in the tumors because those are the candidates for future studies,” Molina told GeneTherapyLive in a previous interview.

In the study, participants that pass screenings for HLA LOH will undergo leukapheresis, be monitored for safety after leukapheresis, and followed for relapses. If relapse occurs, the participant’s banked T cells will be available for autologous CAR T-cell therapy.

Agnes Hamburger, PhD, vice president, drug discovery, A2 Biotherapeutics, also presented feasibility data at SITC 2021 on the company’s Tmod technology.⁴ Data showed that the Tmod system has a robust protective effect on surrogate normal human cells in vitro, even in mixed-cell populations, while also yielding a robust cytotoxic effect on tumor cells in xenograft models. The system, which targets MSLN and CEA, can be paired with other blockers to scale the approach beyond HLA-A*02 patients.

REFERENCES

1. Hecht JR, Kopetz S, Patel SP, et al. Next generation sequencing (NGS) to identify relapsed gastrointestinal (GI) solid tumor patients with human leukocyte antigen (HLA) loss of heterozygosity (LOH) for future logic-gated CAR T therapy to reduce on target off tumor toxicity. Presented at: 2022 ASCO GI Symposium. Poster #J9
2. A2 Bio to Present at ASCO-GI 2022 on Use of Next Generation Sequencing (NGS) to Identify GI Cancer Patients for Future TmodTM CAR T Therapy. News release. A2 Biotherapeutics. January 18, 2022. https://www.a2bio.com/a2-bio-to-present-at-asco-gi-2022-on-use-of-next-generation-sequencing-ngs-to-identify-gi-cancer-patients-for-future-tmodtm-car-t-therapy/
3. 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.
4. Hamburger A, Xu H, Ando Y, et al. A powerful, precise targeting system controlled by tumor deletions transforms CEA and MSLN CAR-T cells into tumor-selective agents. Presented at: 2021 SITC Annual Meeting; November 10-14, 2021; Washington, DC. Abstract 122.