A2 Bio’s Screening Study Identifies Eligible Patients for Treatment With Tmod CAR-T

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The BASECAMP-1 screening study has now identified 28 patients whose solid tumors are positive for HLA-A*02 LOH.

A2 Biotherapeutics (A2 Bio)’s BASECAMP-1 screening study (NCT04981119) has made progress in identifying patients with solid tumors that are positive for somatic human leukocyte antigen (HLA)-A*02 loss of heterozygosity (LOH).1 This latest update on the progress of the study, which is seeking to identify patients who could potentially be treated with A2 Bio’s investigational logic-gated Tmod chimeric antigen receptor T-cell (CAR-T) therapy if their cancer relapses after standard of care treatment, was presented at the Society for Immunotherapy of Cancer’s (SITC) 38th Annual Meeting, held November 1-5, 2022, in San Diego, California.

Between the initiation of enrollment activities in October 2021 and the September 2023 data cut off, BASECAMP-1 has screened 880 patients in total and has found 376 of these patients (43%) to be HLA-A*02 heterozygous. Furthermore, among 191 patients screened for LOH, 28 patients (15%) were found to have tumors positive for HLA-A*02 LOH. Diane Simeone, MD, the Laura and Isaac Perlmutter professor of surgery in the Department of Surgery at NYU Grossman School of Medicine, who delivered the oral presentation at SITC’s meeting, pointed out that both of these findings were in line with expectations based on previous studies of real-world populations.

“The aims of this study are to identify patients with solid tumors with HLA-A*02 LOH,” Simeone said during her talk.1 “We specifically chose HLA-A*02 LOH because this is the most common HLA allele in the US population, representing about 39% of the population.”

Notably, 16 of the patients in BASECAMP-1 who were found to have tumors positive for HLA-A*02 LOH have undergone leukapheresis. As such, if these patients later decide to enroll in A2 Bio’s now-active phase 1/2 EVEREST-1 clinical trial (NCT05736731), which will evaluate the company's Tmod CAR-T therapy A2B530 in several solid tumor types, their leukapheresed cells will be ready for manufacture and rapid administration of the autologous study therapy, thus reducing the risk of substantial disease progression while patients wait for treatment.

“In these selected patients there can be preemptive apheresis collected for downstream novel T-mod CAR T-cell therapy,” Simeone added. “We started off screening patients with non–small cell lung cancer, colon cancer, or pancreatic cancer in 2 settings. [These include] patients who underwent surgical resection who are at high risk for recurrence and additionally patients in the metastatic setting. We have now expanded the tumor types to include ovarian mesothelioma and others.”

Key Takeaways

  1. The BASECAMP-1 screening study is making progress in identifying patients with solid tumors who are positive for somatic HLA-A*02 loss of heterozygosity—crucial for potential treatment with the investigational logic-gated Tmod CAR-T therapy after standard of care.
  2. The study, which began in Oct 2021, has screened 880 patients and found 376 of them to be HLA-A02 heterozygous, with 28 patients having tumors positive for HLA-A02 LOH. These findings align with expectations based on previous population studies.
  3. The Tmod CAR-T therapy, known as A2B530, has a logic gate that selectively targets cancer cells expressing carcinoembryonic antigen and has a blocker intended to prevent off-target side effects on normal cells.

Simeone also noted that BASECAMP-1 has expanded its eligibility from initially being limited to patients with HLA-A*02:01 to include a population with greater allelic diversity of HLA-A*02. She noted that there is significant diversity in allelic frequencies across different racial and ethnic groups in the United States. As such, this move should allow for greater eligibility for participation in the study for Americans with black, Native American, Hispanic/Latino, and/or Asian/Pacific Islander ancestry. Simeone also stated that in addition to standard study recruitment practices, A2 Bio is leveraging Tempus AWARE, a program run by biotech company Tempus that analyzes tissue submitted by patients as part of their routine clinical workup, to expand its identification of patients with solid tumors with HLA-A*02 LOH who may be eligible to participate in BASECAMP-1.

A2 Bio’s Tmod CAR-T therapy being evaluated in EVEREST-1 is referred to as A2B530.2 It is intended to allow for the selective elimination of carcinoembryonic antigen (CEA)-expressing cancer cells that have permanently lost the HLA-A*02 gene. EVEREST-1 is currently dosing patients with pancreatic, colorectal, and lung cancers. CGTLiverecently spoke with Maria Pia Morelli, MD, PhD, assistant professor, department of gastrointestinal (GI) medical oncology, division of cancer medicine, MD Anderson Cancer Center, The University of Texas, who serves as a principal investigator on EVEREST-1.

“We have a product that actually has a logic gate which exploits a specific characteristic of the cancer, loss of heterozygosity,” Morelli said during the interview. “So basically, we screen our patients for their HLA… we know that cancer cells usually lose their heterozygosity, so [A2 Bio] developed a gated blocker. So basically, you have a CAR-T that with one arm is able to bind the CEA expressed on the cancer cell and triggers the activation of the T-cell in the cancer cell, but at the same time has a blocker that recognizes the HLA expression on the normal cells, so it will prevent those off-cancer, on-target side effects.”

REFERENCES
1. Simeone DM, Hecht JR, Smith C, et al. BASECAMP-1: A master prescreening study to identify patients with high-risk or metastatic solid tumors with HLA loss of heterozygosity (LOH) in preparation for TmodCAR T-cell therapy trials. Presented at: SITC 38th Annual Meeting, held November 1-5, 2022, in San Diego, California. Abstract #636
2. A2 Bio Presents Oral and Poster Presentations Highlighting BASECAMP-1 and EVEREST-1 Patient Screening at 2023 Society for Immunotherapy of Cancer (SITC) Annual Meeting. News release. A2 Biotherapeutics, Inc. November 2, 2023. Accessed November 7, 2023. https://www.a2bio.com/a2-bio-presents-oral-and-poster-presentations-highlighting-basecamp-1-and-everest-1-patient-screening-at-2023-society-for-immunotherapy-of-cancer-sitc-annual-meeting/
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