Authors
Dr. Caleb Smith, Dr. Sally Lau, Dr. Edward Garon, Dr. Sandip Patel, Dr. Yanyan Lou, Dr. Daniel Greenwald, Dr. Vamsidhar Velcheti, Dr. Kedar Kirtane, Dr. Yi Lin, Dr. Sattva Neelapu, Dr. Frederick Locke, Dr. Sarah Larson, Dr. Marcela Maus, Dr. Diane Simeone, Dr. Scott Kopetz, Ariane Lozac’hmeur, Dr. Ameen Salahudeen, Judy Vong, Kirstin Liechty, Dr. John Welch, Dr. Eric Ng, Dr. William Go, Dr. David Maloney, Dr. Julian Molina
BACKGROUND: Chimeric antigen receptor T-cell therapy has demonstrated clinical efficacy in hematologic cancers (Locke, et al. NEJM 2022). However, translating engineered T-cell therapies to solid malignancies proves challenging due to the lack of tumor-specific targets that can distinguish cancer cells from normal cells. Previously, the use of a CEA T-cell receptors and MSLN CARs both resulted in dose-limiting on-target, off-tumor toxicities (Parkhurst, et al. Mol Ther 2011; Haas, et al. Mol Ther 2019). Tmod CAR T-cell therapy addresses these challenges by leveraging dual-signaling receptors that target tumor cells, while leaving healthy cells intact (Hamburger, et al. Mol Immunol 2020; DiAndreth, et al. Clin Immunol 2022). The activator receptor recognizes an antigen, such as MSLN or CEA, on the surface of the tumor cells that may also be present on normal cells (Figure 1). Specificity for tumor cells is provided by a blocker that recognizes a second surface antigen lost only in tumor cells (Sandberg, et al. Sci Transl Med 2022; Tokatlian, et al. J Immunother Cancer 2022). LOH is observed at the HLA-A locus in ~23% of non-small cell lung cancer in Tempus and other data sets, and similar frequencies are observed in other solid tumors (Hecht, et al. J Clin Oncol 2022). As such, HLA LOH offers a promising tumor versus normal discriminator target for CAR T-cell therapy. BASECAMP-1 is a currently enrolling observational study with the following key objectives: 1) to identify patients with somatic HLA-A LOH eligible for Tmod CAR T-cell therapy, and 2) subsequent apheresis and manufacturing feasibility for future EVEREST Tmod CAR T-cell trials.
METHODS: BASECAMP-1 (NCT04981119) eligibility has 2 parts. Patients will be initially screened to identify germline HLA-A*02 heterozygosity. Primary archival tumor tissue from the identified patients with germline HLA-A*02 heterozygosity will be analyzed for somatic tumor HLA-A*02 LOH by Tempus xT NGS. If the tumor demonstrates HLA-A*02 LOH and the patient is eligible after screening, the patient will undergo leukapheresis and be followed for relapse. Banked T cells will be available for the autologous EVEREST Tmod CAR T-cell therapy interventional study at the time of relapse.
RESULTS: With a data cutoff date of 11/21/2022, 152 patients have been screened. Fifty-six HLA-A*02 heterozygous patients (42% of resulted subjects) and 5 LOH patients (23% of resulted subjects) have been identified, consistent with predicted population frequencies of A*02 and LOH. LOH patients are being scheduled for apheresis.
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