Article Text
PDF
Abstract
Background Chimeric antigen receptor (CAR) T-cell therapy has been challenging in solid tumors due to an absence of tumor-specific targets and the resultant on-target, off-tumor toxicity. Tmod, a novel logic-gated CAR T-cell therapy, utilizes a blocking receptor to discriminate tumor from normal cells, thus mitigating on-target, off-tumor toxicity (figure 1).1 2 The blocker recognizes human leukocyte antigen (HLA), an antigen that is subject to LOH.3 4 Among advanced colorectal, pancreatic, and non-small cell lung cancers, HLA LOH occurs in 15.6%, 19.6%, and 23.1% of patients, respectively (Tempus Database).5 However, HLA LOH can only be therapeutically exploited if patients are identifiable through a feasible clinical workflow.
BASECAMP-1 is an ongoing prescreening study to: 1) Identify patients with tumor-associated HLA LOH and eligible for Tmod CAR T-cell therapy, and 2) Obtain leukapheresis in preparation for the autologous CAR T-cell therapy trials EVEREST-1 (A2B530 targeting carcinoembryonic antigen; NCT05736731) and EVEREST-2 (A2B694 targeting mesothelin).
Methods BASECAMP-1 (NCT04981119) eligibility has 2 parts (figure 2). Patients with metastatic solid tumors or at high risk of relapse will be screened for germline HLA-A*02. Tumor tissue from patients with germline HLA-A*02:01 heterozygosity will be analyzed for somatic tumor HLA-A*02:01 LOH via Tempus next-generation sequencing testing. In addition, patients may be identified via the Tempus AWARE program. AWARE analyzes tissue from patients submitted to Tempus as part of the patient’s routine clinical workup. Institutional investigators are then informed of molecular results and can communicate with treating physicians regarding enrollment opportunities. Patients with tumors demonstrating HLA-A*02 LOH may be screened for subsequent leukapheresis, and banked T cells will be available for the EVEREST-1 and EVEREST-2 studies.
Results As of June 1, 2023, 664 patients were consented at 9 institutions (figure 3). HLA status was determined for 584 patients; 234 were identified as HLA-A*02:01 heterozygous (40%). LOH results were available for 117 patients; 13 were LOH positive (11%).
In addition, the AWARE program has been deployed since January 2022. We have identified 52 patients across sites with study-specific disease types with HLA-A*02:01 LOH; of these, 13 are currently being screened, 23 have been found ineligible, and 16 have consented. This demonstrated the feasibility of leveraging a diagnostic during routine clinical workup to identify rare, molecularly defined patients for personalized clinical studies.
Trial Registration NCT04981119
Please note, this trial is a screening/non-interventional clinical trial.
References 1. Hamburger AE, DiAndreth B, Cui J, et al. Engineered T cells directed at tumors with defined allelic loss. Mol Immunol. 2020;128:298-
2. DiAndreth B, Hamburger A, Xu H, Kamb A. The Tmod cellular logic gate as a solution for tumor-selective immunotherapy. Clin Immunol. 2022;241:109030.
3. 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. Sci Transl Med. 2022;14:eabm0306.
4. Tokatlian T, Asuelime GE, Mock J-Y, et al. Mesothelin-specific CAR-T cell therapy that incorporates an HLA-gated safety mechanism selectively kills tumor cells. J Immunother Cancer. 2022;10:e003826.
5. Simeone DM, Hecht R, Patel SP, et al. BASECAMP-1: Leveraging human leukocyte antigen (HLA) loss of heterozygosity (LOH) in solid tumors by next-generation sequencing (NGS) to identify patients with relapsed solid tumor for future logic-gated Tmod CAR T-cell therapy. J Clin Oncol. 2022;40(16_Suppl):TPS2676.
Ethics Approval This study was approved by site IRBs
Logic-gated CAR T with the goal to reduce toxicity: CEA and MSLN (activators) and HLA-A*02 (blocker)
Study Schema for BASECAMP-1
BASECAMP-1 Progress to Date and Screening Process Details (June 1, 2023)
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.