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  • 634 EVEREST-1: A seamless phase 1/2 study of CEA logic-gated Tmod CAR T-cell therapy (A2B530) in patients with solid tumors associated with CEA expression also exhibiting HLA loss of heterozygosity (LOH)

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Regular and Young Investigator Award Abstracts
Clinical Trial In Progress
634 EVEREST-1: A seamless phase 1/2 study of CEA logic-gated Tmod CAR T-cell therapy (A2B530) in patients with solid tumors associated with CEA expression also exhibiting HLA loss of heterozygosity (LOH)
  1. Salman R Punekar1,
  2. Theodore Welling1,
  3. J Randolph Hecht2,
  4. Julian Molina3,
  5. Caleb Smith3,
  6. Edward Garon2,
  7. M Pia Morelli4,
  8. Marwan Fakih5,
  9. Kedar Kirtane6,
  10. Patrick M Grierson7,
  11. Sandip P Patel8,
  12. Yi Lin3,
  13. Scott Kopetz4,
  14. Frederick L Locke6,
  15. Jeffrey Ward9,
  16. Ariane Lozac’hmeur10,
  17. Matthew Frigault11,
  18. Sarah Nikiforow12,
  19. Wen-Kai Weng13,
  20. Jennifer Specht14,
  21. Tomislav Dragovich15,
  22. Judy Vong16,
  23. Armen Mardiros16,
  24. Kirstin Liechty16,
  25. William Y Go16,
  26. John Welch16,
  27. Eric W Ng16,
  28. Marcela Maus11,
  29. David Maloney14 and
  30. Diane M Simeone1
  1. 1New York University Langone Health, New York, NY, USA
  2. 2David Geffen School of Medicine at University of California, Los Angeles, CA, USA
  3. 3Mayo Clinic, Rochester, MN, USA
  4. 4The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  5. 5City of Hope, Duarte, CA, USA
  6. 6Moffitt Cancer Center, Tampa, FL, USA
  7. 7Washington University in St. Louis, Saint Louis, MO, USA
  8. 8University of California, San Diego, La Jolla, CA, USA
  9. 9Washington University School of Medicine, Saint Louis, MO, USA
  10. 10Tempus Labs, Inc, Chicago, IL, USA
  11. 11Massachusetts General Hospital, Boston, MA, USA
  12. 12Dana-Farber Cancer Institute, Boston, MA, USA
  13. 13Stanford University, Stanford, CA, USA
  14. 14Fred Hutchinson Cancer Center, Seattle, WA, USA
  15. 15Banner MD Anderson Cancer Center, Gilbert, AZ, USA
  16. 16A2 Biotherapeutics, Inc., Agoura Hills, CA, USA

  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.

Abstract

Background Chimeric antigen receptor (CAR) T-cell therapy has demonstrated clinical efficacy in hematologic malignancies1; however, implementation of these therapies in solid tumors has been challenging due to a lack of tumor-specific targets that discriminate cancer from normal cells. Previous studies using carcinoembryonic antigen (CEA) T-cell receptors and T-cell engagers have resulted in dose-limiting, on-target, off-tumor toxicities.2 3

EVEREST-1 (NCT05736731) is a seamless, phase 1/2, open-label, nonrandomized study to evaluate the safety and efficacy of A2B530, a logic-gated CEA-targeting Tmod CAR T-cell therapy, in adult patients. Tmod CAR T-cell therapy addresses challenges of on-target, off-tumor toxicity by combining a CAR-activating receptor with a blocking receptor to discriminate tumor from normal cells (figure 1).4 5 The activator receptor recognizes CEA on the surface of both tumor and normal cells. CEA is normally widely expressed in epithelial cells, particularly of the gastrointestinal (GI) system and can be upregulated in GI and lung tumors. Specificity for tumor cells is provided by a blocker that recognizes human leukocyte antigen (HLA) A*02, which is absent on tumor cells with HLA-A*02 LOH.6 LOH for HLA-A*02 is observed in solid tumor malignancies and can be detected using the Tempus next-generation sequencing testing. With this definitive discriminator target, A2B530 can potentially provide a therapeutic window to treat patients with CEA-expressing solid tumors exhibiting HLA LOH.

Methods Patients are enrolled through BASECAMP-1 (NCT04981119), a master prescreening study that identifies patients with HLA LOH at any time in the course of their disease. BASECAMP-1 eligible patients undergo leukapheresis and, when clinically appropriate, their banked T cells are manufactured for the EVEREST-1 study (figure 2). The key inclusion criteria include histologically confirmed recurrent, unresectable, locally advanced, or metastatic cancers that are associated with CEA expression: non-small cell lung (NSCLC), colorectal (CRC), or pancreatic (PANC) cancers. Patients should have received ≥1 line of prior therapy (eg, checkpoint inhibitor, molecular-targeted, or chemotherapy). The primary objective of phase 1 is to evaluate the safety and tolerability of A2B530 in patients with NSCLC, CRC, and PANC, and to identify the maximum tolerated dose and recommended phase 2 dose (RP2D). The dose-expansion phase will confirm RP2D and collect biomarker data to further characterize A2B530.

Trial Registration NCT05736731

References 1. Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386:640–654.

2. Parkhurst MR, Yang JC, Langan RC, et al. T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol Ther. 2011;19:620–626.

3. Tabernero JT, Melero I, Ros W, et al. Phase Ia and Ib studies of the novel carcinoembryonic antigen (CEA) T-cell bispecific (CEA CD3 TCB) antibody as a single agent and in combination with atezolizumab: Preliminary efficacy and safety in patients with metastatic colorectal cancer (mCRC). J Clin Oncol. 2017;35(15_Suppl):3002.

4. Hamburger AE, DiAndreth B, Cui J, et al. Engineered T cells directed at tumors with defined allelic loss. Mol Immunol. 2020;128:298–310.

5. 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.

6. 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.

Ethics Approval This study was approved by site IRBs.

Abstract 634 Figure 1
Abstract 634 Figure 1

CEA CAR Tmod Single Vector Construct

Abstract 634 Figure 2
Abstract 634 Figure 2

Everest-1 Study Design

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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/.

http://dx.doi.org/10.1136/jitc-2023-SITC2023.0634

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