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  • 229 A2B530, an autologous CEA-directed Tmod T-cell therapy with an inhibitory receptor gated by HLA-A*02 to target colorectal, pancreatic, and lung cancer

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Regular and Young Investigator Award Abstracts
Cell Therapies
229 A2B530, an autologous CEA-directed Tmod T-cell therapy with an inhibitory receptor gated by HLA-A*02 to target colorectal, pancreatic, and lung cancer
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  1. J Randolph Hecht1,
  2. Mark Sandberg2,
  3. Xueyin Wang2,
  4. Aaron Martin2,
  5. Daniel Nampe2,
  6. Grant Gabrelow2,
  7. Chuck Li2,
  8. Michele Mcelvain2,
  9. Wen-Hua Lee2,
  10. Sanam Shafaattalab2,
  11. Sara Martire2,
  12. Fernando Fisher2,
  13. Yuta Ando2,
  14. Edwin Liu2,
  15. David Ju2,
  16. Jing-Ping Hsin2,
  17. Alexandre Zampieri2,
  18. Diane Simeone3,
  19. Scott Kopetz4,
  20. Maria Pia Morelli4,
  21. Mitesh Borad5,
  22. Theodore Welling3,
  23. Sandip Patel6,
  24. Edward Garon1,
  25. Kedar Kirtane7,
  26. Frederick Locke7,
  27. John Welch2,
  28. Eric Ng2,
  29. William Go2,
  30. Armen Mardiros2,
  31. David Maloney8,
  32. Lu-Min Wong2,
  33. Alexander Kamb2,
  34. Han Xu2 and
  35. Julian Molina9
  1. 1University of California at Los Angeles, Los Angeles, CA, USA
  2. 2A2 Biotherapeutics, Inc., Agoura Hills, CA, USA
  3. 3New York University Langone Health, New York, NY, USA
  4. 4The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  5. 5Mayo Clinic Cancer Center, Scottsdale, AZ, USA
  6. 6University of California San Diego, La Jolla, CA, USA
  7. 7H. Lee Moffit Cancer Center, Tampa, FL, USA
  8. 8Fred Hutchinson Cancer Research Center, Seattle, WA, USA
  9. 9Mayo Clinic, Rochestser, MN, USA

Abstract

Background Nearly all colorectal and most pancreatic and lung cancers express carcinoembryonic antigen (CEA). However, due to its expression in normal gut epithelial cells, CEA-targeted therapies have resulted in on-target, off-tumor toxicity. To overcome this, we have developed Tmod™, a logic-gated T-cell therapy platform. Tmod constructs are composed of an activating CAR or T-cell receptor that targets a tumor antigen and an inhibitory receptor recognizing an antigen expressed on normal healthy tissues, but not on tumor cells due to loss of heterozygosity (LOH).1,2 A2B530 is a CEA-directed Tmod construct utilizing an LIR-1-based inhibitory receptor (blocker) targeting human leukocyte antigen A*02 (HLA-A*02).

Methods To generate CEA Tmod, T cells from HLA-A*02(+) donors were transduced with a single lentivirus to express i) the CAR, ii) the blocker, and iii) an shRNA targeting β2M. Cytotoxicity was measured by culturing CEA(+) target cell line pairs (A*02[-] and A*02[+]), expressing either GFP or RFP, with engineered T cells and quantifying live target cells over time. In vivo activity was examined using NSG mice subcutaneously implanted with “normal” (CEA[+]A*02[+]) and tumor cells (CEA[+]A*02[-]), in the right and left flanks. Mice were treated intravenously with CEA Tmod cells or control T cells.

Results Control CEA CAR T cells killed CEA(+) target cell lines in vitro irrespective of HLA-A*02 expression. In contrast, CEA Tmod cells selectively killed tumor cells (CEA[+]A*02[-]) while sparing “normal” cells (CEA[+]A*02[+]). In mixed target cell cultures, CEA Tmod cells killed only the A*02(-) target cells, whereas the CEA CAR T cells killed both the A*02(-) and A*02(+) cell lines. Further, CEA Tmod cells exhibited bidirectional control between the activated and blocked states. While mice treated with control CEA CAR T cells experienced a reduction in volume and bioluminescence of both normal and tumor grafts, CEA Tmod cells specifically cleared A*02(-) tumors in mice (table 1). Finally, although expansion of Tmod cells in peripheral blood trended lower than CAR and TCR controls, anti-tumor activity was comparable in these groups.

Conclusions A2B530 is an autologous CEA Tmod cell product that exploits common LOH at the HLA locus in cancer cells, enabling these engineered T cells to discriminate between normal and tumor cells. BASECAMP-1 (NCT04981119), an observational study identifying patients with somatic HLA LOH, is recruiting. Eligible patients with metastatic colorectal, pancreatic, or non-small cell lung cancer will be apheresed for a future A2B530 EVEREST-1 interventional study.

References

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

  2. DiAndreth B, Hamburger AE, Xu H, Kamb A. The Tmod cellular logic gate as a solution for tumor-selective immunotherapy. Clin Immunol. 2022;241:109030.

View this table:
Abstract 229 Table 1

http://dx.doi.org/10.1136/jitc-2022-SITC2022.0229

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