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1478 A phase I study of personalized adoptive TCR T cell therapy in patients with solid tumors: safety, efficacy, and T cell trafficking to tumors of non-virally gene edited T cells
  1. Susan Foy1,
  2. Kyle Jacoby1,
  3. Daniela Bota2,
  4. Theresa Hunter1,
  5. Adam Schoenfeld3,
  6. Zheng Pan1,
  7. Eric Stawiski1,
  8. Yan Ma1,
  9. William Lu1,
  10. Songming Peng1,
  11. Clifford Wang1,
  12. Benjamin Yuen1,
  13. Olivier Dalmas1,
  14. Katharine Heeringa1,
  15. Barbara Sennino1,
  16. Andy Conroy1,
  17. Michael Bethune1,
  18. Ines Mende1,
  19. William White1,
  20. Monica Kukreja1,
  21. Swetha Gunturu1,
  22. Emily Humphrey1,
  23. Adeel Hussaini1,
  24. Duo An1,
  25. Boi Quach1,
  26. Alphonsus Ng4,
  27. Yue Lu4,
  28. Chad Smith1,
  29. Katie Campbell5,
  30. Daniel Anaya1,
  31. Lindsey Skrdlant1,
  32. Eva Huang1,
  33. Ventura Mendoza1,
  34. Jyoti Mathur1,
  35. Luke Dengler1,
  36. Bhamini Purandare1,
  37. Robert Moot1,
  38. Michael Yi1,
  39. Roel Funke1,
  40. Alison Sibley1,
  41. Todd Stallings-Schmitt1,
  42. David Oh6,
  43. Bartosz Chmielowski5,
  44. Mehrdad Abedi7,
  45. Yuan Yuan8,
  46. Jeff Sosman9,
  47. Sylvia Lee10,
  48. Claire Williams11,
  49. Sean Kim11,
  50. Matthwe Keefe11,
  51. Michael Leon11,
  52. Youngmi Kim11,
  53. Jason Reeves11,
  54. Wes Goldman11,
  55. David Baltimore12,
  56. James Heath4,
  57. Alex Franzusoff1,
  58. Antoni Ribas5,
  59. Arati Rao1 and
  60. Stefanie Mandl1
  1. 1PACT Pharma, South San Francisco, CA, United States
  2. 2University of California, Irvine, Orange, CA, United States
  3. 3Memorial Sloan Kettering Cancer Center, New York, NY, United States
  4. 4Institute for Systems Biology, Seattle, WA, United States
  5. 5University of California, Los Angeles, Los Angeles, CA, United States
  6. 6University of California, San Francisco, San Francisco, CA, United States
  7. 7University of California, Davis, Sacramento, CA, United States
  8. 8City of Hope National Medical Center, Duarte, CA, United States
  9. 9Northwestern University, Chicago, IL, United States
  10. 10Fred Hutchinson Cancer Research Center, Seattle, WA, United States
  11. 11Nanostring, Seattle, WA, United States
  12. 12California Institute of Technology, Pasadena, CA, United States


Background NeoTCR-P1 is a personalized autologous T cell therapy for treatment of patients with solid tumors. Neoantigen-specific T cell receptors (neoTCRs) were isolated from the patients’ own circulating CD8 T cells using the imPACT Isolation Technology®, followed by non-viral precision genome engineering into an autologous apheresis product for infusion back into the patient.

Methods This phase 1 trial is a first-in-human, multi-center, dose-escalation study to evaluate the safety, tolerability, and manufacturing feasibility of NeoTCR-P1 alone or in combination with IL-2 in solid tumors.

Patients with TCRs identified at screening and meeting eligibility criteria underwent apheresis to manufacture personalized NeoTCR-P1 cell product. Lymphodepleted patients received a single dose of up-to-three distinct NeoTCR cell products at dose levels of 0.4, 1.2, or 4×109 NeoTCR-edited T cells.

Pre- and post-treatment blood and biopsy samples were collected to evaluate NeoTCR-P1 pharmacokinetics, tumor trafficking, signs of T cell engagement or potential mechanisms of resistance.

Results Sixteen patients were infused with NeoTCR-P1 T cells including patients with MSS-colorectal cancer (11), breast cancer (2), ovarian cancer (1), melanoma (1), or non-small cell lung cancer (1). Four of the sixteen patients were treated with NeoTCR-P1 + IL-2.

Two patients experienced toxicities associated with NeoTCR-P1 cell infusions: a grade 1 CRS and a grade 2 ICANS. Five patients had stable disease as their best response at their first tumor assessment (day 28).

NeoTCR+ T cells detected in the peripheral blood had an average peak of 3.6% (range 0.9-7.3%) for DL1, 11.7% (7.7-20.8%) for DL2, and 19.8% (12.0-37.3%) for DL3. Increases in NeoTCR T cells were observed at higher dose levels, stronger lymphodepletion, or higher gene editing rates of the infused product.

Eight post-infusion biopsies were available for sequencing and imaging analysis; 17 of 22 neoTCR-T cells were detected in post-infusion biopsies with 12 neoTCRs among the top 4% of CDR3 sequences detected. The targeted neoantigens were detected in 7 of 8 post-treatment biopsies (15 of 22 targets), and personalized ctDNA confirmed targeting of a predicted sub-clonal mutation. An APOBEC signature and HLA-LOH were identified as potential mechanisms of resistance. By single-cell, spatial molecular imaging, neoTCR-T cells were visualized in post-treatment biopsies and found to differentially express potential markers of engagement.

Conclusions This study demonstrates the feasibility of isolating and manufacturing NeoTCR-T cells using non-viral precision genome engineering, the safety of infusing up-to-three gene edited NeoTCR-T cell products, and T cell persistence and trafficking to a variety of solid tumors.

Trial Registration NCT03970382

Ethics Approval Ethics approvals have been obtained from each clinical site enrolling patients: City of Hope, Duarte California; University of California Los Angeles, Los Angeles California; University of California, Irvine Medical Center, Orange, California; University of California, Davis, Sacramento California; University of California, San Francisco, San Francisco California; Northwestern University Medical Center, Chicago Illinois; Memorial Sloan Kettering Cancer Center, New York, New York; Tennessee Oncology, Nashville, Tennessee; and Fred Hutchinson Cancer Research Center, Seattle, Washington.

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