Abstract

In our phase 1 clinical trial examining the use of CISH-knockout TIL for the treatment of stage 4 metastatic colorectal cancer, the TIL therapy was generally safe and well-tolerated, with major side effects being attributable to the preconditioning regimen, IL-2 treatment, or the underlying disease. Out of 22 patients enrolled, 12 were dosed, resulting in stable disease at 28 days in 6 patients and at 56 days in 4 patients. The TIL infusion product was successfully manufactured in 17 of 19 patients where it was attempted. Notably, one of the patients with failed manufacturing was re-enrolled in the study, and a new TIL infusion product was successfully made. Here, we describe the case of a 34-year-old woman with an MSI-H form of metastatic young adult colorectal cancer that was refractory to standard-of-care chemotherapies as well as anti-PD-1/anti-CTLA-4-directed immune checkpoint inhibitor therapies, who achieved a complete and ongoing response (>28 months).

Key Takeaways

• TCR repertoire sequencing pre- and post-infusion confirmed the TILs were polyclonal, neoantigen-specific, and functionally diverse.

• Sensitive bulk and single-cell sequencing confirmed successful expansion of tumor-reactive clones and allowed correlative analysis of immune repertoire features with clinical response.

• CISH edited TIL were generally safe and well-tolerated, with expected side effects due to preconditioning or IL2 therapy.

• CISH edited TIL manufacturing was generally successful.

• One patient achieved a complete and ongoing response following TIL therapy.

• The patient demonstrated two “waves” of new TCR clones that were not present pre-infusion or in the infusion TIL, starting around Day 10 and Day 28
• Infusion TIL that persisted >1 year exhibited high GZMA, RCBTB2, CXCR3, GBP5, and JAML expression as well as very low CISH.

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