NICE-TIL (NKG2D-CAR/mbIL15/tEGFR-transduced TILs) and antitumor activity via dual TCR-HLA and NKG2D-NKG2DL killing pathways.

Abstract

e21506 Background: CAR-T therapy’s efficacy in solid tumors is limited by T-cell dysfunction, heterogeneous antigen expression, and safety concerns. NICE-TIL (NKG2D-CAR-engineered TILs) integrates: 1) TILs inherent tumor-homing capacity and diversified TCR to tumor cell antigens; 2) NKG2D’s targeting of NKG2D ligands (NKG2DLs) broadly expressed on tumor cells and downstream signal activation; 3) membrane-bound IL-15 (mbIL15) for TME-resilient survival; 4) truncated EGFR (tEGFR) as a safety switch 5). In this study, we present data of NICE-TIL in vitro tumor killing activities and first in human clinical results. Methods: A: in vitro study: NICE-TIL and conventional TILs (CTR-TIL) were tested for 1) tumor cell killing activities to: different cancer cell lines and patient-derived organoids; 2) cell Proliferation activities after cancer cell killing in CD3 + /CD4 + /CD8 + subsets; 3) cancer cell killing mechanisms via blocking antibody (HLAI/NKG2D) study. 4) Safety assessment via tEGFR-mediated depletion. B: first-in-human clinical report. Results: 1) NICE-TIL exhibited superior cytotoxicity vs. CTR-TIL: Cell lines: >60% lysis (3rd sequential co-culture round) vs. <30% of CTR-TIL (melanoma/lung/cervical cell lines).Organoids: 80% (10:1 E:T) vs. 60% (CTR-TIL) for lung organoids; 2) Proliferation (Ki-67 + %) in NICE-TIL subsets was markedly enhanced by tumor co-culture (CD3 + : 60% vs. 20% without tumor; CD4 + : 65% vs. 20%; CD8 + : 60% vs. 20%). 3) Blocking antibody assays confirmed dual TCR-HLA and NKG2D-NKG2DL killing pathways (dual blockade reduced cytotoxicity to 45% vs. 90% in control). 4) Safety assessments: tEGFR-mediated depletion eliminated >95% of NICE-TIL in vitro. NICE-TIL demonstrates potent, sustained activity across different solid tumor models (cell lines + organoids) via dual killing pathways. Its tEGFR safety switch and lack of off-target toxicity address key clinical concerns. This engineered TIL platform leverages NKG2D’s broad targeting, mbIL15’s pro-survival effects, and TILs’ tumor-homing capacity, supporting its translation for melanoma, lung, cervical, and pancreatic cancer. The NICE-TIL therapy has entered the clinical trial phase. The first subject was a patient with advanced melanoma who had developed resistance to anti-PD-1, anti-VEGFR and chemotherapy, and achieved a confirmed partial response (PR), with 63% reduction in tumor burden. Conclusions: In summary, both in vitro data and clinical result suggest NICE-TIL may be an effective treatment for late-stage solid tumors.