NT-175 (TP53 R175H–HLA-A*02:01 eTCR; TGFβR2-knockout) drives 47.6% ORR across refractory solid tumors (83% PR in PDAC)

NT-175 is an autologous CRISPR/Cas9-edited engineered TCR T-cell therapy targeting the TP53 R175H neoantigen in an HLA-A*02:01-restricted manner, with endogenous TGFβR2 deleted (to reduce TGF-β–mediated suppression) and the transgenic TCR inserted at the TRAC locus. In this open-label Phase 1 dose-escalation study (NCT05877599), heavily pretreated adults with unresectable/metastatic TP53 R175H–mutated solid tumors (median 3 prior systemic lines) received fludarabine/cyclophosphamide lymphodepletion, a single NT-175 infusion plus s.c. IL-2; as of Oct 31, 2025, 21/26 enrolled patients were infused (DL1 n=3; DL2 n=4; DL3 n=13; other n=1) with CRC (n=10), PDAC (n=6), breast cancer (n=2), and other tumors (n=3). No DLTs or Grade 5 events were reported; CRS occurred in 52.4% (Grade ≥3: 9.5%) and ICANS in 4.8% (Grade 3), while efficacy by investigator-assessed RECIST showed ORR 47.6% (7 confirmed + 3 unconfirmed; DL3 ORR 53.8%) with 10 PRs (including 5/6 [83%] PDAC; 2/10 CRC; 2/2 breast) and DCR 66.7%; among 7 evaluable PR patients with ≥6 months follow-up, 5 remained in PR, and peripheral blood PK showed dose-dependent expansion (peak week 1) with persistence >300 days. Benchmarked to typical later-line SOC in these diseases—e.g., refractory mCRC oral options regorafenib or trifluridine/tipiracil have ~1–2% ORR (so “shrinkage” is uncommon), while post-gemcitabine nal-IRI+5-FU/LV in PDAC yields modest response rates—this level of tumor regression (especially in PDAC) is well outside expectations for standard chemotherapy in comparable refractory settings.