Initial phase 1 study results of NT-175 engineered T-cell therapy in <i>TP53</i> R175H–mutated unresectable advanced solid tumors.

Abstract

2506 Background: TP53 is the most frequently mutated tumor suppressor gene across various tumor types, but no approved targeted therapies exist. NT-175 is an autologous engineered T-cell receptor (eTCR) T-cell therapy expressing an HLA-A*02:01-restricted TCR that targets the TP53 R175H tumor neoantigen. Methods: This open-label Phase 1 study (NCT05877599) enrolled HLA-A*02:01-positive adults with advanced/metastatic, TP53 R175H-mutated solid tumors. NT-175 was manufactured from autologous T cells modified by CRISPR/Cas9 gene-editing to delete endogenous TGFβR2 and replace the TCRα locus with the A*02:01-restricted R175H specific TCR. Patients (pts) received lymphodepletion with fludarabine and cyclophosphamide followed by a single NT-175 infusion along with subcutaneous recombinant IL-2. NT-175 was administered at 3 escalating dose levels (DLs) of eTCR+ T-cells. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per ASTCT consensus definitions. Response was determined by investigator assessment per RECIST v1.1. The primary objective was safety; secondary and exploratory objectives included preliminary antitumor activity and pharmacokinetics (PK), respectively. Results: As of Oct 31, 2025, 26 pts were enrolled and 21 were infused with NT-175 (median age 58 years, [range 43–77] across all DLs (DL1, n = 3; DL2, n = 4; DL3, n = 13; other, n = 1). Pts had a median of 3 prior lines of systemic therapy. Median time from apheresis to NT-175 infusion was 36 days and median follow-up was 6.0 (range: 0.9–9.5) months. Pts had colorectal adenocarcinoma (CRC, n = 10), pancreatic adenocarcinoma (PDAC, n = 6), breast cancer (BC, n = 2), and other solid tumors (n =3). There were no DLTs or Grade 5 events. CRS occurred in 11 (52.4%) pts (Grade ≥3 in 2 [9.5%]); ICANS occurred in 1 pt (Grade 3, 4.8%). Across all dose levels, objective response rate (ORR, including 7 confirmed and 3 unconfirmed responses) was 47.6% (95% CI, 25.7–70.2); in DL3, ORR was 53.8% (95% CI, 25.1–80.8). Partial responses (PR) were observed in 10 pts including 5/6 pts (83%) with PDAC and 5 pts across various tumor histologies (2/10 CRC, 2/2 BC, 1 other), and stable disease in 4 pts. Of 7 evaluable PR pts with ≥6 months of follow up, 5 remain in PR (2 PDAC, 1 leiomyosarcoma, and 2 CRC). Overall, disease control rate was 66.7% (95% CI, 43.0–85.4). Peripheral blood PK analyses (n =21) showed dose-dependent NT-175 expansion, peaking at Week 1 post-infusion, and persistence &gt; 300 days. Conclusions: Manufacturing and treatment with autologous NT-175 eTCR T cells was safe and feasible in pts with heavily pre-treated metastatic TP53-mutated malignancies. Further, NT-175 demonstrated encouraging preliminary antitumor activity across multiple histologies, with most notable early signals in PDAC and may offer a prolonged treatment-free interval in pts with refractory solid tumors. Clinical trial information: NCT05877599 .