Phase 1 study results with PRAME-directed T-cell receptor (TCR) T-cell therapies in synovial sarcoma.

11516 Background: Patients with advanced or recurrent synovial sarcoma (SS) have limited treatment options that can provide sustained disease control beyond 6 mos. SS expresses multiple cancer testis antigens, including PRAME, which is expressed in >50 cancers. Anzutresgene autoleucel (anzu-cel, IMA203) is a PRAME-directed TCR T-cell therapy engineered to recognize an intracellular PRAME-derived peptide presented by HLA and initiate a potent and specific antitumor response. IMA203CD8 is a TCR T-cell therapy that additionally engineers a CD8 co-receptor to allow both CD4+ and CD8+ T cells to detect and destroy PRAME-expressing tumor cells that evade conventional therapeutic approaches. Here we present phase 1 results for the subset of pts with SS from IMA203-101 treated with anzu-cel or IMA203CD8 (hereafter TCR T). Methods: Pts were ≥18 y, HLA-A*02:01+, PRAME+, with R/R solid tumors, measurable disease (RECIST 1.1), ECOG PS 0-1, and no remaining SOC treatment options. Following leukapheresis and TCR T manufacture, pts underwent lymphodepletion (LD) with Cy (500 mg/m 2 × 4 d) and Flu (30 mg/m 2 × 4 d), followed by TCR T infusion +/- low-dose SUBQ IL-2. Results: As of Oct 27, 2025, 21 pts with SS were treated with anzu-cel (n=9) or IMA203CD8 (n=12). The most common TEAEs were LD-related cytopenias (100%). Cytokine release syndrome occurred in 18 pts (86%; G1: 38%, G2: 38%, G3: 10%). One event of G1 immune effector cell–associated neurotoxicity occurred (5%). Twenty pts were evaluable for efficacy and received a low median dose of 1.51 x 10 9 total TCR T cells (range: 0.35-9.36 x 10 9 ). These pts had a median sum of target lesions at baseline of 10.22 cm (range: 1.24-41.1 cm) and received a median of 2.5 prior lines of therapy (range: 1-5). At baseline, 65% had ≥2 previous lines of systemic therapy and 75% received prior radiotherapy. The confirmed objective response rate (cORR), including all pts evaluable for efficacy across escalating doses, was 50% (10/20), including 1 confirmed CR (8%) with IMA203CD8 at a dose of 2.05 x 10 9 total TCR T cells. Median tumor reduction for pts with confirmed objective response was -63.4%. Median duration of response at these escalating dose levels was 12.7 mo (mFU: 23 mo) with 5 responses lasting for ≥12 mo including 2 ongoing PRs at 27 and 23 mo. Median overall survival was 18 mo. Results include 1 pt who received 3 sequential TCR T-cell therapies: the MAGE-A4-targeted afamitresgene-autoleucel (BOR: SD; PFS: 21.4 mos), PRAME-targeted anzu-cel (BOR: cPR; PFS: 24.4 mo), and IMA203CD8 (BOR: cPR; PFS ongoing at 24.4 mo). Conclusions: PRAME-directed TCR T-cell therapies exhibited a safety profile consistent with previous observations, and despite low doses, promising antitumor activity with durable responses that deepened over time in pts with SS. These results warrant further investigation. Clinical trial information: NCT03686124 .