Abstract T cell receptor (TCR)-based adoptive cell therapy represents an innovative and promising treatment for pts with solid cancers who continue to have a high unmet medical need. This ongoing trial (NCT03686124) evaluates IMA203, an autologous TCR-engineered T cell therapy (TCR-T) utilizing a novel, pairing-enhanced TCR with high affinity and specificity against an HLA-A*02:01-presented peptide derived from PRAME. PRAME is a multi-cancer target with a prevalence of 80-100% in cut. and uveal melanoma, sarcoma subtypes, uterine and ovarian cancer; it has a high prevalence in many other solid cancer types, such as lung, triple-negative breast and head and neck cancer, among others. Eligible pts have recurrent and/or refractory solid cancer, are ≥18 y, ECOG PS of 0-1 and have exhausted all available SOC treatments. PRAME expression is assessed by RT-qPCR analysis of archived or fresh tumor tissue. After lymphodepletion with Cy/Flu (500 mg/m2 and 30 mg/m2 IV x 4d), IMA203 is infused followed by low-dose IL-2 (1 mil IU SC daily x 5d, then twice daily x 5d). Herein, we present preliminary results from 38 pts treated across the phase 1a dose escalation (N=27) and phase 1b dose expansion cohort A at the provisional RP2D (N=11) (data cut-off April 04, 2023). Pts were heavily pre-treated with a median of 4 prior systemic therapies. At baseline, tumor burden was 113 mm (median sum of diameters of target lesions) and LDH >ULN in 63% of pts. Pts in phase 1a (dose level, DL, 1-4) received a median of 0.41x109, pts in phase 1b (DL4/5) a median of 3.94x109 IMA203 T cells. TEAEs were manageable with most common events being expected cytopenias (100%), CRS (92% G1-2, 3% G3) and ICANS (13% G1-2). 61% (11/18) of pts in phase 1a and phase 1b treated at DL4/5 above 1x109 IMA203 T cells showed an initial objective response according to RECIST1.1 at week 6 post infusion. 11 pts in phase 1b were infused with IMA203 T cells manufactured with an improved process leading to significantly increased TCR-T levels and persistence. In these pts IMA203 achieved an initial objective response rate (ORR) of 64% (7/11) at week 6 and a confirmed ORR of 67% (6/9) at month 3. Objective responses were observed across multiple tumor types, including PD1-refractory cut. melanoma, uveal melanoma, platinum-resistant ovarian cancer, synovial sarcoma and head and neck cancer. 5 of 7 responders in phase 1b had an ongoing response at 9 (N=2), 6 (N=1), 3 (N=1), and 1.5 months (N=1) post infusion. At a mFU of 8.5 months, mDOR was not reached (min 1.3+, max 8.8+ months). IMA203 T cells were detectable in all evaluable post treatment tumor tissues and degree of infiltration was associated with objective responses. Objective responses were observed at low, medium and high PRAME expression levels. In summary, IMA203 showed a manageable tolerability profile and, to our knowledge, is the first TCR-T product candidate achieving a high rate of objective responses independent of tumor type, thus providing a potential innovative treatment option for many solid cancer pts with PRAME-positive tumors. Citation Format: Martin Wermke, Winfried Alsdorf, Dejka Araujo, Manik Chatterjee, Norbert Hilf, Tobias A.W. Holderried, Amir A. Jazaeri, Mamta Kalra, Andrea Mayer-Mokler, Regina Mendrzyk, Ali Mohamed, Sapna P. Patel, Ran Reshef, Arun Satelli, Harpreet Singh, Apostolia-Maria Tsimberidou, Steffen Walter, Toni Weinschenk, Cedrik M. Britten, Jason Luke. IMA203 TCR-T targeting PRAME demonstrates potent anti-tumor activity in patients with different types of metastatic solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr PR018.