5509 Background: Pts with advanced ovarian cancer (OC) that progresses after platinum-based chemotherapy and subsequent treatment are lacking therapeutic options for durable clinical benefit. TCR T-cell therapies enable immune recognition of intracellular tumor antigens presented by HLA, expanding the therapeutic landscape beyond targets accessible to conventional immunotherapies. PRAME is a cancer-associated antigen expressed across >50 cancers, including OC. IMA203CD8 is a TCR T-cell therapy that engineers CD8+ and CD4+ T cells to detect and destroy PRAME-expressing tumor cells that evade conventional therapeutic approaches. Results from a phase 1a basket trial (NCT03686124) indicated the potential to target several PRAME+ tumors. Here we present updated dose-escalation results for the subset of pts with OC. Methods: Pts were ≥18 y, HLA-A*02:01+, had R/R solid tumors, measurable disease (RECIST 1.1), ECOG PS 0-1, and had exhausted SOC options, including platinum therapy. Following leukapheresis and IMA203CD8 manufacture, pts underwent lymphodepletion (LD) with Cy (500 mg/m 2 × 4 d) and Flu (30 mg/m 2 × 4 d), followed by IMA203CD8 infusion +/- low-dose SUBQ IL-2. Dose escalation is ongoing. Results: As of Oct 27, 2025, 16 heavily pretreated pts with OC were infused with IMA203CD8. Most common TEAEs were LD-related cytopenias (100%). Cytokine release syndrome occurred in 100% of pts and was mostly mild to moderate (G1: 44%, G2: 50%, G3: 6%). Immune effector cell–associated neurotoxicity syndrome occurred in 1 pt (G1: 6%). Tolerability in pts with OC was generally consistent with the known IMA203CD8 safety profile. Eleven pts were efficacy evaluable with ≥1 post-baseline scan (median 4 prior lines of therapy) after treatment with IMA203CD8 across escalating dose levels (median: 2.26×10 9 total TCR T cells; range: 1.4-7.1×10 9 TCR T cells). Tumor reduction was observed in 7 pts with maximum reduction of 74%; 3 responses were >6 mo and durable disease control occurred for up to 12 mo. A dose-dependent signal of activity was observed in pts treated at higher doses (n=5; range: 2.3-7.1×10⁹ TCR T cells), including 2 confirmed partial responses (PRs) with 1 ongoing metabolic complete response (CRs) at 6 mo, and 1 unconfirmed PR. All responses were observed in pts without post-infusion low-dose IL-2. Updated results from ≥20 efficacy-evaluable pts (including several unconfirmed PRs and CRs after data cutoff) with longer follow-up will be presented. Conclusions: In pts with metastatic and/or relapsed OC, IMA203CD8 demonstrated a tolerability profile consistent with prior experience in other solid tumors and encouraging dose-dependent antitumor activity, including durable objective responses according to RECIST. Dose escalation with and without IL-2 at higher doses is currently ongoing to determine RP2D and unlock the full potential of IMA203CD8 in OC. Clinical trial information: NCT03686124 .

IMA401 is a T cell receptor (TCR)-based next-generation bispecific T cell engaging receptor (TCER) targeting an HLA-A*02:01-presented peptide derived from MAGE-A4/MAGE-A8 with its high-affinity TCR-based domain, incorporating a low-affinity T-cell-recruiting domain and an optimized Fc domain to prolong half-life. In this prespecified interim analysis of a phase 1 first-in-human trial, 61 patients with advanced solid tumors received intravenous IMA401 (0.0066 mg-2.5 mg) with or without pembrolizumab. The primary endpoint was determination of the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of IMA401 monotherapy and in combination with pembrolizumab. Secondary objectives included safety and tolerability, antitumor activity and pharmacokinetics. The MTD was not reached as defined by the clinical trial protocol, and the RP2D was 1-2 mg IMA401 biweekly. Treatment-related adverse events (TRAEs) were well manageable; the most common any-grade TRAEs were cytokine release syndrome (38%, grades 1-2 only), transient lymphopenia (33%) and reversible neutropenia (31%). Five patients experienced dose-limiting toxicity (DLT) events primarily related to neutropenia. No further DLTs occurred in the RP2D range with dexamethasone premedication. One possibly-related death (pneumonia in a patient with rapidly progressing lung metastases) was reported outside RP2D at 2.5 mg IMA401. In the overall efficacy-evaluable population across all dose levels (n = 56), including low starting doses (from 0.0066 mg), the confirmed objective response rate (ORR) was 14% (8/56). In patients receiving IMA401 at the RP2D, an ORR of 20% (8/41) was observed across 15 different indications (post hoc analysis). In the largest subgroup of patients treated at RP2D, namely head and neck cancer, the ORR was 29% (4/14) with a median duration of response of 8.8 months. These findings show that the bispecific TCER platform has a manageable safety profile with mostly transient adverse events and promising antitumor activity at the RP2D of IMA401 with or without pembrolizumab. ClinicalTrials.gov identifier: NCT05359445 .

In contrast to chimeric antigen receptor T cells, T cell receptor (TCR)-engineered T cells can target intracellular tumor-associated antigens crucial for treating solid tumors. However, most trials published so far show limited clinical activity. Here we report interim data from a first-in-human, multicenter, open-label, 3 + 3 dose-escalation/de-escalation phase 1 trial studying IMA203, an autologous preferentially expressed antigen in melanoma (PRAME)-directed TCR T cell therapy in HLA-A*02+ patients with PRAME+ recurrent and/or refractory solid tumors, including melanoma and sarcoma. Primary objectives include the evaluation of safety and tolerability and the determination of the maximum tolerated dose (MTD) and/or recommended dose for extension. Secondary objectives include the evaluation of IMA203 TCR-engineered T cell persistence in peripheral blood, tumor response as well as duration of response. A total of 27 patients were enrolled in the phase 1a dose escalation and 13 patients in the phase 1b dose extension. IMA203 T cells were safe, and the MTD was not reached. Of the 41 patients receiving treatment (that is, who started lymphodepletion), severe cytokine release syndrome was observed in 4.9% (2/41), and severe neurotoxicity did not occur. In the 40 patients treated with IMA203, an overall response rate consisting of patients with unconfirmed or confirmed response (u/cORR) of 52.5% (21/40) and a cORR of 28.9% (11/38) was observed with a median duration of response of 4.4 months (range, 2.4-23.0, 95% confidence interval: 2.6-not reached) across multiple indications. Rapid T cell engraftment and long-term persistence of IMA203 T cells were observed. IMA203 T cells trafficked to all organs, and confirmed responses were more frequent in patients with higher dose. T cell exhaustion was not observed in the periphery; deep responses were enriched at higher PRAME expression; and higher T cell infiltration resulted in longer progression-free survival. Overall, IMA203 showed promising anti-tumor activity in multiple solid tumors, including refractory melanoma. ClinicalTrials.gov identifier: NCT03686124 .

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2508 Background: Frequent recurrence and limited long-term survival in unresected or metastatic melanoma after relapse from 1L checkpoint inhibitor treatment highlight the critical need for new therapies that deliver deeper, more durable responses. ACTengine IMA203 is an autologous TCR-T targeting PRAME, an intracellular protein displayed as peptide antigen at high density on the surface of multiple solid tumors, including melanoma. Methods: Patients treated in this ongoing Ph1a/b trial (NCT03686124) are ≥18yo, HLA-A*02:01+, PRAME+, have recurrent and/or refractory solid tumors with no additional standard of care treatments available, measurable disease (RECIST1.1) and ECOG PS 0-1. Patients receive Cy/Flu (500 mg/m 2 & 30 mg/m 2 x4 d) lymphodepletion prior to infusion, followed by low-dose IL-2 for 10 days. Results: As of Aug 23, 2024: 70 heavily pretreated patients with solid tumors (median 3 prior systemic therapies) across all dose levels (median total infused dose 2.09x10 9 TCR-T cells (0.08-10.02x10 9 )) were enrolled and assessed for safety. Baseline tumor burden (median sum of diameter): 11.78 cm; LDH > 1 x ULN: 64% of patients. IMA203 had an overall favorable tolerability profile. Most common TEAEs: chemotherapy-related cytopenias (100%), mild to moderate CRS (G1-2: 83%, G3: 11%), infrequent ICANS (G1: 6%, G2: 4%, G3: 4%), no G5 events. Objective responses were observed in melanoma, ovarian cancer, synovial sarcoma, and other tumor types. Successful trafficking of IMA203 cells to various organs was evidenced by their ability to shrink metastatic tumor lesions in the lung, liver, pleura, peritoneum, skin, lymph nodes, adrenal gland, bladder, kidney, spleen, and muscle. Across patients treated in dose escalation and dose expansion, higher doses of IMA203 TCR-T cells were associated with a higher rate of confirmed responses (p = 0.018), whereas tolerability profile remained favorable. Exposure data (C max , AUC) demonstrated a clear dose-dependent improvement in clinical efficacy: Patients with confirmed PR had a higher concentration of IMA203 TCR-T cells in the periphery, compared to patients with unconfirmed PR, SD, and PD. In heavily pretreated patients (median 2 prior systemic therapies) with melanoma at RP2D (1-10x10 9 ) in Ph1b, cORR was 54% (14/26), with tumor shrinkage in 88% (23/26) of patients. Median DOR was 12.1 months with 7/14 confirmed responses ongoing (longest > 2 years). Median PFS was 6 months and median OS not reached at 8.6 months mFU. Updated data with longer follow-up will be presented. Conclusions: IMA203 TCR-T was well tolerated and showed durable objective responses in patients with advanced melanoma. Given its promising risk/benefit profile and high PRAME prevalence in melanoma, a registration-directed Phase 3 trial (SUPRAME; NCT06743126) is underway to further evaluate its efficacy in patients with previously treated (2L) advanced cutaneous melanoma. Clinical trial information: NCT03686124 .