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BackgroundAdoptive cell therapy demonstrated significant clinical benefit in patients with hematological malignancies but results in most solid tumors have been less encouraging so far.In the IMA203 trial we are treating advanced solid cancer patients utilizing TCR-engineered T cells (TCR-T) directed against an HLA-A*02-restricted peptide derived from the highly prevalent cancer testis antigen PRAME. This target was selected due to homogenous expression and exceptionally high target peptide density per tumor cell (assessed by quantitative mass spectrometry), two features we hypothesize to be critical determinants of anti-tumor activity in TCR-T trials.MethodsThis ongoing first-in-human, dose escalation, multi-indication trial enrolls HLA-A*02:01- and PRAME-positive recurrent and/or refractory solid cancer patients, who failed all available standard treatments. Eligible patients undergo leukapheresis and an autologous TCR-T product is manufactured. After lymphodepletion with fludarabine and cyclophosphamide, T cells are infused, followed by low-dose IL-2. The primary objective of the trial is to assess the safety and tolerability of IMA203. Secondary objectives are to evaluate the anti-tumor activity and pharmacodynamics using molecular and immunological methods.ResultsAs of August 15, 2021, 16 heavily pre-treated patients received IMA203 T cells across multiple escalating dose levels (DL). Absolute IMA203 doses infused ranged from 0.08 to 0.81x109 transduced CD8 T cells per patient, which to our knowledge did not lead to anti-tumor responses in other TCR-T trials. Treatment-emergent adverse events after IMA203 infusion were transient and manageable. Most common events were expected cytopenias (G1-4), CRS and ICANS (both G1-2) and 1 DLT in DL2 (reported earlier). All evaluable patients (N=12) achieved disease control (i.e. best overall response: stable disease [SD] or partial response [PR]) and 6 patients demonstrated PRs according to RECIST1.1 with 2 of these PRs being confirmed. While all 3 patients treated at DL1 (median dose: 0.11x109) experienced SD, a PR was observed in 6/9 patients treated beyond DL1 (median dose: 0.30x109). Responses were seen in patients with synovial sarcoma (N=3), malignant melanoma (N=2) and head and neck cancer (N=1). Robust engraftment of T cells was observed in all patients and tumor infiltration by TCR-modified T cells was demonstrated in patients with evaluable on-treatment biopsies.ConclusionsTo our knowledge IMA203 is the first TCR-T product candidate that induced frequent tumor responses across multiple solid cancers using transduced T cells at doses below 1 billion and has a manageable safety profile. The next step is to assess response rates at higher dose levels and durability of responses.Trial RegistrationNCT03686124Ethics ApprovalThe study was approved by the institutional review board/ethics committee as required for each participating site.

In this issue, Walter et al. report the results of two clinical trials of a new therapeutic vaccine, IMA901, for the treatment of renal cell carcinoma (RCC). IMA901 consists of ten tumor-associated peptides identified as naturally presented T cell epitopes in RCC, and the authors show longer overall survival in subjects with immune responses to multiple vaccine peptides and identify serum and cellular biomarkers that may help predict overall survival in future studies of the vaccine. IMA901 is the first therapeutic vaccine for renal cell cancer (RCC) consisting of multiple tumor-associated peptides (TUMAPs) confirmed to be naturally presented in human cancer tissue. We treated a total of 96 human leukocyte antigen A (HLA-A)*02 + subjects with advanced RCC with IMA901 in two consecutive studies. In the phase 1 study, the T cell responses of the patients to multiple TUMAPs were associated with better disease control and lower numbers of prevaccine forkhead box P3 (FOXP3) + regulatory T (T reg ) cells. The randomized phase 2 trial showed that a single dose of cyclophosphamide reduced the number of T reg cells and confirmed that immune responses to multiple TUMAPs were associated with longer overall survival. Furthermore, among six predefined populations of myeloid-derived suppressor cells, two were prognostic for overall survival, and among over 300 serum biomarkers, we identified apolipoprotein A-I (APOA1) and chemokine (C-C motif) ligand 17 (CCL17) as being predictive for both immune response to IMA901 and overall survival. A randomized phase 3 study to determine the clinical benefit of treatment with IMA901 is ongoing.

BackgroundCellular therapies have demonstrated promising activity in treatment-refractory advanced cutaneous melanoma (CM) and synovial sarcoma (SS); there are opportunities to further improve outcomes in this setting by combining cell therapy with other immunotherapy modalities. PRAME is an intracellular protein presented on the surface of tumor cells that are targeted by T cell receptors (TCR). PRAME expression is associated with poorer prognosis and shorter survival; it is expressed in 95% of CM and SS cells. IMA203 is a PRAME-directed TCR T-cell therapy engineered to recognize intracellular PRAME-derived peptides presented by HLA-A*02:01 on the cell surface and initiate a potent and specific anti-tumor response. In a phase 1 trial (NCT03686124), IMA203 exhibited favorable tolerability and encouraging anti-tumor activity in heavily pretreated patients with advanced melanoma at RP2D. Confirmed ORR was 56% (18/32), mDOR 12.1 months, mPFS 6.1 months, and mOS 15.9 months. Most frequent TEAEs in all indications (N=74) were lymphodepletion-related cytopenias (99%). CRS was mostly lower grade (84% G1/2; 11% G3; no ≥G4) and ICANS was infrequent (10% G1/2; 4% G3; no ≥G4).1 mRNA-4203 is an investigational mRNA/LNP product that encodes a PRAME sequence specifically designed to enhance the cellular kinetics and cytotoxic effects of IMA203 to deliver improved overall efficacy. This ongoing open-label, multicenter, first-in-human phase 1a/b trial (NCT06946225) will investigate the safety, tolerability, and anti-tumor activity of IMA203 in combination with different doses of mRNA-4203 in patients with CM or SS.MethodsEligible patients are HLA-A*02:01+ adults with measurable unresectable or metastatic CM or SS (RECIST 1.1) and ECOG PS 0/1. Patients must have progressed or be intolerant to standard therapy, including ≥1 PD-1 inhibitor for CM, and ≥1 prior systemic therapy for SS. Patients with active brain metastases are excluded. Patients undergo lymphodepletion with cyclophosphamide (500 mg/m2 and fludarabine 30 mg/m2 x 4 days), followed by a one-time infusion of IMA203 and low-dose IL-2 given subcutaneously x10 days. mRNA-4203 is administered starting 15 days post-IMA203 infusion on Days 1 and 15 of Cycle 1, then Day 1 of each subsequent 28-day cycle through Cycle 12. The primary objectives are to evaluate the safety and tolerability of the combination and determine the recommended mRNA-4203 dose for expansion. Secondary objectives include assessment of clinical activity as measured by ORR, DOR, DCR, and PFS. Additionally, pharmacokinetics of IMA203 transgene levels in peripheral blood will be evaluated. The trial is expected to enroll approximately 15 patients across 4 sites.AcknowledgementsStudy funding provided by Immatics US, Inc. and Moderna Inc.Trial RegistrationNCT06946225ReferenceWermke M, Alsdorf W, Araujo DM, et al. Phase 1 clinical update of IMA203, an autologous TCR-T targeting PRAME in patients with PD1 refractory metastatic melanoma. Abstract 2508. Presented at: ASCO Annual Meeting; June 2025; Chicago, IL.Ethics ApprovalThe protocol and all amendments were approved by the appropriate institutional review board or independent ethics committee at each participating study site. The study is being conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines.

Rationale of the trialAlthough the use of engineered T cells in cancer immunotherapy has greatly advanced the treatment of hematological malignancies, reaching meaningful clinical responses in the treatment of solid tumors is still challenging. We investigated the safety and tolerability of IMA202 in a first-in-human, dose escalation basket trial in human leucocyte antigen A*02:01 positive patients with melanoma-associated antigen A1 (MAGEA1)-positive advanced solid tumors.Trial designThe 2+2 trial design was an algorithmic design based on a maximally acceptable dose-limiting toxicity (DLT) rate of 25% and the sample size was driven by the algorithmic design with a maximum of 16 patients. IMA202 consists of autologous genetically modified cytotoxic CD8+ T cells expressing a T cell receptor (TCR), which is specific for a nine amino acid peptide derived from MAGEA1. Eligible patients underwent leukapheresis, T cells were isolated, transduced with lentiviral vector carrying MAGEA1-specific TCR and following lymphodepletion (fludarabine/cyclophosphamide), infused with a median of 1.4×109 specific T cells (range, 0.086×109–2.57×109) followed by interleukin 2.Safety of IMA202No DLT was observed. The most common grade 3–4 adverse events were cytopenias, that is, neutropenia (81.3%), lymphopenia (75.0%), anemia (50.0%), thrombocytopenia (50.0%) and leukopenia (25.0%). 13 patients experienced cytokine release syndrome, including one grade 3 event. Immune effector cell-associated neurotoxicity syndrome was observed in two patients and was grade 1 in both.Efficacy of IMA202Of the 16 patients dosed, 11 (68.8%) patients had stable disease (SD) as their best overall response (Response Evaluation Criteria in Solid Tumors V.1.1). Five patients had initial tumor shrinkage in target lesions and one patient with SD experienced continued shrinkage in target lesions for 3 months in total but had to be classified as progressive disease due to progressive non-target lesions. IMA202 T cells were persistent in peripheral blood for several weeks to months and were also detectable in tumor tissue. Peak persistence was higher in patients who received higher doses.ConclusionIn conclusion, IMA202 had a manageable safety profile, and it was associated with biological and potential clinical activity of MAGEA1-targeting genetically engineered TCR-T cells in a poor prognosis, multi-indication solid tumor cohort.Trial registration numbersNCT04639245, NCT05430555.

BackgroundOutcomes in metastatic melanoma after failure of immune checkpoint inhibition are poor with limited long-term survival. There is an urgent need for therapies delivering more durable survival. PRAME is an intracellular protein presented on the surface of tumor cells that are targeted by T cell receptors (TCR); PRAME is expressed in 95% of cutaneous melanoma (CM) cells and PRAME expression has been associated with poorer prognosis and shorter survival. IMA203 is a PRAME-directed TCR T-cell therapy engineered to recognize intracellular PRAME-derived peptides presented by HLA-A*02:01 on the cell surface and initiate a potent and specific anti-tumor response. In the phase 1 trial (NCT03686124), IMA203 exhibited favorable tolerability and encouraging anti-tumor activity in patients with advanced melanoma at RP2D. Confirmed ORR was 56% (18/32), mDOR was 12.1 months, mPFS was 6.1 months, and mOS was 15.9 months. Most frequent TEAEs in all indications (N=74) were lymphodepletion-related cytopenias (99%). CRS was mostly lower grade (84% G1/2; 11% G3; no ≥G4) and ICANS was infrequent (10% G1/2; 4% G3; no ≥G4).1 SUPRAME will evaluate IMA203 in advanced cutaneous melanoma after immune checkpoint inhibition.MethodsSUPRAME (NCT06743126) is a prospective, multicenter, open-label, randomized, actively controlled, phase 3 trial evaluating the efficacy and safety of IMA203 vs investigator’s choice in previously treated patients with unresectable or metastatic cutaneous melanoma (including acral melanoma). Eligible patients are ≥18 y, HLA-A*02:01+, measurable disease (RECIST v1.1), ECOG PS 0-1 and disease progression on or after ≥1 PD-1 inhibitor. Patients with BRAF mutation should have received 1 prior BRAF-directed therapy (± MEK inhibitor) at investigator discretion. Patients with active brain metastases, leptomeningeal disease or with primary mucosal, uveal melanoma and melanoma of unknown primary are excluded. Those with asymptomatic stable brain metastasis will be assessed for eligibility. The study will randomize 360 patients 1:1 who will undergo leukapheresis. Patients in the IMA203 arm will undergo lymphodepletion with Cy 500 mg/m2 and Flu 30 mg/m2 x 4 days, followed by a one-time infusion of IMA203 (1-10x 109 TCR T cells), and low-dose IL-2 (1 M IU QD x5 days, BID x5 days, SC). Patients in the control arm will receive nivolumab/relatlimab, nivolumab, ipilimumab, pembrolizumab, lifileucel (US), or chemotherapy. The primary endpoint is PFS. Secondary endpoints include OS, ORR, safety, and patient-reported outcomes. The trial is currently enrolling patients in the US and Germany and plans to enroll patients in France, the Netherlands, Canada, and the United Kingdom.AcknowledgementsStudy funding provided by Immatics US, Inc.Trial RegistrationNCT06743126ReferenceWermke M, Alsdorf W, Araujo DM, et al. Phase 1 clinical update of IMA203, an autologous TCR-T targeting PRAME in patients with PD1 refractory metastatic melanoma. Abstract 2508. Presented at: ASCO Annual Meeting; June 2025; Chicago, IL.Ethics ApprovalThe protocol and all amendments were approved by the appropriate institutional review board or independent ethics committee at each participating study site. The study is being conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines.