First-in-human dose escalation trial to evaluate the clinical safety and efficacy of an anti-MAGEA1 autologous TCR-transgenic T cell therapy in relapsed and refractory solid tumors

Abstract

Rationale of the trial: Although 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 design: The 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 IMA202: No 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 IMA202: Of 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.

Conclusion: In 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 numbers: NCT04639245, NCT05430555.

Keywords: Adoptive cell therapy - ACT; Solid tumor; T cell Receptor - TCR.

Figure 1. Characterization of the MAGEA1-specific TCR. (A) Functional avidity measurement using IFN-γ release of IMA202 TCR-expressing CD8⁺ T cells on co-culture with peptide-loaded T2 cells. One representative of two donors using mRNA electroporation for TCR expression is shown. The mean EC₅₀ value was 11 nM. MAGEA1 peptide concentrations for peptide loading ranged from 10 µM to 10 pM, and 2×10⁴ T cells were used at an E:T ratio of 1:1. (B) Specificity characterization. The IMA202 TCR recognizes the target peptide MAGEA1 loaded on T2 cells, but no similar peptides or controls. CD8⁺ T cell activation after 20 hours of co-culture with peptide-loaded T2 cells was measured by IFN-γ ELISA. One of two independent donors is shown and 2×10⁴ T cells were used at an E:T ratio of 1:1. The sequence and the target peptide motif similarity of each similar peptide is depicted in the table next to the graph. (C) Reactivity toward HLA-A*02 positive (A2+) human primary cells. T cells were lentivirally transduced with the IMA202 TCR and co-cultured with different primary human normal MAGEA1-negative cells and the MAGEA1-positive tumor cell lines UACC-257 and U266B1 at an E:T ratio of 3:1, with 6×10⁴ effector cells. The mean of IFN-γ release after 20 hours from replicates is shown. Error bars indicate SDs. One representative donor of two is depicted. (D) Functional assessment. T cells were lentivirally transduced with the IMA202 TCR and co-cultured with 5×10³ MAGEA1⁺ fluorescently labeled U2OS cell lines at indicated E:T ratios normalized to TCR positivity for 86 hours. One representative donor of two transductions is shown. (E) Cytotoxic potential of transduced IMA202 T cells demonstrated against another MAGEA1-positive cell line UACC-257 across five healthy donors in an InCucyte assay at E:T of 3:1. NT represent non-transduced T cells from 4/5 donors (F) Biolayer interferometry analysis of binding affinity of the MAGEA1-specific TCR used in the IMA202 trial revealed a K_D value of 8.7 µM. E:T, effector-to-target; HCASMC, Human Coronary Artery Smooth Muscle Cells; HCM, Human Cardiomyocytes; HCMEC, Human Cardiac Microvascular Endothelial Cells; HREpC, Human Renal Epithelial Cells; HTSMC, Human Tracheal Smooth Muscle Cells; iCell HA, induced pluripotent stem cell-derived human astrocytes; iCell HH, induced pluripotent stem cell-derived human hepatocytes; NHDF, Normal Human Dermal Fibroblasts.

Figure 2. CONSORT diagram and number of infused T cells. Study consort diagram (left). Figure depicting dose level based on TCR-T cell dose (cells/m²) for all 16 treated patients (right). DL1 is defined as 50×10⁶ transduced cells/m² BSA±20% (range 40 to 60 x 10⁶ cells/m²), DL2 as 300×10⁶ transduced cells/m² BSA±20% (range 240–360×10⁶ cells/m²), and DL3 as 1000×10⁶ transduced cells/m² BSA±20% (range 800–1200×10⁶ cells/m²). Enrichment cohorts represent intermediate dose levels between DL1 and DL2 as well as DL2 and DL3, respectively. BSA, body surface area; CONSORT, Consolidated Standards of Reporting Trials; I/E, inclusion/exclusion.

Figure 3. Cytokine release syndrome. The figure shows CRS grading over time post-IMA202 Infusion. The x-axis indicates time from IMA202 infusion while patient numbers and DLs are given on the y-axis. Grades for CRS were determined according to CARTOX criteria and are color-coded according to actual severity. Enrichment cohorts were opened to obtain further safety data and provide products for patients in need. CRS, cytokine release syndrome; DL, dose level; EC, enrichment cohort.

Figure 4. Clinical outcomes of treated patients. (A) Shown are best changes in sum of diameter of target lesions and best overall response based on RECIST 1.1 for all 16 patients. *Maximum change of target lesions and RECIST 1.1 best overall response at different time points. ^#Patient #09 had clinical progression at week 6. (B) The graph shows tumor responses postinfusion over time. ^#Patient #09 had clinical progression at week 6. (C) An exemplary CT scan of patient #03 at baseline as well as 6 weeks and twelve weeks after IMA202 infusion is depicted. BOR, best overall response; DL, dose level; EC, enrichment cohort; NSCLC, non-small cell lung cancer; PD, progressive disease; RECIST, Response Evaluation Criteria in Solid Tumors; SCC, squamous cell carcinoma; SD, stable disease.

Figure 5. Biological characterization of the IMA202 TCR-T product postinfusion. (A) IMA202 product persistence up to 300 days postinfusion was determined using qPCR assay. (B) Correlative data of peak expansion and total infused cells. (C) Bar graph showing IMA202 TCR-T cell infiltration into tumors in individual patients at day 42 postinfusion. (D) Correlative data of tumor infiltration and total infused cells. *Sample was collected on day 60 postinfusion. (E) Immunofluorescent staining images of CD8⁺ T cells in tumor preinfusion and postinfusion of IMA202 cells. In addition, the respective H&E staining is shown for each sample; blue stain.