A first-in-human phase 1 clinical trial published in Nature Medicine has reported encouraging early results for IMA401, an investigational T-cell receptor (TCR)-based bispecific T-cell engager designed to target MAGE-A4 and MAGE-A8 tumor antigens. The findings suggest that this next-generation immunotherapy may offer a novel treatment option for patients with recurrent or refractory solid tumors who have exhausted standard therapeutic approaches.
Despite major advances in cancer immunotherapy, the treatment of advanced solid tumors remains challenging. Many patients eventually develop resistance to currently available therapies, including immune checkpoint inhibitors, underscoring the need for innovative strategies that can selectively direct immune responses against cancer cells while minimizing damage to normal tissues.
IMA401 represents a new class of TCR-based bispecific molecules that recognize MAGE-A4 and MAGE-A8 peptides presented on HLA-A*02:01-positive tumor cells. By simultaneously binding tumor cells and T lymphocytes, the therapy promotes targeted immune-mediated destruction of malignant cells. Unlike conventional antibody-based therapies that recognize surface proteins, IMA401 can detect intracellular tumor antigens presented through major histocompatibility complex (MHC) molecules, significantly expanding the range of actionable cancer targets.
The multicenter phase 1 study enrolled 61 patients with advanced, relapsed, or refractory solid tumors representing more than 15 cancer types, including melanoma, non-small-cell lung cancer, ovarian cancer, bladder cancer, gastric cancer, and synovial sarcoma. Most participants had received multiple prior lines of systemic therapy.
Investigators evaluated escalating doses of intravenous IMA401 administered either as monotherapy or in combination with the programmed cell death protein-1 (PD-1) inhibitor pembrolizumab. The primary objectives were to determine the maximum tolerated dose and recommended phase 2 dose while assessing safety, pharmacokinetics, and preliminary antitumor activity.
The study demonstrated a favorable safety profile, with the maximum tolerated dose not reached during dose escalation. Based on the overall balance between efficacy and tolerability, investigators selected a recommended phase 2 dose range of 1–2 mg administered every two weeks.
Treatment-related adverse events were generally manageable and consistent with expected immune activation. The most commonly reported toxicities included low-grade cytokine release syndrome, transient lymphopenia, and reversible neutropenia. Notably, no cases of immune effector cell-associated neurotoxicity syndrome (ICANS) were observed.
Importantly, early signs of clinical efficacy were observed across multiple tumor types. Among all evaluable patients, the confirmed objective response rate was 14%. In patients treated within the recommended phase 2 dose range, the objective response rate increased to 20%, while disease control was achieved in approximately 50% of treated patients.
Particularly encouraging results were reported in head and neck cancers, where the objective response rate reached 29%. Several patients experienced substantial reductions in tumor burden, and responses were durable, with a median duration of 8.8 months. Clinical activity was also observed in melanoma and non-small-cell lung cancer, including in patients whose disease had progressed despite prior treatment with immune checkpoint inhibitors.
The combination of IMA401 with pembrolizumab appeared feasible and did not result in significant additional toxicity. Preliminary findings suggest that the therapy may help overcome resistance to checkpoint inhibition, although larger studies will be required to confirm this potential benefit.
The results add to the growing body of evidence supporting TCR-directed immunotherapies in solid tumors. An earlier phase 1 study by Wermke and colleagues evaluated IMA203, an autologous PRAME-targeted TCR-engineered T-cell therapy, in patients with recurrent or refractory HLA-A*02-positive solid tumors. Both IMA401 and IMA203 target intracellular cancer-testis antigens presented by HLA molecules and have demonstrated manageable safety profiles along with promising antitumor activity in heavily pretreated patient populations.
Investigators emphasized that the current findings should be interpreted cautiously, given the early-phase nature of the study, the relatively small number of participants, and the inclusion of diverse tumor types. Larger clinical trials will be necessary to further define efficacy, identify patients most likely to benefit, and establish long-term safety.
The study provides important clinical validation for TCR-based bispecific T-cell engagers in solid tumors. If these findings are confirmed in future trials, IMA401 could represent a significant addition to the expanding field of precision immunotherapy and offer new hope for patients with advanced cancers that remain difficult to treat.
References
- Wermke M, Ochsenreither S, Jaeger D, Becker H, Bleckmann A, Bozorgmehr F, et al. MAGE-A4/MAGE-A8-targeted TCR-based bispecific T cell engager in recurrent and/or refractory solid tumors: a phase 1 trial. Nat Med. 2026 May 31.
- Wermke M, Araujo DM, Chatterjee M, Tsimberidou AM, Holderried TA, Jazaeri AA, Reshef R, Bokemeyer C, Alsdorf W, Wetzko K, Brossart P. Autologous T cell therapy for PRAME+ advanced solid tumors in HLA-A* 02+ patients: a phase 1 trial. Nature medicine. 2025 Jul;31(7):2365-74.