Episode 71: MAGE-A4/MAGE-A8-targeted TCR-based bispecific T cell engager in recurrent and/or refractory solid tumors: a phase 1 trial

**Monday Immune Engager** — our weekly pick from the latest immune-engager digest. **Paper:** [MAGE-A4/MAGE-A8-targeted TCR-based bispecific T cell engager in recurrent and/or refractory solid tumors: a phase 1 trial](https://doi.org/10.1038/s41591-026-04455-x) **Authors:** Martin Wermke, Sebastian Ochsenreither, Dirk Jaeger, Heiko Becker, et al. **Journal:** Nature Medicine, 2025 **Why it matters:** By using an engineered T cell receptor domain instead of an antibody to target intracellular cancer-testis antigens presented on the cell surface via HLA, IMA401 opens a route to solid tumor immunotherapy that sidesteps the target-scarcity problem that has long limited bispecific T cell engagers in this setting. --- **Summary** Conventional bispecific T cell engagers (TCEs) are constrained to surface antigens, which are rarely tumor-specific enough in solid tumors to avoid on-target, off-tumor toxicity. IMA401 addresses this by replacing the antibody-based targeting arm with a high-affinity TCR domain that recognizes a peptide derived from the cancer-testis antigens MAGE-A4 and MAGE-A8 presented on the HLA-A\*02:01 allele — proteins that are epigenetically silenced in normal adult tissue but re-expressed across a broad range of solid tumors. The molecule also incorporates a deliberately low-affinity CD3-recruiting domain, which reduces peripheral T cell "sink" sequestration and limits hyperactivation-driven exhaustion, and a silenced Fc region that extends serum half-life to roughly 15–17 days, enabling biweekly dosing. This prespecified interim analysis of a phase 1 basket trial enrolled 61 heavily pretreated patients (median 3–4 prior lines) across more than 15 solid tumor indications, using a Bayesian logistic regression model to guide dose escalation from 0.0066 mg to 2.5 mg. The maximum tolerated dose was not reached per protocol, and the recommended phase 2 dose (RP2D) was set at 1–2 mg biweekly. At 2.5 mg, three of seven patients experienced dose-limiting grade 4 neutropenia; introducing 8 mg dexamethasone premedication with step dosing eliminated further dose-limiting toxicities within the RP2D range. Cytokine release syndrome occurred in 38% of patients but was exclusively grades 1–2, and no cases of immune effector cell-associated neurotoxicity syndrome (ICANS) were observed. One possibly treatment-related death from pneumonia occurred at 2.5 mg without dexamethasone premedication, in a patient with rapidly progressing lung metastases. In the RP2D-treated population (n = 41), the confirmed objective response rate (ORR) was 20%, rising to 29% in the largest histology subgroup — head and neck squamous cell carcinoma (4/14 patients) — with a 64% disease control rate and a median duration of response of 8.8 months. Objective responses were also observed in patients who had previously progressed on immune checkpoint inhibitors, including in a combination cohort with pembrolizumab that showed no additive toxicity. One melanoma patient maintained ongoing progression-free survival exceeding 33.9 months. --- **Three takeaways** 1. IMA401 demonstrated a 20% confirmed ORR at the RP2D across 15 tumor types, reaching 29% in head and neck squamous cell carcinoma — in patients with a median of 3–4 prior lines of therapy. 2. The safety profile at the RP2D was characterized by exclusively low-grade (grades 1–2) cytokine release syndrome, zero cases of ICANS, and a dose-dependent neutropenia that was clinically mitigated with dexamethasone premedication and step dosing. 3. Objective responses were observed in patients with prior immune checkpoint inhibitor resistance, and combining IMA401 with pembrolizumab produced no additive toxicity while maintaining antitumor activity. --- **Read the source:** https://doi.org/10.1038/s41591-026-04455-x