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

@article{wermke2026magea4magea8targeted,
  title = {{MAGE-A4/MAGE-A8-targeted TCR-based bispecific T cell engager in recurrent and/or refractory solid tumors: a phase 1 trial}},
  author = {Martin Wermke and Sebastian Ochsenreither and Dirk Jaeger and Heiko Becker and Annalen Bleckmann and Farastuk Bozorgmehr and Manik Chatterjee and Stefanie Groepper and Mathias Haenel and Judith S. Hecker and Max‐Felix Häring and Daniel Heudobler and Norbert Hilf and Martin Hofmann and Meike Hutt and Andrea Mayer-Mokler and Sarah Missel and Manuel Ruh and Heiko Schuster and Ольга Веремчук and Moritz Kleemiss and Stefan Knop and Simon A. Laban and Martin Sebastian and Silvia Spoerl and Cedrik Michael Britten and Carsten Reinhardt},
  journal = {Nature Medicine},
  year = {2026},
  month = may,
  doi = {10.1038/s41591-026-04455-x},
  url = {https://doi.org/10.1038/s41591-026-04455-x},
  note = {CC BY-NC-ND},
}

TY  - JOUR
TI  - MAGE-A4/MAGE-A8-targeted TCR-based bispecific T cell engager in recurrent and/or refractory solid tumors: a phase 1 trial
AU  - Martin Wermke
AU  - Sebastian Ochsenreither
AU  - Dirk Jaeger
AU  - Heiko Becker
AU  - Annalen Bleckmann
AU  - Farastuk Bozorgmehr
AU  - Manik Chatterjee
AU  - Stefanie Groepper
AU  - Mathias Haenel
AU  - Judith S. Hecker
AU  - Max‐Felix Häring
AU  - Daniel Heudobler
AU  - Norbert Hilf
AU  - Martin Hofmann
AU  - Meike Hutt
AU  - Andrea Mayer-Mokler
AU  - Sarah Missel
AU  - Manuel Ruh
AU  - Heiko Schuster
AU  - Ольга Веремчук
AU  - Moritz Kleemiss
AU  - Stefan Knop
AU  - Simon A. Laban
AU  - Martin Sebastian
AU  - Silvia Spoerl
AU  - Cedrik Michael Britten
AU  - Carsten Reinhardt
PY  - 2026
DA  - 2026/05/31
JO  - Nature Medicine
DO  - 10.1038/s41591-026-04455-x
UR  - https://doi.org/10.1038/s41591-026-04455-x
AB  - 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 .
SN  - 1078-8956
SN  - 1546-170X
SN  - 1744-7933
ER  -