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

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 .

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Publication Details

Journal
Nature Medicine
Published
2026-05-31
DOI
https://doi.org/10.1038/s41591-026-04455-x
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Daniel Heudobler, Mathias Haenel, Ольга Веремчук, Farastuk Bozorgmehr et al.
Nature Medicine
CAR-T cell therapy research
article

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

Daniel Heudobler, Mathias Haenel, Ольга Веремчук, Farastuk Bozorgmehr, Annalen Bleckmann, Meike Hutt, Stefanie Groepper, Sebastian Ochsenreither, Martin Wermke, Cedrik M. Britten, Silvia Spoerl, Max‐Felix Häring, Judith S. Hecker, Manuel Ruh, Norbert Hilf, Manik Chatterjee, Sarah Missel, Andrea Mayer-Mokler, Martin Hofmann, Stefan Knop, Moritz Kleemiss, Simon Laban, Heiko Becker, Dirk Jaeger, Martin Sebastian, Carsten Reinhardt, Heiko Schuster
article en

Abstract

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 .

Nature Medicine
Goethe University Frankfurt (DE), Heidelberg University (DE), University Hospital Bonn (DE), University Medical Center Freiburg (DE), University Hospital Heidelberg (DE), TUM Klinikum (DE), University Hospital Regensburg (DE), Universitätsklinikum Erlangen (DE), Nuremberg Hospital (DE), Comprehensive Cancer Center Mainfranken (DE), University Hospital Münster (DE), National Center for Tumor Diseases (DE), University Children's Hospital Tübingen (DE), Marien Hospital Düsseldorf (DE), Immatics Biotechnologies (Germany) (DE), Frankfurt Cancer Institute (DE), Klinikum Chemnitz (DE), Technical University of Munich (DE), Technische Universität Dresden (DE), Charité - Universitätsmedizin Berlin (DE)
Amgen, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, AstraZeneca, GlaxoSmithKline, Sanofi, Gilead Sciences, Regeneron Pharmaceuticals, Jazz Pharmaceuticals, Novocure, Les Laboratories Pierre Fabre, BeiGene, Astellas Pharma, Servier, Swedish Orphan Biovitrum, PharmaMar, Ipsen, Genentech, Daiichi Sankyo Europe
Openalex Percentile: Top 7%
CAR-T cell therapy research
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