New study published in Journal of Experimental Medicine reveals a CARMIL2 mutation with therapeutic antitumor potential

Carmil Therapeutics to develop next-generation immunotherapies based on this innovation

Paris & Le Genest St Isle, June 23, 2025 Carmil Therapeutics today announces the publication of a landmark preclinical study in the Journal of Experimental Medicine (JEM)¹. The study reveals that a gain-of-function (GOF) mutation in the CARMIL2 gene unlocks powerful T cell activity, offering a promising new avenue for the development of advanced immunotherapies.

The research was conducted by scientists at the Centre d'Immunologie de Marseille-Luminy (Aix-Marseille Université, CNRS, INSERM, CIML U1104), and Centre d’Immunophénomique (Aix-Marseille Université, CNRS, INSERM, CIPHE US012 and UMS/UAR 3367) under the leadership of Dr. Bernard and Marie Malissen, world-renowned experts in T cell biology and funded by the European Research Council (ERC). The study demonstrates that this CARMIL2-GOF mutation not only enhances T cell activation but also confers resistance to key immune checkpoint pathways, including PD-1 and CTLA-4.

“Our work shows that CARMIL2 is a critical modulator of the T-cell function,” said Dr. Bernard Malissen, Emeritus CNRS Research Director, co-founder and Chief Scientific Officer of Carmil Therapeutics. “This gain-of-function strategy offers new ways to boost the efficacy of adoptive cell therapies, notably for hard-to-treat solid tumors and refractory cancers.”

Following this breakthrough, Inserm Transfert filed a patent in the name of INSERM, CNRS and Université Aix Marseille. Inserm Transfert and JC Discovery - another spin-off of INSERM co -founded by Dr B. Malissen, - put in place a Convention industrielle de formation par la recherche (CIFRE) around the project. Dr. B. Malissen co-founded Carmil Therapeutics in 2024. Carmil’s mission is to translate this discovery into a new generation of immunotherapies. The company holds exclusive global rights from Inserm Transfert to develop therapeutic applications of CARMIL2-GOF variants.

“Carmil was created to turn this breakthrough into real-world treatments,” added Dr. Arnaud Foussat, Chief Executive Officer of Carmil Therapeutics. “We are now developing a novel therapeutic platform based on CARMIL2-GOF, both through internal programs and future alliances.”

A new mechanism to enhance T cell therapies

CD28 is a costimulatory receptor essential for optimal activation of naive T cells. The newly published study demonstrates that a CARMIL2 gain-of-function mutation can bypass the need for CD28 ligand engagement, while still delivering most of its immunological benefits. This creates a novel CD28-independent activation pathway, with significant implications for tumors that evade immune surveillance by downregulating CD80/CD86.

Importantly, the mutation also renders T cells resistant to PD-1 and CTLA-4 checkpoint inhibition, two major immunosuppressive mechanisms used by tumors. These findings position CARMIL2-GOF as a powerful new lever in adoptive cell therapy, particularly for enhancing the efficacy of CAR-T, TCR-T or TILs therapies.

A foundation for Carmil Therapeutics’ platform

The data published in JEM are foundational to Carmil Therapeutics’ scientific and therapeutic platform, establishing a new paradigm for intracellular immunomodulation. In particular, the study provides mechanistic insight into how CARMIL2-GOF reshapes intracellular signaling to drive superior T cell activity, with clear translational value for next-generation cell therapies.