A breakthrough preclinical study published in the Journal of Experimental Medicine has identified a gain-of-function mutation in the CARMIL2 gene that significantly enhances T cell activity and offers new therapeutic possibilities for cancer immunotherapy. The research, conducted by scientists at the Centre d'Immunologie de Marseille-Luminy and Centre d'Immunophénomique, demonstrates that this mutation not only boosts T cell activation but also confers resistance to key immune checkpoint pathways, including PD-1 and CTLA-4.
The study was led by Dr. Bernard and Marie Malissen, world-renowned experts in T cell biology, with funding from the European Research Council. Their findings reveal that the CARMIL2 gain-of-function (GOF) mutation creates a novel mechanism for T cell enhancement that could transform adoptive cell therapies.
Novel CD28-Independent Pathway
The research demonstrates that the CARMIL2-GOF mutation can bypass the need for CD28 ligand engagement while still delivering most of its immunological benefits. CD28 is a costimulatory receptor essential for optimal activation of naive T cells, and this discovery creates a novel CD28-independent activation pathway with significant implications for cancer treatment.
This mechanism is particularly important for tumors that evade immune surveillance by downregulating CD80/CD86, the natural ligands for CD28. By circumventing this evasion strategy, the CARMIL2 mutation offers a way to maintain T cell activation even in immunosuppressive tumor environments.
Checkpoint Resistance Properties
Importantly, the mutation also renders T cells resistant to PD-1 and CTLA-4 checkpoint inhibition, two major immunosuppressive mechanisms used by tumors to escape immune destruction. This dual benefit positions CARMIL2-GOF as a powerful new tool in adoptive cell therapy, particularly for enhancing the efficacy of CAR-T, TCR-T, and tumor-infiltrating lymphocyte (TIL) therapies.
"Our work shows that CARMIL2 is a critical modulator of the T-cell function," said Dr. Bernard Malissen, Emeritus CNRS Research Director and 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."
Commercial Development
Following this breakthrough, Inserm Transfert filed a patent in the name of INSERM, CNRS and Université Aix Marseille. Dr. Malissen co-founded Carmil Therapeutics in 2024 to translate this discovery into clinical applications. 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," said 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."
Therapeutic Platform Foundation
The data published in the Journal of Experimental Medicine are foundational to Carmil Therapeutics' scientific and therapeutic platform, establishing a new paradigm for intracellular immunomodulation. 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.
Carmil Therapeutics is a French biotechnology company developing T-cell therapies based on gain-of-function variants of the intracellular scaffold protein CARMIL2. Founded in 2024 and built on decades of research from Inserm, the company is advancing a proprietary platform to enhance the therapeutic efficacy of adoptive T cell therapies in cancer and autoimmune diseases. The company was financed by the French state within the framework of France 2030.
