CELL-ATTACK Program: Improving CAR-T cell therapies to make them more effective, longer-lasting, and better suited to treating treatment-resistant cancers

CAR-T cell therapies, which were first developed by academic institutions, have significantly improved the treatment of certain hematologic cancers, such as lymphomas, multiple myeloma, and acute leukemias. Research and clinical trials conducted at several hospitals and research centers around the world have demonstrated the academic community’s ability to develop, produce, and clinically test innovative cancer therapies.  

These advances have opened up new possibilities for patients whose previous treatments have failed. They have also confirmed the potential of cell therapies, which can mobilize a patient’s immune system to recognize and destroy cancer cells. However, their effectiveness remains inconsistent today depending on the disease, the patient, and the clinical context.

In practice, several obstacles still limit their effectiveness. In some cases, the administered cells do not persist long enough in the body. In others, they gradually lose their effectiveness, particularly due to a phenomenon known as T-cell “exhaustion,” which reduces their ability to act over time. Added to this is the influence of the tumor microenvironment—that is, the collection of cells, signals, and biological mechanisms surrounding the tumor that can suppress the immune response.

Another major challenge involves identifying sufficiently specific targets. Many antigens currently targeted by cell therapies are present not only on tumor cells but also on certain healthy tissues, which can lead to significant adverse effects. It is therefore essential to discover new targets that allow for a more specific attack on cancer cells, while limiting toxicity.

Research conducted at Gustave Roussy has shown that the efficacy of CAR-T therapy depends not only on the cells administered but also on other patient-specific factors. The gut microbiota and certain immune cells present in the tumor—particularly tumor-associated macrophages (TAMs)—can influence the response to treatment and contribute to resistance mechanisms. Gaining a better understanding of these interactions has become a key challenge in improving the efficacy and durability of cell therapies.

The CELL-ATTACK program aims to strengthen the academic development of cell therapies at Gustave Roussy, particularly CAR-T cells, in order to offer new treatment options to patients with hematologic cancers that are particularly difficult to cure or with glioblastoma, a cancer for which there are currently still few treatment options. Its primary objective is to establish an on-site CAR-T cell production capacity within the Institute itself, to accelerate the transition from research to clinical trials and better address unmet medical needs.

The program also aims to improve the efficacy, persistence, and safety of these therapies. To this end, it focuses on several complementary approaches, such as the patient’s biological factors—notably the gut microbiota and certain immune cells in the tumor microenvironment, such as tumor-associated macrophages (TAMs)— and the reprogramming of T cells to make them more effective, longer-lasting, and more resistant to exhaustion.

Finally, CELL-ATTACK is pursuing a strategic goal for the future of immunotherapies: identifying new therapeutic targets that are more specific to cancer cells. Using highly precise analyses, the program seeks to identify new tumor antigens that could be used to develop the next generation of CAR-T cells. 

Ultimately, this approach should make it possible to broaden the scope of cell therapies, reduce toxicity, and offer more precise treatments to patients with cancers that are currently difficult to treat.

CELL-ATTACK primarily relies on the equipment and expertise already in place at Gustave Roussy to produce CAR-T cells in an academic setting. In particular, the program uses an automated system, recently installed at the Institute, that enables the production of these CAR-T cells in a closed, highly secure environment that complies with pharmaceutical manufacturing standards. 

The program also relies on a very detailed analysis of treated patients to better understand why this treatment works well in some cases and not in others. Through the PIONEER study, conducted at Gustave Roussy, samples of blood, bone marrow, stool, and tumor tissue are collected before and after CAR-T cell therapy. These samples are then studied using cutting-edge technologies that enable researchers to observe immune cells, track CAR-T cells in tissues, and analyze the gut microbiota and certain biological markers associated with treatment response. This approach makes it possible, in particular, to explore the role of the microbiota and certain cells in the tumor microenvironment, such as tumor-associated macrophages (TAMs).

CELL-ATTACK also aims to improve the therapeutic cells themselves. To do this, the teams identify the mechanisms that limit their action and then test different ways to make them more resistant, longer-lasting, and more active against the tumor. This work relies on genetic modification tools (molecular scissors) and experimental models already in use at Gustave Roussy to rigorously evaluate the most promising strategies before they are translated into clinical practice.

Finally, the program seeks to identify new targets present on the surface of cancer cells in order to develop more precise CAR-T cell therapies. To do this, researchers analyze patient samples using several complementary technologies to detect abnormalities specific to tumor cells, particularly in acute myeloid leukemia. The goal is to identify new targets better suited for future treatments, with the hope of improving their effectiveness while minimizing side effects. 

Ultimately, CELL-ATTACK aims to foster the development of a new generation of cell therapies that are better suited to cases of resistance, relapse, or cancers that are currently difficult to treat. By drawing on a deeper understanding of the mechanisms underlying treatment failure, the program aims to develop more robust, better-targeted, and longer-lasting treatments.

The knowledge generated could also have an impact beyond CAR-T cells alone. It is likely to inform other approaches to cell therapy, particularly in the field of tumor-infiltrating lymphocytes and, more broadly, synthetic immunology. 

Finally, CELL-ATTACK is a program that is transforming the way immunotherapy innovations are developed in France by bringing basic research, production, and biological and clinical exploration closer together. This continuity is essential for accelerating the availability of new treatment options for patients who need them most.