Senolytic CAR T cells as novel therapeutic concept for solid tumors and senescence-associated diseases.

Project Information

CARsen

Grant agreement ID: 949667

DOI

10.3030/949667

EC signature date 18 January 2021

Start date 1 January 2022

End date 31 December 2027

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 818 637,50

EU contribution

€ 1 818 637,00

Coordinated by

EBERHARD KARLS UNIVERSITAET TUEBINGEN
Germany

Periodic Reporting for period 2 - CARsen (Senolytic CAR T cells as novel therapeutic concept for solid tumors and senescence-associated diseases.)

Reporting period: 2023-07-01 to 2024-12-31

Summary of the context and overall objectives of the project

Cell therapies with genetically engineered immune cells expressing chimeric antigen receptors (“CARs”) have shown great success against certain hematological diseases, leading to the approval of CAR T cell products for specific indications. However, several challenges have emerged including high rates of relapse, poor efficacy against solid tumors and severe toxicities that have impeded the broader use of CAR therapies.
CARsen aims to extend the successful application of CAR therapies to senescence-associated diseases and to solid tumors with dismal prognosis. Cellular senescence is a stress-response program characterized by a stable cell cycle arrest that serves as a tumor-suppressive mechanism. However, accumulation of senescent cells generates a chronic inflammatory milieu, which contributes to a plethora of pathologies, such as liver or lung fibrosis and can promote tumor progression.
Therefore, CARsen sets out to develop tailored CAR therapies to specifically eliminating senescent cells. If successful, this therapeutic approach will ameliorate senescence-related diseases and can serve as a novel therapeutic concept for patients with hard-to-treat solid tumors by combining senescence-inducing agents and CAR therapies. Thus, CARsen has the potential to provide novel treatment strategies with high therapeutic efficacy in a broad range of clinical applications including malignant and non-malignant diseases.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

CARsen has investigated gene editing and engineering strategies to optimally adjust CAR therapies to the senescence-/ disease-specific requirements and to provide high therapeutic efficacy in combinatorial treatment approaches with senescence-inducing agents. These efforts have led to the establishment of novel technologies, the generation of tailored CAR designs and the development of a comprehensive immune cell engineering and evaluation platform to precisely tailor and assess the modified cell products. CARsen has provided novel insights into CAR biology, combination therapies and into the interaction of CAR T cells and (senescent) target cells, advancing therapeutic efficacy and extending the application of senolytic CAR products. The therapeutic concept of senolytic CAR therapies is currently being evaluated in a broad range of solid tumor models and in non-malignant diseases.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Successful CAR therapies beyond their use in certain hematological malignancies are limited and urgently needed. CARsen aims to change this notion and goes beyond current applications for CAR therapies by developing senolytic CAR therapies against a broad range of solid tumors and non-malignant diseases. CARsen has generated and evaluated modular cell products tailored to the specific disease settings to enable efficient and safe elimination of senescent cells as well as synergistic treatment approaches with pro-senescence therapies to efficiently eradicate solid tumors. CARsen combines different concepts of anticancer therapies and leverages major mechanistic insights to enhance CAR efficacy and safety using gene editing and engineering approaches. Thus, biological findings and technological advances go hand in hand to enhance treatment strategies against hard-to-treat malignancies and senescence-associated diseases.
Until the end of the project, CARsen will extend and improve senolytic CAR therapies that will serve as the basis for clinical translation. Overall, this work aims at improving the outcome of patients with cancer and senescence-associated diseases.

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