A scientific program based on a new approach to cellular therapies to increase the effectiveness of cancer treatments.
Project leader: Jean-Luc Perfettini
Reprogramming "monocytes" immune cells in a personalized way is a new concept at the heart of the emerging biotherapy program, led by Dr. Jean-Luc Perfettini, director of the INSERM U1030 research unit and of the "Cell Death, Immunity and Therapeutic Innovation" team. The use of the patient's own modified autologous monocytes as "therapeutic Trojan horses" allows them to infiltrate the tumor, phagocytose the cancer cells and achieve effective anti-tumor immunity. This is a promising way to increase the efficacy of anti-cancer drugs and overcome resistance to treatment.
Despite the emergence of new immunotherapies and targeted therapies, a majority of patients do not respond or only partially respond to anti-cancer treatments. "Cancer cells manage to evade immune cells by developing different strategies," explains Dr. Jean-Luc Perfettini, head of Gustave Roussy's emerging Cellular Biotherapies program.
Cellular therapy, a promising strategy, consists of genetically reprogramming the patient's own cells to use them as medicine. The best known of these is based on the transfer of human T cells genetically modified to express chimeric antigen receptors, also known as CAR T cells. But while the technique is effective in treating certain hematological malignancies, it is not effective in solid tumors.
A novel concept of "therapeutic Trojan horses"
The emerging biotherapeutics program is based on a novel concept using patients' modified autologous monocytes as "therapeutic Trojans", which, through overexpression of the p21 protein, infiltrate tumors, differentiate into macrophages and then phagocytose cancer cells and stimulate the immune system to act as a therapeutic vaccine.
Tumor-associated macrophages (TAMs) have anti-inflammatory activity and an inability to phagocytose cancer cells. However, thanks to their plasticity and ability to adapt to the microenvironment, macrophages, once reprogrammed, are able to eliminate cancer cells and confer long-lasting anti-tumor immunity.
Thanks to their expertise in immunology and molecular virology, Dr. Perfettini's teams have been developing therapeutic strategies based on these approaches for several years by targeting MAT to attenuate their immunosuppressive properties and exploit their tumoricidal capacities. Based on blood samples, monocytes (patients' innate immune cells) are retrieved, rearmed with genes and reprogrammed to invade and phagocytose the tumor. "The monocyte is a very good vector and has a natural ability to penetrate the solid tumor directly to express itself", explains Dr. Jean-Luc Perfettini.
Proof of concept: from discovery to first drugs
Based on these initial conclusive results, the emerging program has several objectives:
- Provide preclinical and clinical proof of concept that phagocytosis-guided cell therapies using patient-engineered monocytes can improve cancer treatment and induce durable anti-tumor immunity.
- Enable the creation of an advanced technology platform for the personalized production of this new generation of cancer cell therapy.
- Support the clinical use of these therapeutic Trojans to cure cancer and prevent aggressive tumor relapse or resistance to conventional cancer treatments and immunotherapies.
The preclinical proof of concept of these biotherapies will be deployed on innovative models such as organoids, or avatars of patients, but also on aggressive tumors for which therapeutic options currently remain limited (such as triple-negative breast cancer, pancreatic cancer, adolescent or pediatric tumors and certain bronchial tumors).
This emerging program will benefit from clinical trials, the creation of a new clinical unit on biotherapies (the ICE unit), collaborations with international centers and the creation of a start-up to promote and support the development of new treatments based on the use of "therapeutic Trojan horses" at Gustave Roussy. "Our ambition is to federate all of the Institute's medical and scientific expertise in order to create a functional and virtuous continuum, linking exploratory and clinical research, therapeutic innovation in biotherapy, trials and Gustave Roussy's clinical departments, in order to go from discovery to medicine. This ambition is also perfectly in line with that of the Paris Saclay Cancer Cluster, and aims to offer new therapeutic opportunities to cancer patients as quickly as possible in a personalized manner," summarizes Dr. Perfettini.
To launch this unique program, Jean-Luc Perfettini's research team has received a starting package of €250,000 from the generosity of Gustave Roussy donors.
