Better understand, predict & overcome anti-PD1(L1) resistance in lung cancer patients and beyond
After targeted therapies at the end of the 90s, immunotherapy today improves the treatment of patients with non-small-cell lung cancer. In that respect, by restoring the ability of patients’ T-cells to recognize and to kill cancer cells, the PD-1(L1) immune checkpoint inhibitors lead to spectacular reduction in tumor volume and a significant lengthening of life expectancy in 20% of patients.
Despite this progress, lung cancer remains the leading cause of cancer death worldwide (around 1.5 million deaths per year). Indeed, for reasons yet to be fully understood (molecular profile of the tumor, impact of the surrounding microenvironment, the patient’s immune status…), the majority of patients with non-small-cell lung cancer see their cancer progress despite the anti-PD-1(L1) treatment.
The Pioneer collective gave itself 5 years to take up the main current challenge of immuno-oncology: better understand, predict & overcome these resistances, notably in lung cancer. This indication is one of the principle domains of expertise of the AP-HM, and the centre for early clinical trials of Marseille is at the cutting edge of clinical research in immunotherapy, especially in lung cancer. While future results obtained in the framework of this project may not be entirely transferable to all cancers, they should enlarge the array of available immunotherapies and enlighten on how they should be associated to perfect the personalisation of these new treatments.
3 complementary axes
The Pioneer Project is focused on 3 complementary research axes
- A program of exploratory clinical trials to evaluate the efficacy and safety of new associations of immunotherapies that target simultaneously several immune checkpoints and cells implicated in the anti-tumoral immune response.
- The comparative analysis of biological samples taken from patients (blood and biopsy) to identify and validate predictive biomarkers for response to immunotherapy treatments and to develop associated diagnostic tests.
- The validation of new generation immune checkpoint modulators on in vivo models of the disease.
An unprecedented research project
Beyond non responders
The Pioneer clinical study will include the patients that do not respond to anti-PD1(L1), but also the patients that progress early or late under treatment. To this aim, all patients will be subjected to a biopsy before the start of the treatment for a reference, and to a biopsy and blood sampling at 6 and 12 weeks once the anti-PD1(L1) treatment has started.
High precision immunotherapy
The 4 study arms of the Pioneer project target two checkpoints of the immune response simultaneously and several players of immunity. The goal is not only to circumvent the resistance to anti-PD1(L1), but also to adapt a treatment to the immunological profile of each patient and tumor.
All the dimensions of the Immunogram
To identify predictive biomarkers starting from biological patient samples, Pioneer integrates all the parameters that influence the response to immunotherapy : the degree of mutation accumulation in cancer cells, their metabolism, inhibitor or activator signals that may be present at their surface and in their microenvironment, as well as the patient’s anti-tumor immune response.
The next wave of immune checkpoint modulators
Beyond the 4 drug candidates evaluated in the clinical study, The Pioneer Project aims to achieve preclinical validation of new immune checkpoint modulators.
The main current challenge of immuno-oncology
To date, no laboratory has been able to overcome anti-PD1(L1) resistance in lung cancer patients and no biomarker can identify this resistance in advance. The Pioneer Project is therefore a very ambitious biomedical research program that comes with a high degree of complexity in the making. By combining our resources, our domains of expertise and our talents, we intend to:
- Elucidate the complex mechanisms of resistance to PD-1(L1) inhibitors;
- Expand the set of immunotherapies in lung cancer and beyond;
- Develop new therapeutic combinations;
- Develop diagnostic assays to predict patient response to these treatments;
- And of course, offer a well awaited solution to patients in a therapeutic dead-end.