Periodic Reporting for period 1 - BioFlow (The development of a predictive biomarker for immunotherapy outcome based on flow cytometry test)
Période du rapport: 2022-09-01 au 2024-02-29
Immunotherapy based on immune checkpoint inhibitors (ICIs) has revolutionised the cancer therapy field. ICIs harness the patient’s own immune system to fight cancer, producing unprecedented durable remissions in a subset of patients. Over the last decade, multiple ICIs such as PD-1, PD-L1 and CTLA-4 inhibitors have been approved for treating a broad range of cancer types. However, despite the remarkable success of ICI therapy, it is estimated that only 20-30% of patients respond to treatment, for reasons that are not well understood. This is a major unmet need, namely, to develop predictive biomarkers for identifying patients who are likely to benefit from ICIs. While currently there are several clinically validated predictive biomarkers for ICI immunotherapies including tumour expression of PD-L1; tumour mutational burden (TMB); and tumour microsatellite instability (MSI), their predictive power is quite limited. Additionally, many of these biomarker tests require tumour biopsies sampled by an invasive procedure that is not always possible. In this project, our objective is to identify a new biomarker with superior predictive power, and that can be taken with a minimally invasive procedure. These efforts will expand the benefit for cancer patients, allowing only those who will respond to therapy administered with ICI, while the rest will not suffer from the side effects and will be provided with additional therapeutic options if they are more likely not to respond to ICI therapy.
To identify a blood-borne new biomarker for immunotherapy, as this will be the best way to ensure liquid biopsy rather than solid biopsy from the tumor, we have used several pre-clinical tumor models developed in our lab which a priory we determined response to immunotherapy. Using these models along with high throughput systems, e.g. CyTOF (mass cytometry) and single cell RNA sequencing, we identified a specific neutrophil subpopulation enriched only in tumors that are likely to respond to therapy. We analyzed the different markers they express and found that Ly6E is a specific marker highly expressed by neutrophils associated with response to therapy. We first identified the role of Ly6E neutrophils in tumors, and also their mechanisms of action for their enrichment in responsive tumors. We found that they express factors such as IL12 and IL23 which are known to increase the activity of cytotoxic T cells. We also showed that they are enriched due to the tumor secreting type I interferon, due to its increased mutational burden. Thus, once we identified their role and found that they can sensitize otherwise resistant tumors to immunotherapy, we searched in databases of human samples for the equivalent cells found in mice, in human specimens. The major achievements of this project is not only that we analyzed approximately 120 samples of non-small cell lung cancer and melanoma patients, predicting their response to immunotherapy based on levels of Ly6E neutrophils, but also that we were able to identify these subpopulation in over 1400 cancer patients of 6 different types of tumors, and in high predictive power, further emphasizing the role of Ly6E neutrophils in tumors. This work was recently published in Cancer Cell 2024.
Ly6E neutrophils that can be analyzed by a simple blood test, is a major biomarker breakthrough in the field of immunotherapy. This is perhaps the first liquid biomarkers with such a high predictive power (AUC~0.9). The identification of immune cell subsets with such a predictive power is not only a scientific breakthrough but also a commercialization breakthrough as it can be evaluated in each medical center which encompasses a flow cytometry. Using a simple flow cytometry output by any flow cytometry technician, each hospital can actually provide the levels of Ly6E neutrophils in patients, and therefore can support clinical decision making regarding immunotherapy administration. IN addition, the fact that it is a simple blood test, which can be done in the medical center, also provide an additional benefit that the results are provided within an hour since the blood was drawn. All the clinical and lab procedures are simple to do, and will provide benefit to the patients.