blood derived pre-immune platforms
Immunological and Molecular Biomarkers in Peripheral Blood for the Selection of Cancer Patients for Immunotherapy
blood derived pre-immune platforms
B-PREIMMUN is a project of Action of National Scope: RESEARCH-CREATE-INNOVATE SECOND CYCLE within the framework of the NSRF, co-financed by the European Union.
[Special Service for Management of Business Program Competitiveness, Entrepreneurship and Innovation (EYD EPANEK), Special Service for Management and Implementation of Actions in the fields of Research, Technological Development and Innovation (EYD ETAK)]
The main objective of B-PREIMMUN is the evaluation of combined molecular and immunological biomarkers in the blood for the selection of patients for immunotherapy. Biomarkers include preexisting immunity (PreI), TCR-Vβ clonality of CD8+ cells, and tumor mutational burden (bTMB). The dynamics of these biomarkers and their combinations will be estimated in blood samples. We will study patients with unresectable, PD-L1(+), stage III NSCLC receiving maintenance treatment with durvalumab (ICI; anti-PDL1) after radical concurrent chemo-/radiotherapy in the setting of standard clinical practice.
Genomic changes during carcinogenesis result to the appearence of neo-antigens which are recognized as “foreign” by the cytotoxic CD8+ T-cells through the variable β-chain of T Cell Receptor (TCR-Vβ) leading, thus, to pre-existing immunity (PreI) and immunological memory. Both are necessary conditions for the efficacy of immune checkpoints inhibitors (ICIs).
However, immunosuppressive mechanisms are developed in the tumor microenvironment resulting to the immune escape of tumor cells and, thus, to tumor progression. Immunotherapy with ICIs has improved the prognosis of Non-Small Cell Lung Cancer (NSCLC) patients providing prolonged remissions and overall survival (OS) through the inhibition of immunosuppressive mechanisms in the tumor microenvironment (TME).
Nevertheless, most patients are refractory or develop resistance to ICIs. Τhus, there is an unmet need, both from the clinical and economical point of view, to better select those patients who will more likely respond to this treatment. The currently established predictive biomarkers, such as PD-L1 expression and microsattelite instability (MSI-H), which are evaluated in tissue sections, have been unable to accurately identify the subset of patients who benefit more from such therapies
Moreover, these biomarkers cannot provide information regarding the plasticity of the immune system during immunotherapy. In addition, the tumor mutation burden (TMB) which, so far, is also evaluated in the tissue, is still under investigation. We and others have previously reported that patients with metastatic NSCLC have PreI based on the detection of peripheral blood CD8+ T-cells which specifically recognize tumor associated antigens.
Our preliminary data have shown that in patients with PreI, the administration of ICIs resulted in significantly higher OS compared to patients without PreI, suggesting that immunosuppressive mechanisms, prevailing at the tumor microenvironment, inhibit the cytotoxic activity of CD8+ T-cells. Since ICIs eliminate cancer cells that are recognized by specific CD8+ T-cells, it is reasonable to hypothesize that both the TCR repertoire and the tumor mutation burden in the plasma (bTMB) would be changed during treatment with ICIs; therefore, both TCR repertoire and bTMB could represent more reliable, real time and complementary predictive biomarkers for patient selection.