Pulsar to Overcome Acquired Resistance (AR) to Immunocheck-Point Inhibitors (ICIs) in Oligometastastic Cancer Progression: A Clinical and Translational Research

Design: Acquired Resistance (AR) to immuno-check point inhibitors (ICIs) still remains a common and insufficiently studied clinical challenge in most metastatic tumors which have been initially responder to immunotherapy. In attempt to overcome this phenomenon, PULSAR in conjunction with immuno-checkpoint inhibitors (ICIs) might be a reasonable field of research. "Personalized, ultrahypofractionated stereotactic adaptive radiation therapy" (PULSAR) is a new SBRT modality delivering pulsed fractions during ICIs therapy. The rationale of this research is to induce the PD-L1 over expression by the tumor in order to overcome the AR to ICIs and reverse the tumor microenviroment (TME) from refractory cold tumor to responder hot tumor. To assess this effect the lymphocytes populations and the PD-L1 expression on tumoral circulating extracellular vescicles (EVs) will be investigated. As primary end point of this multicenter observational prospective trial is to assess the usefulness of PULSAR on Metastatic Progression Free Survival in oligometastatic patients developing AR to ICIs in terms of clinical response and immunoresponse by immunophenotype and PD-L1 expression on circulating tumoral EVs. The secondary end point is to assess the optimal timing between the pulsed fractions and the response among different metastatic anatomical sites (liver, lung, nodes, bones). Method: Patients suffering from oligometastic cancer who progress under ICIs therapy showing de novo lesions or refractory lesions in liver, lungs, nodes and bones will be prospectively enrolled in this study. ICIs therapy will be not discontinued during PULSAR and delivered as per protocol according the cancer hystology. A 6 Gy pulse fraction will be given every week ( group A) or every two weeks (group B) to a total 3-6 fractions, depending on the volume. One-three sites will be treated concurrently. Clinical response will be evaluated with FDG-Pet before and after 3 weeks off PULSAR according i-RECIST criteria. As surrogate of TME response, the lymphocyte population and the PD-L1 expression on tumoral circulating EVs in peripheral blood will be analyzed. Peripheral blood will be collected at T0 (at baseline before the first pulse), at T1-T3-6 and T 21 (3 weeks after PULSAR off). The promoter centre will collect, analyze the blood samples and then elaborate the statistical data. The Metastatic Progression Free Survival will be estimated with Kaplan -Maier test. The Shapiro-Wilk test will be used to verify all data distribution. Irradiated lesions, ICI type, cancer type will be related to the clinical and immunological outcomes. The differences among data will be carried out using t-test o test di Wilcoxon. The frequences difference will be assessed with Chi-square or Fisher exact test. The statistical significance will be setted at 0.05. To achieve a 0.95 statistic power, 210 patients will be enrolled within in 3 years. Conclusion: By this multicenter observational prospective study, information on the effictiveness of PULSAR in overcoming AR during ICI are expected; information on effective pulsed fractions timing and response by anatomical sites are also awaited.