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A burst of highly differentiated CD4 TL identifies a subset of fast progressors, and correlates with hyperprogressive disease in NSCLC patients treated with ICI

Abstract Background Hyperprogressive disease (HPD) is a new pattern of tumor response described with immune checkpoint inhibitors (ICI), characterized by a sharp acceleration of tumor growth after the administration of the treatment. Several definitions based on clinical and/or radiological criteria have been proposed, although different factors limit their applicability. The mechanistic rationale has still not been elucidated. Our group has monitored lymphocyte populations in peripheral blood from non-small cell lung cancer patients (NSCLC) under ICI treatment with flow cytometry, and correlated the findings with HPD. Methods 41 NSCLC patients treated with ICI after progression to ≥ 1 lines of chemotherapy for advanced disease have been included. We analyzed lymphocyte subpopulations from peripheral blood samples obtained immediately before the administration of the 1st and 2nd cycle of ICI. The expression of the following markers has been considered: CD3, CD4, CD8, CD27, CD28, CD45RA, CD62L, PD1. We correlated the findings with HPD as defined by TGR (Champiat S, 2017) and TGKR (Sâada-Bouzid E, 2017). Results Overall response rate (ORR) was 23.8%, and disease control rate (DCR) was 31%. 10 patients (23.8%) presented HPD by TGKR, and 7 patients (16.7%) by TGR. 9 patients (21.4%) could not be evaluated for HPD, mainly due to progression by non-measurable disease or death before further radiological. Median progression free survival (mPFS) was 6 weeks for HPD by TGR and 6.3 weeks by TGKR. We found that the mean proportion of post/pre-treatment LT CD4+ CD27- CD28- was significantly higher for HPD patients (1.86; CI95% 1.14 to 2.58 than non-HPD (1.09; CI95% 0.89 to 1.30) (p = 0.0033). An increase > 30% in LT CD4+/CD27-/CD28- after the first cycle of immunotherapy was associated with fast progression (ORR 0%, mPFS 6 weeks [CI95% 5.8 to 6.2], 8-weeks PFS 0%). Cohen’s kappa between HPD by TGR and by LT was 0.503 (p = 0.004). Conclusions HPD as defined by LT CD4+ CD27- CD28- burst > 30% might complement the limitations of radiological criteria as it does not require the evaluation of the tumor kynetics previous to the beggining of immunotherapy, nor it is influenced by non-measurable disease or tumor burden. Legal entity responsible for the study The authors. Funding AECC, ISCIII. Disclosure All authors have declared no conflicts of interest.