Charles Dariane

Efficacy of targeted therapies after PD-1/PD-L1 blockade in metastatic renal cell carcinoma

BACKGROUND Monoclonal antibodies that target the programmed death-1 (PD-1)/programmed death-ligand 1(PD-L1) pathway have shown antitumour activity in metastatic renal cell carcinoma (mRCC) and are currently being developed in first-line (in combination) and in previously treated patients. The efficacy targeted therapy (TT) after PD-1/PD-L1 blockade is still unknown. METHODS Medical records of mRCC patients treated with investigational PD-1 or PD-L1 inhibitors at 4 academic institutions were reviewed. Patients who received subsequent treatment with TT were selected to collect outcome measures of subsequent TT. RESULTS Of 99 patients who received PD-1/PD-L1 blockade as part of clinical trials, 56 patients have received subsequent therapy: 44 patients received vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR) inhibitors and 12 received mammalian target of rapamycin (mTOR) inhibitors as first subsequent TT. Median follow up, from the start of subsequent TT was 16.1 months (range: 0.2, 30.6 months). TT post PD-1/PD-L1 blockade was administered as second-line, third-line or beyond third-line in 9 (16%), 24 (43%) and 23 patients (41%) respectively. Median time to treatment failure on subsequent TT was 6.6 months (range: 0.2+, 23.0). 1-year and 2 year overall survival from the initiation of subsequent TT was 58% (95% confidence interval (CI): 41-72%) and 36% (95% CI: 18-54%), respectively. CONCLUSION Both VEGF/VEGFR and mTOR inhibitors demonstrate antitumour activity following PD-1/PD-L1 blockade.

Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells

Immune cells are important components of the tumor microenvironment and influence tumor growth and evolution at all stages of carcinogenesis. Notably, it is now well established that the immune infiltrate in human tumors can correlate with prognosis and response to therapy. The analysis of the immune infiltrate in the tumor microenvironment has become a major challenge for the classification of patients and the response to treatment. The co-expression of inhibitory receptors such as Program Cell Death Protein 1 (PD1; also known as CD279), Cytotoxic T Lymphocyte Associated Protein 4 (CTLA-4), T-Cell Immunoglobulin and Mucin Containing Protein-3 (Tim-3; also known as CD366), and Lymphocyte Activation Gene 3 (Lag-3; also known as CD223), is a hallmark of T cell exhaustion. We developed a multiparametric in situ immunofluorescence staining to identify and quantify at the cellular level the co-expression of these inhibitory receptors. On a retrospective series of frozen tissue of renal cell carcinomas (RCC), using a fluorescence multispectral imaging technology coupled with an image analysis software, it was found that co-expression of PD-1 and Tim-3 on tumor infiltrating CD8+ T cells is correlated with a poor prognosis in RCC. To our knowledge, this represents the first study demonstrating that this automated multiplex in situ technology may have some clinical relevance.

Prospective assessment of the adherent perinephric fat in partial nephrectomies: Predictors and impact on peri-operative outcomes.

543 Background: The surgical complexity of partial nephrectomy (PN) can be partly anticipated using renal morphometric scores that do not consider patient related issues such as obesity or perirenal fat. Our primary objective was to prospectively assess the predictive factors for adherent perinephric fat (APF) and its impact on the onset of complications. The secondary objective was to correlate the surgical appraising with the histological reality of APF. Methods: Fifty consecutive patients undergoing robotic or open PN were prospectively included from November 2014 to March 2015. The previously published Mayo adhesive probability score (MAP score) was calculated and compared to the per-operative surgical assessment of APF using a 0 to 3 scale (APF being defined by a score ≥ 2). Fat was analyzed histologically for fibrosis (HES staining and picrosirius red) and inflammatory infiltrate of macrophages (immunohistochemistry using anti-CD68 antibody). Results: APF was present in 18 patients (36%), with no im...