Rôle potentiel de l’immunothérapie par inhibiteurs de checkpoint dans les carcinomes rénaux papillaires
| Titre | Rôle potentiel de l’immunothérapie par inhibiteurs de checkpoint dans les carcinomes rénaux papillaires |
| Type | Thèse d'exercice : Médecine |
| Auteurs | De Vries-Brilland Manon |
| Directeurs | Albigès Laurence |
| Année | 2019 |
| URL | http://dune.univ-angers.fr/fichiers/20071484/2019MCEM10635/fichier/10635F.pdf |
| Mots-clés | cancer du rein papillaire métastatique, immunothérapie, inhibiteurs de checkpoint, microenvironnement tumoral |
| Résumé | Background : papillary Renal Cell Carcinoma (pRCC) is the most common non-clear cell RCC (nccRCC) and represents up to 15% of RCC. Pivotal studies evaluating immune checkpoint inhibitors mostly excluded nccRCC. Objective : to evaluate the activity of immune checkpoint inhibitors specifically in metastatic pRCC Design, setting, and participants: We retrospectively investigated the efficacy and safety of PD-1/PD-L1 inhibitors in patients with metastatic pRCC from 15 centers in France and Belgium. Outcome measurements and statistical analysis: Primary endpoint was time-to-treatment failure (TTF). Secondary endpoints included objective response rate (ORR), overall survival (OS) and treatment-related adverse events (TRAEs). Descriptive statistics and Kaplan-Meier method were used for the overall cohort and by histology subgroups. Results and limitations : From 02/2016 to 01/2019, 57 pRCC patients were included. Histology included 16 (28%) type 1 pRCC, 34 (60%) type 2 pRCC, and 7 (12%) unclassified pRCC. Immune checkpoint inhibitors treatment was used in the first-line setting in 4 patients (7%), in second-line in 32 patients (56%) and in third-line or beyond in 21 patients (37%). With a median follow up of 12 months (95% Confidence Interval (CI): 9.9-21.0), the median TTF was 3.1 months (95%CI: 2.7-5.0). Median TTF was 5 months (95%CI: 2.7-NA) in type 1, 2.9 months (95%CI: 2.4-6.7) in type 2 and 4.1 months (95%CI: 2.3-NA) in unclassified pRCC (p=0.1). Among the 55 patients evaluable for ORR, best response was complete response/partial response in 6 patients (11%), stable disease in 18 patients (33%) and progressive disease in 31 patients (56%). Median OS was 14.6 months (95%CI: 9.0- not reached). TRAEs of grade 3-4 were noted in 6 patients (10%) leading to treatment discontinuation, no grade 5 TRAEs were observed. Conclusion : PD-1/PD-L1 inhibitors exhibit limited activity as monotherapy in this pRCC population, which remains an unmet need. Our findings underline the need for further prospective clinical trials evaluating immune checkpoint inhibitors combinations in patients with pRCC. Patient summary : in this study, we evaluated the activity of immune checkpoint inhibitors specifically in metastatic papillary renal cell carcinoma. This treatment may be a therapeutic option but it would be interesting to study treatment combinations and to better target patients who could benefit |
| Résumé en anglais | Background : papillary Renal Cell Carcinoma (pRCC) is the most common non-clear cell RCC (nccRCC). Pivotal studies evaluating immune checkpoint inhibitors mostly excluded nccRCC. PD-1/PD-L1 inhibitors exhibit limited activity in metastatic pRCC. The immune microenvironment in pRCC is unknown. Methods : in silico, we studied the expression of cytotoxic lymphocyte infiltration (CYT), using a descriptive (CIBERSORT) and specific quantitative approach, as well as the expression of inhibitors checkpoint immune markers (ICI), in 258 localized papillary renal cell tumors using RNA-seq data from The Cancer Genome Atlas (TCGA) as training set. Based on previous report, we selected 8 genes of interest (CD8a, CD8b, GZMA, PRF1, PD1, PDL1, PDL2 and CTLA4). An independent data set of 34 localized pRCC (gene expression) was used as a validation set. Results : using a clustering method based on the expression level of 8 predefined genes of interest, we identified 3 groups, differentiated by CYT and ICI expression. In validation cohort, we observed similar clustering. Cluster 3, characterized by a CYT and ICI high expression, was significantly associated with increased population of TCD8, TCD4 helper, M1 macrophages and dendritic cells in CIBERSORT analysis. Additionally, these immune clusters were not associated with indels neo-antigen load but were significantly correlated with the MHC class I antigen presenting machinery expression (APM) (p=1.1x10-11), TIS score (p=2.2x10-16) and interferon-gamma gene expression (p=1.6x10-13). Conclusion : we characterized cytotoxic immune infiltration in pRCCs. Cluster 3 could represent the candidate population for PD-1/PD-L1 inhibitors. Transcriptomic immune signature validation in pRCCs patients treated with immunotherapy is warranted. |
| Langue de rédaction | Français |
| Nb pages | 81 |
| Diplôme | Diplôme d'État de docteur en médecine |
| Date de soutenance | 2019-07-04 |
| Editeur | Université Angers |
| Place Published | Angers |
| Libellé UFR | UFR médecine |
| Numéro national | 2019ANGE097M |