Post hoc analysis included a comparison of patients with clear cell and non-clear cell histologies

Post hoc analysis included a comparison of patients with clear cell and non-clear cell histologies. of Texas at MD Anderson Cancer Center and the requester as the information may include data collected under an institutional alliance clinical BMS-582949 trial protocol.?Source data are provided with this paper. Abstract Cryoablation in combination with immune checkpoint therapy was previously reported to improve anti-tumor immune responses in pre-clinical studies. Here we report a pilot study of anti-CTLA-4 (tremelimumab) with (n?=?15) or without (n?=?14) cryoablation in patients with metastatic renal cell carcinoma (“type”:”clinical-trial”,”attrs”:”text”:”NCT02626130″,”term_id”:”NCT02626130″NCT02626130), 18 patients with clear cell and 11 patients with?non-clear cell histologies. The primary endpoint is safety, secondary endpoints include objective response rate, progression-free survival, and immune monitoring studies. Safety data indicate grade 3 treatment-related adverse events in 16 of 29 patients (55%) including 6 diarrhea/colitis, 3 hepatitis, 1 pneumonitis, and 1 glomerulonephritis. Toxicity leading to treatment discontinuation occurs in 5 patients in each arm. BMS-582949 3 patients with clear cell histology experience durable responses. One patient in the tremelimumab arm experiences an objective response, the median progression-free survival for all patients is 3.3 months (95% CI: 2.0, 5.3 months). Exploratory immune monitoring analysis of baseline and post-treatment tumor tissue samples shows that treatment increases immune cell infiltration and tertiary lymphoid structures in clear cell but not in non-clear cell. In clear cell, cryoablation plus tremelimumab leads to a significant increase in immune cell infiltration. These data spotlight?that treatment with tremelimumab plus cryotherapy is feasible and modulates the immune microenvironment in patients with metastatic clear cell histology. tremelimumab monotherapy, Cryoablation+Tremelimumab combination therapy, progressive disease, progression-free survival. Table 1 Patient characteristics of the study. (%)(%)(%)(%)(%)(%)(%)(%)(%)immunohistochemistry, progression-free survival, metastatic BMS-582949 clear cell renal cell carcinoma, metastatic non-clear cell renal cell carcinoma. Clear cell vs non-clear cell histology outcomes As the study was histology agnostic, 18 mRCC patients with clear cell (mccRCC) and 11 mRCC patients with non-clear (mnccRCC) histologies were enrolled and received at least one dose of tremelimumab. The median PFS was 4.3 (95% CI: 2.0, 10.2 months) versus 3.0 (95% CI: 1.7C4.8 months) in favor of patients with clear cell histology with a hazard ratio of Rabbit Polyclonal to MED26 0.5 (95% CI: 0.22,1.13). Patients BMS-582949 with mccRCC had improved outcomes as compared to those with mnccRCC regardless of treatment arm. The median OS was 33.7 (95% CI 16 months, NR) versus 16.2 months (95% CI 7.8, 33.7 months) in favor of patients with mccRCC with a hazard ratio of 0.3 (95% CI: 0.10,0.91) as shown in Fig.?2c. Given that BMS-582949 all three patients with prolonged responses had mccRCC we sought to compare patients with mccRCC and mnccRCC for our tissue correlative studies. For the 29 participants treated on the study, 26 patients had baseline tissue collected: 15 with mccRCC histology and 11 with mnccRCC histology, and 20 patients had additional tissue collected after two doses of tremelimumab: 12 with mccRCC histology, and 8 with mnccRCC histology?(Supplementary Table 3). Supplementary Table?4 lists the samples used for immune monitoring studies. Association of inflamed and favorable tumor immune microenvironment with clear cell histology In pre-treatment tissue samples from mRCC patients with mccRCC, we observed an inflamed tumor microenvironment with enriched expression of genes belonging to both the vascular endothelial growth factor (VEGF) and interferon gamma (IFN-values are from Welchs test. b Bar plots showing differentially activated pathways in tumor tissue samples from patients with mccRCC versus mnccRCC. Upregulated pathways in mccRCC are indicated by red bars while downregulated pathways are indicated by blue bars. values (FDR-adjusted 0.2) are from GSEA algorithm and c Boxplot showing infiltration with Th1 cells. The ends of the box are the upper and lower quartiles (75th and 25th percentiles), the median is the horizontal line inside the box, and whisker lines extend to outliers (minimum and maximum). value was calculated using the two-tailed unpaired MannCWhitney test. Each patient is usually identified by a unique symbol as shown in the inset on the right. Red box whiskers show mccRCC and blue box whiskers show mnccRCC cohort of patients. Patients with ongoing responses are shown in green. metastatic clear cell renal cell carcinoma, metastatic non-clear cell renal cell carcinoma, normalized enrichment score, T helper cells type 1. Source data are provided as Source Data file. Open in a separate windows Fig. 4 Treatment with tremelimumab monotherapy or cryo-tremelimumab combination therapy leads to favorable changes in post-treatment tissue samples of patients with clear cell histology.aCd Pre and post-treatment tissue samples of patients with clear cell (mccRCC) and non-clear cell (mnccRCC) histology were analyzed by NanoString (a and c, mccRCC: pre (values were calculated using the.