Sreyashi Basu

Ipilimumab with Stereotactic Ablative Radiation Therapy: Phase I Results and Immunologic Correlates from Peripheral T Cells

Purpose: Little prospective data are available on clinical outcomes and immune correlates from combination radiation and immunotherapy. We conducted a phase I trial (NCT02239900) testing stereotactic ablative radiotherapy (SABR) with ipilimumab. Experimental Design: SABR was given either concurrently (1 day after the first dose) or sequentially (1 week after the second dose) with ipilimumab (3 mg/kg every 3 weeks for 4 doses) to five treatment groups: concurrent 50 Gy (in 4 fractions) to liver; sequential 50 Gy (in 4 fractions) to liver; concurrent 50 Gy (in 4 fractions) to lung; sequential 50 Gy (in 4 fractions) to lung; and sequential 60 Gy (in 10 fractions) to lung or liver. MTD was determined with a 3 + 3 dose de-escalation design. Immune marker expression was assessed by flow cytometry. Results: Among 35 patients who initiated ipilimumab, 2 experienced dose-limiting toxicity and 12 (34%) grade 3 toxicity. Response outside the radiation field was assessable in 31 patients. Three patients (10%) exhibited partial response and 7 (23%) experienced clinical benefit (defined as partial response or stable disease lasting ≥6 months). Clinical benefit was associated with increases in peripheral CD8+ T cells, CD8+/CD4+ T-cell ratio, and proportion of CD8+ T cells expressing 4-1BB and PD1. Liver (vs. lung) irradiation produced greater T-cell activation, reflected as increases in the proportions of peripheral T cells expressing ICOS, GITR, and 4-1BB. Conclusions: Combining SABR and ipilimumab was safe with signs of efficacy, peripheral T-cell markers may predict clinical benefit, and systemic immune activation was greater after liver irradiation. Clin Cancer Res; 23(6); 1388–96. ©2016 AACR.

Abstract CT083: Clinical activity, immune and molecular correlates of nivolumab vs. nivolumab plus bevacizumab vs nivolumab plus ipilimumab in metastatic renal cell carcinoma

Background: Immune checkpoint blockade including anti-CTLA-4 (ipilimumab, BMS) and anti-PD1 (nivolumab, BMS) as monotherapies have been known to have clinical activity against metastatic renal cell carcinoma (MRCC), but with relatively low clinical response rate (10-25%). Anti-VEGF antibody bevacizumab is a standard therapy for MRCC also with a low response rate ( Methods: In this open-label, pilot, pre-surgical/pre-biopsy trial (NCT02210117), adults with MRCC without prior immune checkpoint therapy and anti-VGEF therapy were enrolled, stratified by planned surgical procedure, and randomized 1:2:1 to receive nivolumab monotherapy, nivolumab + bevacizumab or nivolumab + ipilimumab, followed by cytoreductive nephrectomy, metastasectomy, or post-treatment biopsy, and subsequent maintenance therapy with nivolumab for up to 2 years until disease progression and intolerable toxicity. Pre- and post-treatment blood and tumor samples were obtained for dynamic monitoring of immune and molecular correlates to clinical activity. Results: Sixty patients were treated (median duration 17.1 weeks, range 2.74 to 85.1 weeks as of 12/6/16). Fourty-four were evaluable for clinical responses post-procedures. Five of 12 (42%) nivolumab monotherapy treated patients had partial response (PR), 4 (33%) had stable disease (SD), and 3 (25%) had progression of disease (PD) and 0 withdrew early (W). In the nivolumab + bevacizumab arm, 1 of 19 (5%) had complete response and 9 (47%) patients had PR, for a response rate of 53%, 3 (16%) had SD, 3 (16%) with PD and 3 (16%) W. In the nivolumab + ipilimumab arm, 5 of 13 (38%) patients had PR, 1 (8%) had SD and 5 (38%) had PD and 2 (15%) W. Treatment was generally well tolerated with mostly grade 1 or 2 adverse events. Grade 3 or higher toxicities were 19% in the nivolumab arm, 41% in the nivolumab + bevacizumab arm (including 17% bevacizumab-specific hypertension that was well controlled by anti-hypertensive medications), and 27% in the nivolumab + ipilimumab arm. Correlative laboratory studies including flow cytometry, IHC, and gene profiling analysis identified a number of immune gene signatures including an IFN-γ gene signature that we will report in more details. Conclusions: Combination therapy with nivolumab + bevacizumab and nivolumab + ipilimumab showed promising clinical activities in patients with MRCC. Immune and molecular correlative studies may allow us to identify novel biomarkers that can be used for correlation with clinical outcomes in patients with MRCC. Citation Format: Jianjun Gao, Jose A. Karam, Christopher G. Wood, Surena Matin, Kamran Ahrar, Eric Jonasch, Nizar Tannir, Matthew Campell, Chaan S. Ng, Rebecca S. Slack, Priya Rao, James P. Allison, Jorge M. Blando, Luis M. Vence, Sreyashi Basu, Hao Zhao, Tenghui Chen, Hong Chen, Padmanee Sharma. Clinical activity, immune and molecular correlates of nivolumab vs. nivolumab plus bevacizumab vs nivolumab plus ipilimumab in metastatic renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT083. doi:10.1158/1538-7445.AM2017-CT083

A potential biomarker for anti-PD-1 immunotherapy

A recent study identifies an immune cell type known as classical monocytes in the peripheral blood as a potential biomarker for response to anti-PD-1 immune checkpoint therapy in metastatic melanoma.