Abstract A52: Systemic anti-PD-1 immunotherapy results in PD-1 blockade on T cells in the cerebrospinal fluid

Abstract

Abstract Immune checkpoint inhibitors have shown promising clinical efficacy in many types of cancers, including some with metastasis into the central neural system (CNS). However, little is known about the CNS penetration of immune checkpoint inhibitors and their bioactivity on the locoregional T cells. Here, we analyzed the CNS and systemic concentration of pembrolizumab (Pembro) in high-grade glioma patients, who were concurrently treated with intravenously administered Pembro and locoregionally delivered chimeric antigen receptor (CAR) T cells. A total of 99 paired cerebrospinal fluid (CSF) and serum samples were collected from 10 patients during multicycle treatment of CAR T cell and Pembro. We discovered that after the first Pembro infusion, CSF antibody concentrations were increased slower than serum concentrations. However, CSF antibody concentrations reached steady-state 24 hours after Pembro infusion and were maintained stable over the 21-day infusion cycles. Although average CSF Pembro concentrations (3.2nM) were only 1% of serum levels (329nM), we observed effective PD-1 blockade on the T cells in CSF samples of all analyzed patients. The blocking effect was found on both endogenous T cells and locoregionally administered CAR T cells. Further, PD-1 on CD3/CD28 beads-activated T cells was completely blocked after incubation with cell-depleted CSF samples, suggesting the bioactivity of Pembro that penetrated into the CSF. Using a dose-titration assay, we also confirmed that CSF Pembro concentrations were sufficient to ameliorate the cytotoxic activity of CAR T cells against repetitive tumor challenges. Together, for the first time, we showed the dynamic Pembro levels in the CSF throughout multiple treatment cycles and confirmed that systemically administered immune checkpoint inhibitors can penetrate into the CNS and elicit blocking effect on T cells. Our findings add strength to the rationale for combining immune checkpoint inhibitors with locoregionally delivered CAR T cells and other types of immunotherapy for the treatment of brain tumors. Citation Format: Dongrui Wang, Jana Portnow, Vivi Tran, Vivian Chiu, Alfonso Brito, Darya Alizadeh, Renate Starr, Julie Kilpatrick, Paige McNamara, Stephen J. Forman, Behnam Badie, Timothy W. Synold, Christine E. Brown. Systemic anti-PD-1 immunotherapy results in PD-1 blockade on T cells in the cerebrospinal fluid [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A52.