CMVpp65 Vaccine Enhances the Antitumor Efficacy of Adoptively Transferred CD19-Redirected CMV-Specific T Cells

Overview

Journal Clin Cancer Res

Specialty Oncology

Date 2015 Apr 4

PMID 25838392

Citations 38

Authors

Xiuli Wang

ChingLam W Wong

Ryan Urak

Armen Mardiros

Lihua E Budde

Wen-Chung Chang

Sandra H Thomas

Christine E Brown

Corinna La Rosa

Don J Diamond

Michael C Jensen

Ryotaro Nakamura

John A Zaia

Stephen J Forman

Affiliations

Soon will be listed here.

Abstract

Purpose: T cells engineered with chimeric antigen receptors (CAR) recognizing CD19 can induce complete remission of B-cell malignancies in clinical trials; however, in some disease settings, CAR therapy confers only modest clinical benefit due to attenuated persistence of CAR T cells. The purpose of this study was to enhance persistence and augment the antitumor activity of adoptively transferred CD19CAR T cells by restimulating CAR(+) T cells through an endogenous cytomegalovirus (CMV)-specific T-cell receptor.

Experimental Design: CMV-specific T cells from CMV seropositive healthy donors were selected after stimulation with pp65 protein and transduced with clinical-grade lentivirus expressing the CD19R:CD28:ζ/EGFRt CAR. The resultant bispecific T cells, targeting CMV and CD19, were expanded via CD19 CAR-mediated signals using CD19-expressing cells.

Results: The bispecific T cells proliferated vigorously after engagement with either endogenous CMVpp65 T-cell receptors or engineered CD19 CARs, exhibiting specific cytolytic activity and IFNγ secretion. Upon adoptive transfer into immunodeficient mice bearing human lymphomas, the bispecific T cells exhibited proliferative response and enhanced antitumor activity following CMVpp65 peptide vaccine administration.

Conclusions: We have redirected CMV-specific T cells to recognize and lyse tumor cells via CD19CARs, while maintaining their ability to proliferate in response to CMV antigen stimulation. These results illustrate the clinical applications of CMV vaccine to augment the antitumor activity of adoptively transferred CD19CAR T cells in patients with B-cell malignancies.

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