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

Abstract

Purpose T cells engineered with chimeric antigen receptors (CARs) 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 the study was to enhance persistence and augment the antitumor activity of adoptively transferred CD19CAR T cells by re-stimulating 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 clincal grade lentivirus expressing the CD19R:CD28:ζ/EGFRt CAR. The resultant bi-specific T cells, targeting CMV and CD19, were expanded via CD19 CAR-mediated signals using CD19-expressing cells. Results The bi-specific 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 bi-specific 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.

Peptide-Based Vaccines: Current Progress and Future Challenges

“…One strategy involves using CAR-Ts prepared from lymphocytes that harbor specificity against a particular virus through either the endogenous TCR or a second antigen receptor. 177,178 Subsequent therapeutic vaccination with peptide antigen was shown to stimulate the antitumor response of CAR-Ts. Another method recently described involves peptides conjugated to an amphiphilic lipid that directs the target epitope to lymph nodes.…”

Smart CARs engineered for cancer immunotherapy

“…Other less frequent T cell subsets, such as IL-17-producing T cells (Th17 and Tc17), are also being explored based on their stem-like memory characteristics and show promising therapeutic potential (23, 61, 62). Further, the use of virus-specific memory T cells with known antigen specificity for CAR-engineering may provide protection against viral reactivation, and can be combined with a vaccination approach for specific expansion of CAR T cells either in vitro or in patients (63, 64). As the field explores these rarer T cell populations for CAR therapy, including T SCM (40, 44), Th17 (61), and virus-specific T cells (59), or attempts to generate large banks of allogeneic T cells for an ‘off-the-shelf’ product (65, 66), developing long-term expansion conditions that maintain a ‘younger’ T cell phenotype becomes critical.…”

Redirecting T cells to eradicate B-cell acute lymphoblastic leukemia: bispecific T-cell engagers and chimeric antigen receptors

“…Our group and others have taken a step further by transducing virusspecific T-cells with CARs (bispecific virus-CD19 CAR), as virus-specific memory T-cells are known to persist for longer periods after primary infection. [56][57][58] In both xenograft and in vivo studies, bispecific CAR T-cells were associated with improved persistence compared with traditional CAR T-cells. 56,58 Early safety and potential clinical activity using donor-derived virusspecific CD19-CAR T-cells was reported by the Baylor group as previously discussed.…”

“…[56][57][58] In both xenograft and in vivo studies, bispecific CAR T-cells were associated with improved persistence compared with traditional CAR T-cells. 56,58 Early safety and potential clinical activity using donor-derived virusspecific CD19-CAR T-cells was reported by the Baylor group as previously discussed. 50 Preclinical data highlighted favorable CAR T-cell expansion if multivirus-specific T-cells are transduced earlier, which is being introduced into a clinical study.…”