Project: CMV/CD19 bi-Specific CAR T cells combined with CMV vaccine as post-transplantation immunotherapy for non-Hodgkin lymphoma

Project Leaders: Stephen J. Forman, M.D., and Ryotaro Nakamura, M.D. (Clinical) / Donald Diamond, Ph.D. and Xiuli Wang, Ph.D. (Scientific)

We propose selecting cytomegalovirus (CMV) pp65-specific T cells for ex vivo modification with our phase-I–tested CD19 CAR, infusing the CMV-CD19 bi-specific T cells into patients (in post-transplant and active disease settings), and then conducting an in vivo expansion via CMV-specific modified vaccinia Ankara (MVA) Triplex vaccine injections. This strategy is feasible since more than 70% of adults are CMV immune, the frequency of pp65-specific T cells in CMV+ donors is high, and there is clinical experience with adoptive cellular immunotherapy targeting the CMVpp65 antigen. Importantly, in the post-allo HCT setting, use of CMV selection has a low risk of inducing GVHD and the possible benefit of preventing CMV infection. City of Hope researchers have also developed a novel CMV vaccine, Triplex, which can safely stimulate CMV-specific T cell immunity, through endogenous T cell receptors (TCR)1. This vaccine will be administered to patients after infusion of CMV-CD19CAR T cells to provide an antigen boost as a means to in vivo expand the CMV-specific CAR T cells. Triplex is a multi-antigen recombinant MVA virus vaccine that has thus far proven safe and immunogenic in a phase I trial in healthy volunteers of either +/- CMV serostatus. It is currently under study in a phase II vaccine trial in allo HCT recipients (NCT02506933).
 
Hypothesis: CD19CAR-engineered CMVpp65-specific T cells will be capable of a) safely mediating antitumor activity in the auto and allo HCT settings; b) persisting following adoptive transfer; c) expanding in response to viral antigen in vivo (either vaccine-mediated or CMV-native); and d) sustaining the antitumor immune response long-term.
 
These studies are significant in that they address poor post-HCT outcomes for patients with B cell NHL. Our approach is highly innovative in combining CAR T cells with CMV vaccine.
 
  • Specific Aim 1: Test bi-specific CMV-CD19CAR T cells manufactured to clinical scale as part of pre-IND studies.
  • Specific Aim 2: Pilot/feasibility studies of bi-specific autologous CMV-CD19CAR T cells +/- CMV vaccine following lymphodepletion or autologous HCT for intermediate grade CD19-positive NHL.
  • Specific Aim 3: Pilot/feasibility studies of donor-derived CMV/CD19 bi-specific T cells +/- CMV vaccine following allogeneic transplantation for intermediate grade CD19-positive NHL.