Vaccination to improve the persistence of CD19CAR gene-modified T cells in relapsed pediatric acute lymphoblastic leukemia

Abstract

Trials with second generation CD19 chimeric antigen receptors (CAR) T-cells report unprecedented responses but are associated with risk of cytokine release syndrome (CRS). Instead, we studied the use of donor Epstein-Barr virus-specific T-cells (EBV CTL) transduced with a first generation CD19CAR, relying on the endogenous T-cell receptor for proliferation. We conducted a multi-center phase I/II study of donor CD19CAR transduced EBV CTL in pediatric acute lymphoblastic leukaemia (ALL). Patients were eligible pre-emptively if they developed molecular relapse (>5 × 10) post first stem cell transplant (SCT), or prophylactically post second SCT. An initial cohort showed poor expansion/persistence. We therefore investigated EBV-directed vaccination to enhance expansion/persistence. Eleven patients were treated. No CRS, neurotoxicity or graft versus host disease (GVHD) was observed. At 1 month, 5 patients were in CR (4 continuing, 1 de novo), 1 PR, 3 had stable disease and 3 no response. At a median follow-up of 12 months, 10 of 11 have relapsed, 2 are alive with disease and 1 alive in CR 3 years. Although CD19CAR CTL expansion was poor, persistence was enhanced by vaccination. Median persistence was 0 (range: 0-28) days without vaccination compared to 56 (range: 0-221) days with vaccination (P=0.06). This study demonstrates the feasibility of multi-center studies of CAR T cell therapy and the potential for enhancing persistence with vaccination.

CD19 CAR T cells following autologous transplantation in poor-risk relapsed and refractory B-cell non-Hodgkin lymphoma

“…Potential vaccinial strategies might serve to effectively circumnavigate the low endogenous CD19 antigen burden state of a consolidative platform and thus warrants investigation. 36 Also, phosphoproteomic analyzed differences between CD28 versus 4-1BB costimulatory CD8+ human CAR T cells has demonstrated faster changes in protein phosphorylation correlating with effector-like phenotype in CD28 constructs versus more memory-associated expression of genes in the 4-1BB product, which may contribute to greater persistence of 4-1BB CAR T. 37 Additional strategies to enhance persistence include the use of "armored" CARs expressing additional signaling molecules and/or genes promoting autonomous secretion of lymphoproliferative cytokines with the intention of enhancing persistence and effector function. 38,39 Lastly, CD19 antigen escape has been described with CD19 CAR therapy 40 and two of the subjects who progressed on our study were found to be CD19 (-) on the surface membrane at re-biopsy.…”

Antitumor Activity Associated with Prolonged Persistence of Adoptively Transferred NY-ESO-1 c259T Cells in Synovial Sarcoma

“…This observation suggests that long-term persistence is independent of host factors that might drive survival through the endogenous TCR receptor, such as latent viruses like Epstein-Barr virus or cytomegalovirus. Such approaches have been exploited to assist in long-term engraftment of CAR T cells but are not likely to be at play here, because such a mechanism would be expected to increase the clonality of the persisting population, which was not observed (43,44). The results also demonstrate that persistent T cells were not derived from one cell subset, but rather their clonotypes were present across all T-cell subsets examined, including naïve, TEM, TSCM, TCM, and TEMRA.…”

CAR T cell immunotherapy in hematology and beyond

“…The academic centers in North America who have performed the first successful clinical CAR T cell trials have now liaised with commercial partners to drive broader implementation of the CAR T cell products. In Europe, the first phase I/II CAR T cell trial has confirmed the feasibility of academic manufacturing of CD19-specific CAR T cells for an international multicenter study, but also illustrated the complexity of the logistics involved in clinical translation of this type of therapy [24]. Novel technologies are now being developed that allow to perform the entire process of CAR T cell manufacturing in a semi-automated way in a closed system, reducing technical demands [51].…”

“…T cells expressing first generation CARs therefore required additional signals, e.g. by the native TCR, to induce complete activation responses [23][24][25]. Without a second signal, they failed to persist in the circulation beyond few weeks after infusion.…”