Targeting Post-Transplant Minimal Residual CD19+ ALL with Genetically-

Beckman Research Institute/City Of Hope, Duarte CA

Investigators

Linked publications & trials

Abstract

The studies proposed in Project II focus on the problem of post-HCT disease relapse of B-lineage acute[unreadable] lymphoblastic leukemia (ALL). We hypothesize that the incidence of treatment failure due to relapse[unreadable] following allogeneic HCT can be reduced by targeting post-transplant minimal residual disease (MRD) with[unreadable] adoptively transferred donor-derived leukemia-specific T-cells. As a strategy to reproducibly generate[unreadable] effector cells for adoptive therapy, we have designed a chimeric antigen receptor (CAR) that re-directs the[unreadable] antigen specificity of T-cells to the B-cell lineage-restricted cell-surface molecule CD19. Genetically-modified[unreadable] CD19-CAR* CTL's lyse B-cell lymphoma and leukemia target cells and are activated for TC1 cytokine[unreadable] production in a CAR-regulated manner. T-cell isolation, genetic modification, ;and expansion Standard[unreadable] Operating Procedures are in place at City of Hope to manufacture clinical cell doses in accordance with[unreadable] quality control/assurance standards mandated by the FDA. The studies proposed in Specific Aim #1 will[unreadable] evaluate the feasibility and safety of adoptive therapy using three escalating doses (10[8]/m -10[10]/m2) of donorderived[unreadable] CD19R+HyTK+ CTL clones versus oligoclonal/ polyclonal T-cell lines, shortly following related-donor[unreadable] allogeneic HCT for high-risk CD19+ ALL. In addition to reducing the incidence of GVHD requiring iatrogenic[unreadable] immunosuppression, we hypothesize that donor HCT T-cell depletion (TCD), in combination with a[unreadable] lymphodepleting preparative regimen consisting of TBI, thiotepa, and fludarabine, will promote homeostatic[unreadable] proliferation of transferred T-cells, as well as, limit anti-transgene rejection responses. The correlative studies[unreadable] in Specific Aim #2 focus on delineating the magnitude and duration of persistence of transferred clones[unreadable] versus lines at the three prescribed T-cell dose levels using vector-specific Q-PCR and TCR spectratyping[unreadable] analyses on serially acquired PBMC specimens. We will also evaluate the utility of administering[unreadable] recombinant human IL-2 for enhancing the expansion of transferred T-cells in vivo. The correlative studies[unreadable] proposed in Specific Aim 3 seek to evaluate the bone marrow trafficking of transferred clones versus lines,[unreadable] and, the functional status of transferred T-cells in this anatomic site of ALL minimal residual disease. In[unreadable] aggregate, the results of the studies proposed in Project II will facilitate the evolution of targeting post-HCT[unreadable] MRD with CD19-specific T-cells for enhanced disease-free survival of patients with B-lineage ALL, and[unreadable] substantiate the rationale to expand this approach to a broader array of CD19+ malignancies treated by HCT.