Hahn Khuu

Phase 2 clinical trial of rapamycin-resistant donor CD4+ Th2/Th1 (T-Rapa) cells after low-intensity allogeneic hematopoietic cell transplantation

In experimental models, ex vivo induced T-cell rapamycin resistance occurred independent of T helper 1 (Th1)/T helper 2 (Th2) differentiation and yielded allogeneic CD4(+) T cells of increased in vivo efficacy that facilitated engraftment and permitted graft-versus-tumor effects while minimizing graft-versus-host disease (GVHD). To translate these findings, we performed a phase 2 multicenter clinical trial of rapamycin-resistant donor CD4(+) Th2/Th1 (T-Rapa) cells after allogeneic-matched sibling donor hematopoietic cell transplantation (HCT) for therapy of refractory hematologic malignancy. T-Rapa cell products, which expressed a balanced Th2/Th1 phenotype, were administered as a preemptive donor lymphocyte infusion at day 14 post-HCT. After T-Rapa cell infusion, mixed donor/host chimerism rapidly converted, and there was preferential immune reconstitution with donor CD4(+) Th2 and Th1 cells relative to regulatory T cells and CD8(+) T cells. The cumulative incidence probability of acute GVHD was 20% and 40% at days 100 and 180 post-HCT, respectively. There was no transplant-related mortality. Eighteen of 40 patients (45%) remain in sustained complete remission (range of follow-up: 42-84 months). These results demonstrate the safety of this low-intensity transplant approach and the feasibility of subsequent randomized studies to compare T-Rapa cell-based therapy with standard transplantation regimens.

Costimulated tumor-infiltrating lymphocytes are a feasible and safe alternative donor cell therapy for relapse after allogeneic stem cell transplantation

Donor lymphocyte infusion (DLI), a standard relapse treatment after allogeneic stem cell transplantation (AlloSCT), has limited efficacy and often triggers GVHD. We hypothesized that after AlloSCT tumor-infiltrating donor lymphocytes could be costimulated ex vivo to preferentially activate/expand antitumor effectors. We tested the feasibility and safety of costimulated, tumor-derived donor lymphocyte (TDL) infusion in a phase 1 trial. Tumor was resected from 8 patients with B-cell malignancy progression post-AlloSCT; tumor cell suspensions were costimulated with anti-CD3/anti-CD28 Ab-coated magnetic beads and cultured to generate TDL products for each patient. Costimulation yielded increased proportions of T-bet(+)FoxP3(-) type 1 effector donor T cells. A median of 2.04 × 10(7) TDL/kg was infused; TDLs were well tolerated, notably without GVHD. Two transient positron emission tomography (PET) responses and 2 mixed responses were observed in these refractory tumors. TDL are a feasible, tolerable, and novel donor cell therapy alternative for relapse after AlloSCT.

Rapid donor T-cell engraftment increases the risk of chronic graft-versus-host disease following salvage allogeneic peripheral blood hematopoietic cell transplantation for bone marrow failure syndromes

The risk of graft‐rejection after allogeneic hematopoietic cell transplantation using conventional cyclophosphamide‐based conditioning is increased in patients with bone marrow failure syndromes (BMFS) who are heavily transfused and often HLA‐alloimmunized. Fifty‐six patients with BMFS underwent fludarabine‐based reduced‐intensity conditioning and allogeneic peripheral blood progenitor cell (PBPC) transplantation at a single institution. The conditioning regimen consisted of intravenous cyclophosphamide, fludarabine, and equine antithymocyte globulin. Graft‐versus‐host disease (GVHD) prophylaxis included cyclosporine A alone or in combination with either mycophenolate mofetil or methotrexate. To reduce the risk of graft‐rejection/failure, unmanipulated G‐CSF mobilized PBPCs obtained from an HLA‐identical or single HLA‐antigen mismatched relative were transplanted rather than donor bone marrow. Despite a high prevalence of pretransplant HLA‐alloimmunization (41%) and a heavy prior transfusion burden, graft‐failure did not occur with all patients having sustained donor lympho‐hematopoietic engraftment. The cumulative incidence of grade II–IV acute‐GVHD and chronic‐GVHD was 51.8% and 72%, respectively; with 87.1% surviving at a median follow‐up of 4.5 years. A multivariate analysis showed pretransplant alloimmunization and rapid donor T‐cell engraftment (≥95% donor by day 30) were both significantly (P < 0.05) associated with the development of chronic‐GVHD (adjusted HR 2.13 and 2.99, respectively). These data show fludarabine‐based PBPC transplantation overcomes the risk of graft‐failure in patients with BMFS, although rapid donor T‐cell engraftment associated with this approach appears to increase the risk of chronic‐GVHD. (Clinicaltrials.gov identifier: NCT00003838). Am. J. Hematol. 88:874–882, 2013.

Cell-Based Therapies: A New Frontier of Personalized Medicine

Abstract Based on the concept of harnessing the inherent strength of the immune system and redirecting it to target cancer cells, cellular therapies have shown tremendous promise in the fight against cancer. Frequently incorporating a “personalized” approach, as the redirected cells are often derived from the cancer patient, the approach to early-phase trials of cellular therapy is intrinsically complex. In contrast to drug development—where there are formulaic trial designs for early-phase studies, utilization of a uniformly developed product, an ability to assess pharmacokinetics and well-established criteria to evaluate toxicity; testing of a cellular therapy requires a highly complex infrastructure to develop and implement, especially if gene modification is involved, where significant regulatory oversight is required. Accordingly, the focus of this chapter will be to provide a global overview of the many steps and challenges involved in the implementation of early-phase studies of cellular therapy.