Project 6 proposes clinical trials testing new therapeutic strategies designed to reduce the morbidity, non-leukemic mortality and incidence of relapse associated with allogenic hematopoietic cell transplants (HSCT)applied to the treatment of acute leukemias and myelpdysplastic syndromes (MDS), particularly in older patientsand in patients lacking an HLA-matched sibling donor. The project includes 8 clinical trials organized under 3specific aims.
Specific aim 1 includes 2 phase II clinical trials testing the potential of keratinocyte growth factor(KGF) to reduce transplant-related mortality and enhance DPS by reducing early toxicity and stimulatingthymopoiesis and T cell reconstitution in adults (median age >50)with hematologic malignancies receiving HLA-matched or 1-2 allele disparate CD34+ E- T cell depleted PBSC grafts from related or unrelated donors aftertreatment with myeloablative conditioning regimens developed in this grant period.
Specific Aim 2, proposes twotrials of double unit cord blood transplants,the first (Aim 2A) a trial of double UCBT myeloablative conditioning topatients with acute leukemias, MDS and advanced NHL who lack an 8-10 allele related or unrelated donor;
the second (Aim 2 B) a trail of double UCBT administered after a novel nonmyeloablative regimen including Rituximabin patients with lymphomas responsive to a GVL effect. These trials each include correlative analyses designedto identify cord blood graft and host features that determine the selective engraftment of 1 UCBT in a givenallogenic host. As developed in this center, TCD marrow or PBSC transplants have achieved consistent engraftment with a lowincidence of GVHD without use of post-transplant drug prophylaxis. Effective prevention of GVHD thus allows usto critically examine adoptive cell therapies and immunostimulatory cytokine in the absence of concurrentlyadministered immuno-suppressive drugs or biologicals.
Specific Aim 3 addresses this objective in 3 trials.
Aim3 A is a phase I trial of T cells sensitized by a new technique employing overlapping 15-mer peptides spanningCMV-pp65 for treatment of patients with persistent CMV viremia or infection.
In Aim 3 B, we propose a phase Itrial of T cells sensitized with overlapping 15-mer peptides spanning the sequence of the WT1 protein fortreatment of patients with minimal residual disease or recurrence of WT-1 + acute leukemias, MDS and blasticCML post transplant.
Aim 3 C proposes a pilot phase II trial of adoptive therapy with in vitro isolated, HLAhaploidentical NK cells following stem cell-sparing chemotherapy for patients relapsing in the first year posttransplant with AMI, ALL and blastic CML. Relevance to Public Health: These trials test novel transplantstrategies which show promise of improving prospects for sustained DPS in adults with acute leukemia, MDS andlymphoma, particularly older patients and patients lacking a matched sibling donor. They will also test adoptivetherapies which may be broadly applied to patients with severe viral infection or leukemia relapse.
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