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 patients and in patients lacking an HLA-matched sibling donor. The project includes 8 clinical trials organized under 3 specific 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 stimulating thymopoiesis 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 after treatment with myeloablative conditioning regimens developed in this grant period.
Specific Aim 2, proposes two trials of double unit cord blood transplants,the first (Aim 2A) a trial of double UCBT myeloablative conditioning to patients 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 Rituximab in patients with lymphomas responsive to a GVL effect. These trials each include correlative analyses designed to identify cord blood graft and host features that determine the selective engraftment of 1 UCBT in a given allogenic host. As developed in this center, TCD marrow or PBSC transplants have achieved consistent engraftment with a low incidence of GVHD without use of post-transplant drug prophylaxis. Effective prevention of GVHD thus allows us to critically examine adoptive cell therapies and immunostimulatory cytokine in the absence of concurrently administered immuno-suppressive drugs or biologicals.
Specific Aim 3 addresses this objective in 3 trials.
Aim 3 A is a phase I trial of T cells sensitized by a new technique employing overlapping 15-mer peptides spanning CMV-pp65 for treatment of patients with persistent CMV viremia or infection.
In Aim 3 B, we propose a phase I trial of T cells sensitized with overlapping 15-mer peptides spanning the sequence of the WT1 protein for treatment of patients with minimal residual disease or recurrence of WT-1 + acute leukemias, MDS and blastic CML post transplant.
Aim 3 C proposes a pilot phase II trial of adoptive therapy with in vitro isolated, HLA haploidentical NK cells following stem cell-sparing chemotherapy for patients relapsing in the first year post transplant with AMI, ALL and blastic CML. Relevance to Public Health: These trials test novel transplant strategies which show promise of improving prospects for sustained DPS in adults with acute leukemia, MDS and lymphoma, particularly older patients and patients lacking a matched sibling donor. They will also test adoptive therapies which may be broadly applied to patients with severe viral infection or leukemia relapse.

Public Health Relevance

These trials test novel transplant strategies which show promise of improving prospects for sustained DPS in adults with acute leukemia, MDS and lymphoma, particularly older patients and patients lacking a matched sibling donor. They will also test adoptive therapies which may be broadly applied to patients with severe viral infection or leukemia relapse.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA023766-32
Application #
8094429
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
32
Fiscal Year
2010
Total Cost
$440,614
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Boudreau, Jeanette E; Hsu, Katharine C (2018) Natural Killer Cell Education and the Response to Infection and Cancer Therapy: Stay Tuned. Trends Immunol 39:222-239
Lin, Richard J; Ho, Caleb; Hilden, Patrick D et al. (2018) Allogeneic haematopoietic cell transplantation impacts on outcomes of mantle cell lymphoma with TP53 alterations. Br J Haematol :
Malard, Florent; Labopin, Myriam; Cho, Christina et al. (2018) Ex vivo and in vivo T cell-depleted allogeneic stem cell transplantation in patients with acute myeloid leukemia in first complete remission resulted in similar overall survival: on behalf of the ALWP of the EBMT and the MSKCC. J Hematol Oncol 11:127
Luduec, Jean-BenoƮt Le; Kudva, Anupa; Boudreau, Jeanette E et al. (2018) Novel multiplex PCR-SSP method for centromeric KIR allele discrimination. Sci Rep 8:14853
Shah, Gunjan L; Moskowitz, Craig H (2018) Transplant strategies in relapsed/refractory Hodgkin lymphoma. Blood 131:1689-1697
Avanzi, Mauro P; Yeku, Oladapo; Li, Xinghuo et al. (2018) Engineered Tumor-Targeted T Cells Mediate Enhanced Anti-Tumor Efficacy Both Directly and through Activation of the Endogenous Immune System. Cell Rep 23:2130-2141
Staffas, Anna; Burgos da Silva, Marina; Slingerland, Ann E et al. (2018) Nutritional Support from the Intestinal Microbiota Improves Hematopoietic Reconstitution after Bone Marrow Transplantation in Mice. Cell Host Microbe 23:447-457.e4
Velardi, Enrico; Tsai, Jennifer J; Radtke, Stefan et al. (2018) Suppression of luteinizing hormone enhances HSC recovery after hematopoietic injury. Nat Med 24:239-246
Moskowitz, Craig H (2018) Should all patients with HL who relapse after ASCT be considered for allogeneic SCT? A consult, yes; a transplant, not necessarily. Blood Adv 2:821-824
Kim, Seong Jin; Huang, Yao-Ting; Foldi, Julia et al. (2018) Cytomegalovirus resistance in CD34+ -selected hematopoietic cell transplant recipients. Transpl Infect Dis 20:e12881

Showing the most recent 10 out of 452 publications