This project brings together three important, specific immunotherapeutic technologies focused on WT1, an extensively validated, commonly expressed tumor antigen that is processed and presented on the cell surface as peptides within the context of MHC molecules for recognition by T cell receptors (TCR). Our goal is to focus the T cell or other effector cells on this target by use of TCR like mAb, TCR engineered cells and WT1 vaccines, with a goal of extending the persistence and potency of the approaches as well as the reach of the approach to patients with multiple HLA types. We have now produced a high-affinity """"""""TCR-like''mAb """"""""ESK1"""""""" specific to the neo-epitopes of peptide/MHC complexes derived from that marries the advantages of both approaches. We and others have identified peptides derived from the WT1 protein that induce HLA-restricted cytotoxic CDS T cells, capable of killing tumor cells. We hypothesize that mAb-based constructs specific for WT1 in the peptide/HLA complex (mimicking a TCR), and TCR engineered EBV T cells also directed to WT1 epitopes would be novel and effective therapeutic agents to add to the repertoire of traditional WT1 peptide-based vaccines. In addition, using the natural epitopes defined by the O'Reilly lab in the last funding cycle, we will develop new analog epitopes for a broader group of vaccines, and better T cells for human infusion. In this context, the long-term goals of this project are to improve the effectiveness of SCT of hematopoietic neoplasms by safely increasing the immune response specifically directed at residual leukemia and cancer cells using TCR-like mAb, TCR directed cells, and vaccines to antigens initially identified by T-cells. Thus, the specific aims are: 1). To explore the mechanisms of effector functions of our new """"""""TCR-like"""""""" human IgGI mAb reactive with WT1 peptide (RMF)-MHC complexes. 2). To assess the potential of EBV-specific T-cells transduced to express higher affinity T-cell receptors specific for WT1 peptide/HLA complexes to provide long-lived effector cells for eradication of WT1* leukemia cells. 3). To assess the therapeutic activity of the agents against human WTI* leukemia xenografts in NOD/SCID mu c-/- (NSG) mice. 4).To discover from evaluation of natural human immune responses to overlapping native WTI penta-decamers, new mutated analog peptides, including cryptic CDS epitopes within CD4 epitopes, and explore their use in human clinical trials. Success would have immediate impact on a number of important cancers that have unmet needs for effective and safe therapy, beginning with acute leukemias.
Monoclonal antibodies and engineered T cells are an important form of cancer therapy that can selectively kill cancer cells while sparing normal tissues, thereby reducing side effects for patients. We propose to develop forms of the agents that direct the cells of the immune system to kill cancer cells. We will direct them to a target that is usually not accessible to traditional antibody therapy. If successful, these agents could have widespread use for the treatment of leukemias, mesotheliomas, ovarian cancers and several other common malignancies.
|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-Benoît 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