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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Dao, Tao; Korontsvit, Tatyana; Zakhaleva, Victoria et al. (2017) An immunogenic WT1-derived peptide that induces T cell response in the context of HLA-A*02:01 and HLA-A*24:02 molecules. Oncoimmunology 6:e1252895
Peled, Jonathan U; Devlin, Sean M; Staffas, Anna et al. (2017) Intestinal Microbiota and Relapse After Hematopoietic-Cell Transplantation. J Clin Oncol 35:1650-1659
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Ghosh, Arnab; Smith, Melody; James, Scott E et al. (2017) Donor CD19 CAR T cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity. Nat Med 23:242-249
Fischer, Julius C; Bscheider, Michael; Eisenkolb, Gabriel et al. (2017) RIG-I/MAVS and STING signaling promote gut integrity during irradiation- and immune-mediated tissue injury. Sci Transl Med 9:
Goldberg, Jenna D; Zheng, Junting; Ratan, Ravin et al. (2017) Early recovery of T-cell function predicts improved survival after T-cell depleted allogeneic transplant. Leuk Lymphoma 58:1859-1871
Ito, Reiko; Hale, Laura P; Geyer, Susan M et al. (2017) Late Effects of Exposure to Ionizing Radiation and Age on Human Thymus Morphology and Function. Radiat Res 187:589-598

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