The central hypothesis of this proposal is that human CLL associated or specific antigens exist. However, due to defects in T cell recognition and effector function in the tumor bearing host and/or inefficient or ineffective antigen presentation by the tumor cells, no clinically significant anti-tumor T cell response to CLL is generated. The objective of this proposal is to attempt to develop more effective, novel adoptive T cell immunotherapy to eradicate minimal residual leukemia cells in patients with CLL. We propose undertake basic laboratory experiments, pre-clinical studies and scale up, and clinical trials necessary to achieve this objective. For this, we have the following specific aims: (1) determine the mechanism whereby T cells in patients with CLL are induced to become immune- incompetent; (2) examine the signaling events that follow CD40-ligation necessary and sufficient to induce competent antigen presentation by CLL cells; (3) develop and optimize methodologies to generate and expand autologous T cells and to undertake clinical trials of adoptive immunotherapy; (4) develop and optimize methodologies to generate and expand allogeneic T cells for adoptive immunotherapy following allogeneic stem cell transplantation (SCT); (5) determine the impact of autologous or allogeneic adoptive T cell immunotherapy in patients with minimal disease assessing PCR as a surrogate endpoint, relapse, and survival. The findings on signaling in CLL cells will likely have relevance to studies proposed in Project 1 and Project 2. This project is highly interactive and dependent upon investigators and studies proposed in Project 3.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory Grants (P20)
Project #
1P20CA081534-01
Application #
6259048
Study Section
Subcommittee G - Education (NCI)
Project Start
1999-05-01
Project End
2000-04-30
Budget Start
Budget End
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Veronese, A; Pepe, F; Chiacchia, J et al. (2015) Allele-specific loss and transcription of the miR-15a/16-1 cluster in chronic lymphocytic leukemia. Leukemia 29:86-95
Maji, Santanu; Samal, Sabindra K; Pattanaik, Laxmipriya et al. (2015) Mcl-1 is an important therapeutic target for oral squamous cell carcinomas. Oncotarget 6:16623-37
Wu, Bainan; Barile, Elisa; De, Surya K et al. (2015) High-Throughput Screening by Nuclear Magnetic Resonance (HTS by NMR) for the Identification of PPIs Antagonists. Curr Top Med Chem 15:2032-42
Wu, Bainan; Wang, Si; De, Surya K et al. (2015) Design and Characterization of Novel EphA2 Agonists for Targeted Delivery of Chemotherapy to Cancer Cells. Chem Biol 22:876-887
Lamothe, Betty; Cervantes-Gomez, Fabiola; Sivina, Mariela et al. (2015) Proteasome inhibitor carfilzomib complements ibrutinib's action in chronic lymphocytic leukemia. Blood 125:407-10
Laganà, Alessandro; Acunzo, Mario; Romano, Giulia et al. (2014) miR-Synth: a computational resource for the design of multi-site multi-target synthetic miRNAs. Nucleic Acids Res 42:5416-25
McClanahan, Fabienne; Gribben, John (2014) Transplantation in chronic lymphocytic leukemia: does it still matter in the era of novel targeted therapies? Hematol Oncol Clin North Am 28:1055-71
Barile, Elisa; De, Surya K; Feng, Yongmei et al. (2013) Synthesis and SAR studies of dual AKT/NF-?B inhibitors against melanoma. Chem Biol Drug Des 82:520-533
Vamos, Mitchell; Welsh, Kate; Finlay, Darren et al. (2013) Expedient synthesis of highly potent antagonists of inhibitor of apoptosis proteins (IAPs) with unique selectivity for ML-IAP. ACS Chem Biol 8:725-32
Hudson, Robert S; Yi, Ming; Volfovsky, Natalia et al. (2013) Transcription signatures encoded by ultraconserved genomic regions in human prostate cancer. Mol Cancer 12:13

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