CEA targeted Immunotherapeutics is a new project for pur Program Project Grant, however its origins are entirely from the work done previously in the grant. This project is subtitled, Evaluation and Modulation of Immunoregulatory Mechanisms to enhance Immunocytokine Therapy for Colon Cancer, represents a significant translational research effort to carry forward the anti-CEA antibodies into a new arena, Immunotherapy. The project is divided into two major sections, preclinical work to optimize the immune environment under which the anti-CEA-IL2 immunocytokine is administered and finally the conduct of a clinical trial utilizing the knowledge gained in the first section. The first Specific Aim investigates the ability of low dose cytotoxic chemotherapy to enhance the efficacy of immunocytokine therapy with special focus on determining surrogate endpoints suitable for clinical applications. Under this aim two conventional cytotoxic agents will be evaluated, as well as a novel nanoparticle based chemotherapeutic. Using three different types of agents should provide important insights into the mechanism of action of the ability of low dose cytotoxic agents to enhance immunotherapy as well as provide the rational for selecting one of these agents for the subsequent clinical trial. The answers discovered here will also be applied to ongoing clinical immunotherapy studies outside this application, thereby maximizing the benefits from the knowledge gained.
Specific Aim 2 investigates the ability of enhancing the efficacy of immunocytokine therapies by specifically targeting regulatory T cells with agents directed at CD25 and STAT-3.
This aim i s driven by the recognition that IL2 has been shown to induce regulatory T cells, which must at some level compromise the activity of the IL2 based immunofusions.
The aim will explore three different types of reagents, anti-CD25 antibodies which have been shown to deplete CD4CD25++ cells in murine models as well as ONTAK, an IL2 based immunotoxin. The investigation of these reagents in this setting should be informative on the modifying the immunoregulatory network for improved ICK activity. As the third part of this specific aim we will investigate the role of STAT-3 in the immunocytokine directed killing, as a way of targeting suppressor T cells with molecular targets. This sub aim will allow us to take full advantage of the pioneering work Dr. Yu has done in this area. The third specific aim will investigate the ability of enhancing the efficacy of immunocytokine therapies by local irradiation, delivered by external beam or radiolabeled antibodies.
This aim grew out of increasing evidence that the irradiation of tumors has a variety of immunologic consequences which can be successfully exploited with immunotherapy.
This aim will allow us to fully explore the immunological consequences of our radioimmunotherapy and compare them to more conventional external beam irradiation. The last specific aim will conduct a clinical trial with anti-CEA-IL2 immunocytokine based of the previously determined optimal modulation of the immunoregulatory network in patients with metastatic colorectal cancer.
This aim i s the culmination of the translational research process, investigating our best approaches to treat a significant disease in humans, metastatic colorectal cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA043904-21
Application #
8555215
Study Section
Special Emphasis Panel (ZCA1-RPRB-J (M1))
Project Start
1998-09-18
Project End
2014-06-30
Budget Start
2012-08-23
Budget End
2013-06-30
Support Year
21
Fiscal Year
2012
Total Cost
$471,632
Indirect Cost
$130,740
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
Sta Maria, Naomi S; Barnes, Samuel R; Weist, Michael R et al. (2015) Low Dose Focused Ultrasound Induces Enhanced Tumor Accumulation of Natural Killer Cells. PLoS One 10:e0142767
Kwok, Cheuk S; Frankel, Paul H; Lopatin, George et al. (2014) Using a single parameter to describe time-activity curves. Cancer Biother Radiopharm 29:83-6
Yazaki, Paul J; Lee, Brian; Channappa, Divya et al. (2013) A series of anti-CEA/anti-DOTA bispecific antibody formats evaluated for pre-targeting: comparison of tumor uptake and blood clearance. Protein Eng Des Sel 26:187-93
Specks, Ulrich; Ikle, David; Stone, John H (2013) Induction regimens for ANCA-Associated Vasculitis. N Engl J Med 369:1865-6
Ng, Thomas S C; Wert, David; Sohi, Hargun et al. (2013) Serial diffusion MRI to monitor and model treatment response of the targeted nanotherapy CRLX101. Clin Cancer Res 19:2518-27
Fonge, Humphrey; Leyton, Jeffrey V (2013) Positron emission tomographic imaging of iodine 124 anti-prostate stem cell antigen-engineered antibody fragments in LAPC-9 tumor-bearing severe combined immunodeficiency mice. Mol Imaging 12:191-202
Povoski, Stephen P; Davis, Paul D; Colcher, David et al. (2013) Single molecular weight discrete PEG compounds: emerging roles in molecular diagnostics, imaging and therapeutics. Expert Rev Mol Diagn 13:315-9
Barat, Bhaswati; Kenanova, Vania E; Olafsen, Tove et al. (2011) Evaluation of two internalizing carcinoembryonic antigen reporter genes for molecular imaging. Mol Imaging Biol 13:526-35
Somlo, George; Spielberger, Ricardo; Frankel, Paul et al. (2011) Total marrow irradiation: a new ablative regimen as part of tandem autologous stem cell transplantation for patients with multiple myeloma. Clin Cancer Res 17:174-82
Gagnon, Pete; Cheung, Chia-Wei; Lepin, Eric J et al. (2010) Minibodies and Multimodal Chromatography Methods: A Convergence of Challenge and Opportunity. Bioprocess Int 8:26-35

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