This P01 application will focus on a variety of targeted immunotherapy approaches for the treatment of B-cell malignancies, such as non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM), and chronic lymphocytic lymphoma (CLL). It is comprised of 3 preclinical projects and one clinical project, which are supported by 6 cores. This program project represents a collaboration of three institutions along with additional collaborations and advice of leading experts in each of the research areas. A number of antigen targets will be examined: CD20, CD22, CD74, and HLA-DR because these appear to be the most promising from our own published studies and those of others, and because we now have access to humanized (CDR-grafted) forms of these antibodies. The overall goal is to develop immunotherapy strategies for the more effective, targeted therapy of these neoplasms with one or more of these MAbs, in one or more forms (unlabeled, radiolabeled, and/or drug conjugated), and to be used alone or in combination with other modalities. Of particular interest is the rapid translation of basic and preclinical studies to the clinic. In this regard, 2 clinical protocols, one using a combination of 90Y-humanized anti-CD22 IgG with Rituxan and another utilizing a recombinant bispecific antibody pretargeting approach are planned. However, the immediate goals of this project are to better understand how these various reagents can function alone or in certain combinations for the more effective therapy of B-cell malignancies and to gain a better understanding of the mechanisms involved in their actions, in tumor resistance, and in predicting which tumor types will respond best. Collectively, the integration of all of these different, but related endeavors promises to provide new knowledge and strategies for the improved management of B-cell malignancies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA103985-04
Application #
7478745
Study Section
Subcommittee G - Education (NCI)
Program Officer
Welch, Anthony R
Project Start
2005-08-30
Project End
2010-07-31
Budget Start
2008-08-01
Budget End
2010-07-31
Support Year
4
Fiscal Year
2008
Total Cost
$1,618,062
Indirect Cost
Name
Center for Molecular Medicine/Immunology
Department
Type
DUNS #
118870583
City
Morris Plains
State
NJ
Country
United States
Zip Code
07950
Smith, Mitchell R; Jin, Fang; Joshi, Indira (2014) Milatuzumab and veltuzumab induce apoptosis through JNK signalling in an NF-?B dependent human transformed follicular lymphoma cell line. Br J Haematol 165:151-3
Binsky-Ehrenreich, I; Marom, A; Sobotta, M C et al. (2014) CD84 is a survival receptor for CLL cells. Oncogene 33:1006-16
Chen, X; Chang, C-H; Stein, R et al. (2012) The humanized anti-HLA-DR moAb, IMMU-114, depletes APCs and reduces alloreactive T cells: implications for preventing GVHD. Bone Marrow Transplant 47:967-80
Rossi, Edmund A; Rossi, Diane L; Cardillo, Thomas M et al. (2011) Preclinical studies on targeted delivery of multiple IFN?2b to HLA-DR in diverse hematologic cancers. Blood 118:1877-84
Alinari, Lapo; Yu, Bo; Christian, Beth A et al. (2011) Combination anti-CD74 (milatuzumab) and anti-CD20 (rituximab) monoclonal antibody therapy has in vitro and in vivo activity in mantle cell lymphoma. Blood 117:4530-41
Brem, Elizabeth A; Thudium, Karen; Khubchandani, Sapna et al. (2011) Distinct cellular and therapeutic effects of obatoclax in rituximab-sensitive and -resistant lymphomas. Br J Haematol 153:599-611
Sharkey, Robert M; Goldenberg, David M (2011) Cancer radioimmunotherapy. Immunotherapy 3:349-70
Stein, Rhona; Balkman, Cheryl; Chen, Susan et al. (2011) Evaluation of anti-human leukocyte antigen-DR monoclonal antibody therapy in spontaneous canine lymphoma. Leuk Lymphoma 52:273-84
Olejniczak, Scott H; Blickwedehl, Jennifer; Belicha-Villanueva, Alan et al. (2010) Distinct molecular mechanisms responsible for bortezomib-induced death of therapy-resistant versus -sensitive B-NHL cells. Blood 116:5605-14
Gupta, Pankaj; Goldenberg, David M; Rossi, Edmund A et al. (2010) Multiple signaling pathways induced by hexavalent, monospecific, anti-CD20 and hexavalent, bispecific, anti-CD20/CD22 humanized antibodies correlate with enhanced toxicity to B-cell lymphomas and leukemias. Blood 116:3258-67

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