Surgery, chemotherapy and radiation therapy remain the standard weapons for the treatment of cancer. However, common human cancers are often not successfully treated with these modalities. Basic understanding of the immune system has provided new approaches and tools for cancer therapy. The goal of this program project is to develop effective treatments for cancer based on the exquisite specificity of the immune response. We have selected a restricted differentiation antigens expressed on cancer cells to target therapy. These differentiation antigens represent the closest approximation to realistic and specific targets on cancer cells. The theme of this program is based on several questions. 1) Can monoclonal antibodies (mAb) against restricted differentiation antigens localize and deliver therapeutic doses of nuclides to tumors? 2) Can mAbs with defined biological effector functions induce immune or inflammatory responses at tumor sites and lead to tumor responses? 3) Can immune responses be elicited against differentiation antigens, and can these responses alter the progression of cancer? During the past grant period, substantial progress was made in beginning to address these questions. First we have shown that certain mAbs localize to tumors, with high tumor:normal tissue ratios in patients with leukemia, colon, lung and renal cancer. Furthermore, some antibody-nuclide conjugates are efficiently internalized into target tumor cells (colon cancer and leukemia), opening the possibility of delivery of potent short range nuclides. Objective tumor regressions have been observed in patients with leukemia, lymphoma and neuroblastoma after treatment with mAb conjugated to nuclide. Second, treatment with mAb with defined effector functions has antitumor activity in metastatic melanoma, with a suggestion that cytokines, such as interleukin-2 or tumor necrosis factor-alpha, can increase potency of antitumor effects. Third, vaccination with a ganglioside antigen was shown to induce specific antibody responses in >80% of immunized patients, and a crucial role for immune adjuvants and carrier molecules was determined. Immune responses to the ganglioside in patients with stage III metastatic melanoma was shown to correlate significantly with survival. We plan to conduct therapeutic studies in patients with breast, colon, renal, and lung cancer, melanoma, and leukemia using mAb or vaccines. A new generation of genetically engineered mAb will be studied in clinical trials, including humanized, multimeric and single chain antibody constructs. Nuclides, including auger and alpha particle emitters will be conjugated to mAb for therapy. Novel antigens expressed in tumors will be targeted, including stromal and intracellular antigens. Finally, vaccines produced from purified antigens, peptides, or recombinant molecules, or as anti-idiotype mAb will be tested for immunogenicity against defined tumor antigens. The unifying theme of this project is to develop effective therapies for cancers based on targeting to restricted differentiation antigens on human cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA033049-14
Application #
2007379
Study Section
Special Emphasis Panel (SRC (DD))
Project Start
1982-07-01
Project End
1999-12-31
Budget Start
1997-01-01
Budget End
1997-12-31
Support Year
14
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
McDevitt, Michael R; Thorek, Daniel L J; Hashimoto, Takeshi et al. (2018) Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer. Nat Commun 9:1629
Casey, E; Bournazos, S; Mo, G et al. (2018) A new mouse expressing human Fc? receptors to better predict therapeutic efficacy of human anti-cancer antibodies. Leukemia 32:547-549
Budhu, Sadna; Schaer, David A; Li, Yongbiao et al. (2017) Blockade of surface-bound TGF-? on regulatory T cells abrogates suppression of effector T cell function in the tumor microenvironment. Sci Signal 10:
Alidori, Simone; Thorek, Daniel L J; Beattie, Bradley J et al. (2017) Carbon nanotubes exhibit fibrillar pharmacology in primates. PLoS One 12:e0183902
Scheinberg, David A; Grimm, Jan; Heller, Daniel A et al. (2017) Advances in the clinical translation of nanotechnology. Curr Opin Biotechnol 46:66-73
Weber, Daniela; Jenq, Robert R; Peled, Jonathan U et al. (2017) Microbiota Disruption Induced by Early Use of Broad-Spectrum Antibiotics Is an Independent Risk Factor of Outcome after Allogeneic Stem Cell Transplantation. Biol Blood Marrow Transplant 23:845-852
Mathias, M D; Sockolosky, J T; Chang, A Y et al. (2017) CD47 blockade enhances therapeutic activity of TCR mimic antibodies to ultra-low density cancer epitopes. Leukemia 31:2254-2257
Chang, Aaron Y; Gejman, Ron S; Brea, Elliott J et al. (2016) Opportunities and challenges for TCR mimic antibodies in cancer therapy. Expert Opin Biol Ther 16:979-87
Alidori, Simone; Akhavein, Nima; Thorek, Daniel L J et al. (2016) Targeted fibrillar nanocarbon RNAi treatment of acute kidney injury. Sci Transl Med 8:331ra39
Alidori, Simone; Bowman, Robert L; Yarilin, Dmitry et al. (2016) Deconvoluting hepatic processing of carbon nanotubes. Nat Commun 7:12343

Showing the most recent 10 out of 289 publications