NewsRx.com
March 9, 2006
Data on cancer vaccines are outlined in reports from the United States and Germany.
Study 1: Innate NKT lymphocytes confer superior adaptive immunity via tumor-capturing dendritic cells .
According to recent research from the United States and Argentina, "If irradiated tumor cells could be rendered immunogenic, they would provide a safe, broad, and patient-specific array of antigens for immunotherapies. Prior approaches have emphasized genetic transduction of live tumor cells to express cytokines, costimulators, and surrogate foreign antigens. We asked if immunity could be achieved by delivering irradiated, major histocompatibility complex-negative plasmacytoma cells to maturing mouse dendritic cells (DCs) within lymphoid organs."
"Tumor cells injected intravenously (i.v.) were captured by splenic DCs, whereas subcutaneous (s.c.) injection led only to weak uptake in lymph node or spleen," said Kang Liu at Rockefeller University in the U.S. and collaborators in the U.S. and Argentina. "The natural killer T (NKT) cells mobilizing glycolipid alpha-galactosyl ceramide, used to mature splenic DCs, served as an effective adjuvant to induce protective immunity. This adjuvant function was mimicked by a combination of poly IC and agonistic alpha CD40 antibody. The adjuvant glycolipid had to be co-administered with tumor cells i.v. rather than s.c."
"Specific resistance was generated both to a plasmacytoma and lymphoma," reported the scientists. "The resistance afforded by a single vaccination lasted >2 months and required both CD4+ and CD8+ T cells. Mature tumor capturing DCs stimulated the differentiation of P1A tumor antigen-specific, CD8+ T cells and uniquely transferred tumor resistance to naive mice.
"Therefore, the access of dying tumor cells to DCs that are maturing to activated NKT cells efficiently induces long-lived adaptive resistance," the authors concluded.
Liu and associates published their study in the Journal of Experimental Medicine (Innate NKT lymphocytes confer superior adaptive immunity via tumor-capturing dendritic cells. J Exp Med, 2005;202(11):1507-1516).
For additional information, contact Ralph M. Steinman, Laboratory of Cellular Physiology and Immunology, Rockefeller University, 1230 York Avenue, New York City, NY 10021, USA. steinma@mail.rockefeller.edu.
Study 2: Ex vivo expanded human CD4+ regulatory NKT cells suppress expansion of tumor antigen-specific CTLs.
"NKT cells can produce large amounts of both Th1-and Th2-type cytokines and are an important regulatory cell type. To elucidate their role in acquired immunity, we examined the effect of human V alpha 24+V beta 11+ NKT cells or CD1d-specific ligand alpha-galactosylceramide (alpha GalCer) on the in vitro generation of antigen-specific CTLs from PBMCs using autologous MART-1(26-35) peptide-pulsed dendritic cells as stimulators. Flow cytometry using tetramer for MART-1(26-35) peptide revealed that NKT cells have inhibitory effects on CTL generation," scientists in the United States report.
"Cytokine analysis using cytometric bead array assay and ELISA showed higher IL-4 and IL-10 secretion in the alpha GalCer+ and/or NKT cell+ culture setting, whereas IL-13 secretion in the culture was not affected by the presence of alpha GalCer," said Takuya Osada and colleagues at Duke University. "The CD4+ NKT cell subset seemed to play a major role in this inhibitory effect by secreting large amounts of Th2-type cytokines. Interestingly however, unlike recent reports utilizing mouse models, IL-13 was not a main effector molecule in our human system."
"Culture with alpha-GalCer in the presence of cytokine-neutralizing antibodies for the Th2 cytokines, IL-4, IL-5, and IL-10, resulted in enhanced CTL generation, suggesting the dominant role of Th2 cytokines over Th1 cytokines," reported the researchers. "Thus, CD4+ NKT cells can work as immunoregulatory T cells that suppress anti-tumor immune response and, therefore, NKT cells or alpha-GalCer could be used as therapeutic modalities to modulate systemic immune responses, such as autoimmune diseases."
"Conversely, the use of NKT cells along with anti-Th2 cytokine-neutralizing antibodies or CD4-negative NKT cell subset could enhance the generation of antigen-specific CTLs for adoptive immunotherapy," stated Osada and associates.
Osada and coauthors published their study in International Immunology (Ex vivo expanded human CD4+ regulatory NKT cells suppress expansion of tumor antigen-specific CTLs. Int Immunol, 2005;17(9):1143-1155).
For more information, contact Timothy M. Clay, Program in Molecular Therapeutics, Duke University Medical Center, 401 MSRB, Research Drive, Durham, NC 27710, USA. tim.clay@duke.edu.
Study 3: Chemosensitization of pancreatic carcinoma cells enhanced T cell-mediated cytotoxicity induced by tumor lysate-pulsed dendritic cells.
"Dendritic cells (DCs) can induce cytotoxic T-cell (CTL) responses against tumor antigens in vitro and in vivo, yet few cancer patients experience tumor regression after DC-based vaccination. Combination with other treatment modalities, such as radiation or pharmacologic anticancer agents, may reduce tumor cell resistance against immune responses," researchers in Germany report.
"The authors tested whether treatment with gemcitabine or cyclooxygenase-2 (COX-2) inhibitors increases the sensitivity of pancreatic carcinoma cells to CTL-mediated killing," said Marc Dauer and colleagues at the University of Munich. "Monocyte-derived DCs of HLA-A2+ donors were loaded with lysate from the HLA-A2+ pancreatic carcinoma cell line Panc-1 and co-cultured with autologous CD3+ T cells. ELISPOT and cytotoxicity assays performed after two rounds of in vitro stimulation confirmed induction of a tumor-specific CTL response."
"Changes in the magnitude and the effector mechanism of the CTL response were analyzed after treatment of Panc-1 cells with gemcitabine and COX-2 inhibitors," stated Dauer and his collaborators. "Compared with gemcitabine, COX-2 inhibitors more effectively sensitized Panc-1 cells to CTL-mediated killing and showed less inhibition of T-cell activation by DCs in vitro. Using anti-CD95 blocking antibody, the authors showed that the increase in CTL-mediated tumor cell killing observed after treatment with COX-2 inhibitors is dependent on CD95/CD95 ligand interaction."
"Increased apoptosis of Panc-1 cells treated with COX-2 inhibitor was also observed after incubation with agonistic anti-CD95 antibody," reported the scientists. "Sensitization of cancer cells to CD95-dependent killing by CTLs represents a novel mechanism of action for COX-2 inhibitors and provides a rationale for their concomitant use with immunotherapeutic strategies such as DC-based vaccination."
Dauer and his coauthors published their study in the Journal of Immunotherapy (Chemosensitization of pancreatic carcinoma cells to enhance T cell-mediated cytotoxicity induced by tumor lysate-pulsed dendritic cells. J Immunother, 2005;28(4):332-342).
For additional information, contact Andreas Eigler, Section of Gastroenterology, Medizinische Klinik Innenstadt, University of Munich, Ziemssenstrasse 1, D-80336 Munich, Germany. Andreas.Eigler@med.uni-muenchen.de.
This article was prepared by Biotech Week editors from staff and other reports. Copyright 2006, Biotech Week via NewsRx.com.
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