       Document 0680
 DOCN  M9640680
 TI    Therapy of murine tumors with tumor peptide-pulsed dendritic cells:
       dependence on T cells, B7 costimulation, and T helper cell 1-associated
       cytokines [see comments]
 DT    9604
 AU    Zitvogel L; Mayordomo JI; Tjandrawan T; DeLeo AB; Clarke MR; Lotze MT;
       Storkus WJ; Department of Surgery, University of Pittsburgh,
       Pennsylvania; 15261, USA.
 SO    J Exp Med. 1996 Jan 1;183(1):87-97. Unique Identifier : AIDSLINE
       MED/96136751
 CM    Comment in: J Exp Med 1996 Jan 1;183(1):7-11
 AB    Antigen presentation by host dendritic cells (DC) is critical for the
       initiation of adaptive immune responses. We have previously demonstrated
       in immunogenic murine tumor models that bone marrow (BM)-derived DC
       pulsed ex vivo with synthetic tumor-associated peptides, naturally
       expressed by tumor cells, serve as effective antitumor vaccines,
       protecting animals against an otherwise lethal tumor challenge
       (Mayordomo, J.I., T. Zorina, W.J. Storkus, C. Celluzzi, L.D. Falo, C.J.
       Melief, T. Ildstad, W.M. Kast, A.B. DeLeo, and M.T. Lotze. 1995. Nature
       Med. 1:1297-1302). However, T cell-defined epitopes have not been
       identified for most human cancers. To explore the utility of this
       approach in the treatment of tumors expressing as yet uncharacterized
       epitopes, syngeneic granulocyte/macrophage colony-stimulating
       factor-stimulated and BM-derived DC, pulsed with unfractionated
       acid-eluted tumor peptides (Storkus, W.J., H.J. Zeh III, R.D. Salter,
       and M.T. Lotze. 1993. J. Immunother. 14:94-103) were used to treat mice
       bearing spontaneous, established tumors. The adoptive transfer of 5 x
       10(5) tumor peptide-pulsed DC dramatically suppressed the growth of
       weakly immunogenic tumors in day 4 to day 8 established MCA205 (H-2b)
       and TS/A (H-2d) tumor models, when applied in three biweekly intravenous
       injections. Using the immunogenic C3 (H-2b) tumor model in B6 mice,
       tumor peptide-pulsed DC therapy resulted in the erradication of
       established d14 tumors and long-term survival in 100% of treated
       animals. The DC-driven antitumor immune response was primarily cell
       mediated since the transfer of spleen cells, but not sera, from
       immunized mice efficiently protected sublethally irradiated naive mice
       against a subsequent tumor challenge. Furthermore, depletion of either
       CD4+ or CD8+ T cells from tumor-bearing mice before therapy totally
       suppressed the therapeutic efficacy of DC pulsed with tumor-derived
       peptides. Costimulation of the host cell-mediated antitumor immunity was
       critical since inoculation of the chimeric fusion protein CTLA4-Ig
       virtually abrogated the therapeutic effects of peptide-pulsed DC in
       vivo. The analysis of the cytokine pattern in the draining lymph nodes
       and spleens of tumor-bearing mice immunized with DC pulsed with
       tumor-eluted peptides revealed a marked upregulation of interleukin (IL)
       4 and interferon (IFN) gamma production, as compared with mice immunized
       with DC alone or DC pulsed with irrelevant peptides. DC-induced
       antitumor effects were completely blocked by coadministration of
       neutralizing monoclonal antibody directed against T helper cell
       1-associated cytokines (such as IL-12, tumor necrosis factor alpha,
       IFN-gamma), and eventually, but not initially, blocked by anti-mIL-4
       mAb. Based on these results, we believe that DC pulsed with acid-eluted
       peptides derived from autologous tumors represents a novel approach to
       the treatment of established, weakly immunogenic tumors, and serves as a
       basis for designing clinical trials in cancer patients.
 DE    Animal  Antigen Presentation  Antigens, CD/IMMUNOLOGY
       Cytokines/IMMUNOLOGY  Dendritic Cells/*IMMUNOLOGY  Histocompatibility
       Antigens Class I/IMMUNOLOGY  *Immunotherapy, Adoptive  Lymph
       Nodes/IMMUNOLOGY  Membrane Glycoproteins/IMMUNOLOGY  Mice  Mice, Inbred
       BALB C  Mice, Inbred C57BL  Neoplasm Proteins/*IMMUNOLOGY/METABOLISM
       Neoplasms, Experimental/*THERAPY  Peptides/*IMMUNOLOGY/METABOLISM
       Spleen/IMMUNOLOGY  Support, Non-U.S. Gov't  Support, U.S. Gov't, P.H.S.
       T-Lymphocytes, Cytotoxic/IMMUNOLOGY  T-Lymphocytes,
       Helper-Inducer/IMMUNOLOGY  Th1 Cells/IMMUNOLOGY  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

