DENDRITIC CELL BASED CANCER VACCINES

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Aberrant glycosylation of the mucin molecule (MUC-1) expressed on epithelial tumors leads to the exposure of novel tumor-associated core protein epitopes which are recognized by tumor specific antibodies and cytotoxic T cells (CTL). Consequently, MUC-1 mucin could be considered a possible target for tumor immunotherapy. A candidate anti-mucin cellular vaccine employing autologous dendritic cells instead of tumor cells for the presentation of tumor associated mucin epitopes was tested in chimpanzees because they express the same molecule with the same sequence and tissue distribution. In preparation for the in vivo studies we obtained blood samples from various animals at the time they were undergoing routine physical examinations. We developed a culture system to grow chimpanzee dendritic cells in vitro (ref. 1). This system was then tested in vivo. First we examined the migration potential of in vitro grown DC and found that they migrate appropriately to the n earest dr aining lymph node where they contact T cells and maintain their immunostimulatory phenotype (ref.2). Dendritic cells were then grown for six days in vitro and then loaded with a mucin synthetic peptide or a control antigen ovalbumin. Autologous antigen loaded dendritic cells were then injected IV, and animals boosted once with antigen in conventional adjuvant TiterMax. Three weeks later blood and lymph nodes were collected and examined for the development of mucin-specific or ovalbumin-specific immune response. We found that dendritic cells were effective at inducing OVA-specific immunity, but not much better that the conventional adjuvant (ref. 3). We saw no immunity generated to the mucin peptide with either regimen, confirming our observations in vitro that this peptide sequence does not contain helper epitopes. We have done another study using the same Muc1 immunogen, but another adjuvant, LeIF, known to promote cellular immunity. We did find helper cell responses, IFN-gamma production and Ctl responses elicited in the immunized chimpanzees (ref. 4) FUNDING NIH/ R01 CA57820 $166,648 7/01/92 - 6/30/98 K01 RR00119 $ 56,650 7/01/96 - 6/30/01 PUBLICATIONS Barratt-Boyes, S.M., Kao, H. and Finn, O.J. Chimpanzee dendritic cells derived in vitro from blood monocytes and pulsed with antigen elicit specific immune responses in vivo. J. Immunother. 21:142-148, 1998. P51RR00165-38 1/1/1998 - 12/31/1998 Yerkes Regional Primate Research Center