The hypothesis driving this project is that some of the botanicals in wide use today can act as immunomodulators when taken orally, or immunological adjuvants when administered subcutaneously mixed with vaccines, augmenting or dampening the immune response against the co-administered vaccine. The optimal adjuvants in our experience are the QS-21 and GPI-0100 triterpenoid saponins derived from the bark of the South American tree Quillaja saponaria Molina. There is, however, a pressing need for more potent approaches to further augmenting vaccine immunogenicity. Adjuvant and immunomodulator activity will be determined for selected botanicals when administered with globo H-KLH and GD2-KLH conjugate vaccines. Globo H is a hexaccharide auto-antigen overexpressed in breast cancers and most other epithelial cancers. GD2 is a ganglioside auto-antigen overexpressed on sarcomas, neuroblastomas, and melanomas. Keyhole limpet hemocyanin (KLH) is a potent immunological carrier protein purified from the blood of the keyhole limpet. The antibody response to globo H and KLH will be determined in ELISA, FACS, and cytotoxicity assays, and the T-cell response to KLH will be measured in proliferation and ELISPOT assays. The botanicals will be tested mixed with the globo H-KLH vaccine in Aim 1 as adjuvant alone, in Aim 2 as immunomodulator administered orally, in Aim 3 as adjuvant in combination with GPI-0100, or in Aim 4 with a GD2-KLH vaccine plus botanical as adjuvant or immunomodulator in the setting of established, GD2 positive cancer. Botanicals found to be consistently active in any assay will be referred back to the Research Resource Core for further purification and characterization. Adjuvant and immunomodulator activity of the resulting purified components will be tested again. In this way, widely used botanicals with adjuvant or immunomodulator activity will be identified and their most active components defined. While our bias is that peak reactivity will occur with purified fractions or combinations of purified fractions, it is also possible that peak reactivity will occur with less pure botanical mixtures since there may be issues and factors operating that we do not currently understand. Also, there is a long history documenting the potency of complex adjuvant formulations. In our search for the most immunoreactive botanicals or botanical fractions, we will be alert to this possibility. We will also be alert for negative immunomodulatory activity in the botanicals we screen, as this will suggest botanicals that should not be taken with vaccines or at other times when new immune responses are important. We have, therefore, 2 agendas that run through each of the specific aims: 1) to determine the positive or negative impact of widely used botanicals on the immune system's ability to recognize and react against immunogens, and 2) to define the most active fractions or components of these botanicals for use as adjuvants or as immunomodulators with vaccines against cancer.
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