Our work has demonstrated a key role for Heat Shock Proteins (HSPs) in immune response to cancer. It has shown that: HSP preparations purified from cancers can be used for immunotherapy of a wide variety of pre-existing rodent cancers, both primary and micro-metastatic; HSP-vaccination is exquisitely cancer-specific, i.e. protection is seen only if the cancer used as the source of HSPs is the same as the one used for challenge. These findings have been independently confirmed. The structural basis of these observations lies in the discoveries that (i) HSPs are not immunogenic per se, but chaperoned peptides are; (ii) removal of peptides from HSP preparations ablates their immunogenicity (iii) antigenic peptides associated with HSPs from one tumor are distinct from those associated with other tumors; (iv) the mechanism whereby the HSP-peptide complexes elicit immunity involves re-presentation of HSP-chaperoned peptides by macrophages and dendritic cells. The studies proposed here will pursue the use of cancer-derived hsp70 for immunotherapy of B cell lymphoma. These tumors re-present a unique opportunity to address key questions in cancer immunotherapy: the uniqueness derives from the fact that they express an individually-cancer-specific marker, the idiotype and from the proven role of immunological intervention in B lymphoma.
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