TREATMENT OF INDOLENT B CELL LYMPHOMA & CLL PATIENTS W/ HEAT SHOCK PR

我们的工作已经证明了热休克蛋白（HSPs）在癌症免疫反应中的关键作用。研究表明：从癌症中纯化的热休克蛋白制剂可用于多种先前存在的啮齿动物癌症的免疫治疗，包括原发性和微转移性癌症；热休克蛋白疫苗接种具有精确的癌症特异性，即只有当用作热休克蛋白来源的癌症与用于攻击的癌症相同时，才能看到保护作用。这些发现已得到独立证实。这些观察的结构基础在于发现(i)热休克蛋白本身不具有免疫原性，但伴侣肽具有；（ii）从热休克蛋白制剂中去除多肽会削弱其免疫原性（iii）一种肿瘤中与热休克蛋白相关的抗原肽与其他肿瘤中相关的抗原肽不同；（iv）热休克蛋白肽复合物引发免疫的机制涉及巨噬细胞和树突状细胞对热休克蛋白伴肽的再递呈。本文提出的研究将寻求利用癌源性hsp70进行B细胞淋巴瘤的免疫治疗。这些肿瘤代表了解决癌症免疫治疗关键问题的独特机会：其独特性源于它们表达个体癌症特异性标记物，独特型以及免疫干预在B淋巴瘤中已证实的作用。

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.