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

我们的工作证明了热休克蛋白(HSPs)在癌症免疫反应中的关键作用。研究表明：从癌症中提纯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，包括原发和微转移；热休克蛋白疫苗具有精妙的癌症特异性，即只有当用作热休克蛋白来源的癌症与用于挑战的癌症相同时，才能看到保护作用。这些发现已经得到了独立的证实。这些观察的结构基础在于发现：(1)热休克蛋白本身不是免疫原性的，但伴随肽是免疫原性的；(2)从热休克蛋白制剂中去掉多肽可消除其免疫原性；(3)与一个肿瘤的热休克蛋白相关的抗原肽不同于与其他肿瘤相关的抗原肽；(4)热休克蛋白-肽复合体诱导免疫的机制涉及巨噬细胞和树突状细胞重新呈递热休克蛋白结合的多肽。本文提出的研究将致力于将癌症来源的热休克蛋白70用于B细胞淋巴瘤的免疫治疗。这些肿瘤再次为解决癌症免疫治疗中的关键问题提供了一个独特的机会：其独特性来自于这样一个事实，即它们表达一个单独的癌症特异性标记物--独特型，以及免疫干预在B淋巴瘤中被证明的作用。

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.