WHOLE BODY HYPERTHERMIA & THE ANTITUMOR IMMUNE RESPONSE

描述：有证据表明，2摄氏度（6 - 8小时）的升高， 体温导致生长在体内的人类肿瘤的大量凋亡 SCID小鼠嵌合模型以及可移植的鼠肿瘤 在Balb/c小鼠中生长。 这种全身热疗（WBH）方案与 与传统的全身热疗和局部热疗方案不同， 在较低温度下的热暴露要少得多， 正常发烧的热元素。 理解并最终 利用这种温和的热暴露的机制， 显著的抗肿瘤活性可以提供另外的方法， 癌症的治疗。 初步的数据得出了这样的假设， 发热范围的全身热疗可通过影响机体免疫功能抑制肿瘤生长， 对肿瘤的反应;这一假设的推论是，通过使用 也刺激抗肿瘤免疫应答的其它方法 结合全身热疗，我们可能能够显著地 增强抗肿瘤效果，超过单独使用任何一种治疗所观察到的效果。 这个应用程序的总体目标是进行一系列的实验 旨在测试这些可能性。 一些证据表明 全身热疗刺激免疫系统的一个重要机制 涉及细胞溶解反应，即，自然杀伤细胞（NK）作用 淋巴细胞，先天免疫应答的主要效应细胞， 和溶细胞性T淋巴细胞，适应性免疫的效应细胞， 反应;实验设计来支持这一假设，使用两个人 和鼠肿瘤系统，将作为目标1的一部分进行。 其他数据 提示对WBH也有细胞因子反应，在目标2中， 宿主细胞因子（包括那些可以刺激肿瘤反应性T细胞的细胞因子）的作用 淋巴细胞和NK细胞，并且可能由高温诱导 治疗本身将被评估。 在前两个实验中获得的数据 在目标3中，目标将是有用的，我们将进行研究，以确定 发热范围的全身热疗对肿瘤生长的影响可以通过以下方式增强： 与免疫疗法（包括特异性疫苗疗法）的组合， 加入外源性细胞因子和效应细胞。 重要的是， 加入IFN-γ增强WBH的抗肿瘤作用， 在初步研究中已经观察到。 存在几 适当的模型系统，其中各种假设， 发热范围WBH的作用机制可以在临床前进行测试， 细胞和分子水平，结合多学科方法 这些经验丰富的研究人员，将提供一个很好的 发热范围全身临床试验的科学基础 在不久的将来，

DESCRIPTION: Evidence is provided that a 2 degree C (6-8 hr) elevation of body temperature results in substantial apoptosis of human tumors growing in a SCID mouse chimeric model and as well in transplantable murine tumors grown in Balb/c mice. This whole body hyperthermia (WBH) protocol differs from conventional WBH and local hyperthermia protocols in that it employs a much lengthier heat exposure at lower temperatures and thus, approximates the thermal element of a normal fever. Understanding and eventually exploiting the mechanism(s) by which this mild heat exposure exerts such significant anti-tumor activity may provide an additional approach in the treatment of cancer. The preliminary data have led to the hypothesis that fever-range WBH can inhibit tumor growth by its effects on the immune response against tumors; a corollary to this hypothesis is that by using additional methods which also stimulate the anti-tumor immune response in combination with whole body hyperthermia, we may be able to significantly enhance the anti-tumor effects over that seen with any one treatment alone. The overall goal of this application is to conduct a series of experiments designed to test these possibilities. Several lines of evidence suggest that one important mechanism by which WBH stimulates the immune system involves a cytolytic response, i.e., the action of natural killer (NK) lymphocytes, the predominant effector cell of the innate immune response, and cytolytic T lymphocytes, effector cells of the adaptable immune response; experiments designed to support this assumption, using both human and murine tumor systems, will be conducted as part of Aim 1. Other data suggest that there is also a cytokine response to WBH, and in Aim 2, the role of host cytokines (including those that can stimulate tumor reactive T lymphocytes and NK cells, and which may be induced by the hyperthermia treatment itself, will be assessed. The data obtained in these first two aims will be useful in Aim 3, where we will conduct studies to determine if the effects of fever-range WBH on tumor growth can be enhanced by combination with immunotherapies including specific vaccine therapy and addition of exogenous cytokines and effector cells. Importantly, an enhancement of the anti-tumor effects of WBH with the addition of IFN-g has already been observed in Preliminary Studies. The existence of several appropriate model systems, in which various assumptions regarding the mechanisms of action of fever-range WBH can be tested at the preclinical, cellular and molecular levels, combined with the multidiciplinary approach of this experienced group of investigators, will provide an excellent scientific foundation for clinical trials of fever-range whole body hyperthermia in the near future.