Prostate Cancer Immunotherapy

描述（由申请人提供）：不同类型的免疫疗法已被证明在不同的恶性肿瘤中诱导免疫和临床反应，但目前只有一小部分患者可能受益。该项目的目标是开发更有效的前列腺癌免疫疗法。我们已经证明，用免疫抑制分子CTLA4的抗体增强T淋巴细胞反应可以在一小部分去势抵抗性前列腺癌患者中诱导临床反应。我们已经研究了这种治疗是否可以与细胞因子粒细胞-巨噬细胞刺激因子（GM-CSF）联合使用，GM-CSF也被研究作为前列腺癌的免疫疗法。在一项I期临床试验中，我们已经证明CTLA4阻断和GM-CSF联合治疗是安全的，并且可能以更高的率导致临床反应。为了在临床上进一步开发CTLA4阻断，我们必须确定联合免疫治疗是否确实能改善临床结果。在具体目标1中，我们将进行一项随机II期临床试验，其中激素难治性前列腺癌患者将单独使用抗ctla4抗体或抗ctla4抗体与GM-CSF联合治疗。在第二个目标中，我们将确定CTLA4单独阻断或联合阻断是否会导致效应T细胞的显著激活和调节性T细胞的扩增。在最后的目的，我们将定义抗原特异性免疫反应诱导的治疗。这样做，我们可以验证可能代表新的候选疫苗的新的肿瘤抗原。或者，我们可以定义一个免疫反应特征，可以预测哪些患者可能对这种免疫治疗方法有反应。公共卫生相关性：免疫疗法是前列腺癌治疗的一种新兴模式。前列腺癌患者可以拥有预先存在的对癌症的免疫反应，可以增强临床效果。CTLA4阻断抗体治疗已被证明可以增强这种免疫反应，并在一小部分患者中诱导临床反应。将这种治疗与细胞因子治疗结合GM-CSF提供了一种增强这些T细胞反应并最终提高临床疗效的方法。确定这种免疫反应所针对的靶蛋白可能会改善前列腺癌的治疗方法。

DESCRIPTION (provided by applicant): Different types of immunotherapy have been shown to induce both immune and clinical responses in different malignancies, but at this point, only a small proportion of patients may benefit. The goal of this project is to develop more effective immunotherapy for prostate cancer. We have demonstrated that enhancing T lymphocyte responses with an antibody to immune inhibitory molecule CTLA4 can induce clinical responses in a small proportion of patients with castrate-resistant prostate cancer. We have examined whether this treatment could be combined with the cytokine granulocyte-macrophage stimulating factor (GM-CSF), which is also being studied as an immunotherapy for prostate cancers. In a phase I clinical trial, we have shown that the combination of CTLA4 blockade and GM-CSF treatment is safe and may lead to clinical responses at a higher rate. In order for CTLA4 blockade to be further developed clinically, we must determine whether combination immunotherapy indeed results in improved clinical outcome. In specific aim 1, we will perform a randomized phase II clinical trial where patients with hormone-refractory prostate cancer will be treated with either anti-CTLA4 antibody alone or anti-CTLA4 antibody in combination with GM-CSF. In the second aim, we will determine whether CTLA4 blockade alone or the combination leads to significant activation of effector T cells and expansion of regulatory T cells. In the final aim, we will define antigen-specific immune responses induced by the treatment. In doing so, we may validate novel tumor antigens that may represent novel vaccine candidates. Alternatively, we may define an immune response signature that may predict which patients might respond to this immunotherapeutic approach. PUBLIC HEALTH RELEVANCE: Immunotherapy is an emerging modality in prostate cancer therapy. Prostate cancer patients can possess preexisting immune responses to their cancer that can be enhanced for clinical effect. Treatment with blocking antibodies to CTLA4 has been shown to augment this immune response and induce clinical responses in a small proportion of patients. Combining this treatment to cytokine therapy with GM-CSF provides an approach for enhancing these T cell responses and ultimately enhancing clinical efficacy. Defining the target proteins against which this immune response is induced may lead to improved treatments for prostate cancer.