Enhancing antitumor immunity with anti-PD-1 antibody in follicular lymphoma.

描述(申请人提供)：自发临床缓解的观察，肿瘤中浸润性非恶性免疫细胞的基因表达特征与生存的相关性，以及给予抗CD20单抗利妥昔单抗后的高应答率表明滤泡性淋巴瘤具有特别的免疫反应性。然而，肿瘤微环境中的免疫抑制因素可能使内源性抗肿瘤免疫反应失效。近年来，滤泡性淋巴瘤患者瘤内CD4+和CD8+T细胞上的抑制性受体程序性死亡1(PD-1)显著上调，PD-1是活化T细胞和自然杀伤细胞的负调节因子。PD-1的表达与滤泡性淋巴瘤患者外周血中CD4+和CD8+T细胞的功能受损及PD-1/PD-L通路的阻断有关，PD-1抗体可显著促进瘤内CD4+和CD8+T细胞的增殖，并诱导TH1而非TH2细胞因子的产生。在目前的提案中，我们打算逆转滤泡性淋巴瘤患者中PD-1/PD-Ligand通路的抑制作用。该方案的中心假设是，用抗PD-1封闭抗体CT-011阻断PD-1与其配体的相互作用，将增强滤泡性淋巴瘤患者的内源性抗肿瘤T细胞和自然杀伤细胞免疫反应，并导致肿瘤的临床消退。此外，我们假设CT-011将增强自然杀伤细胞介导的抗体依赖细胞介导的细胞毒作用，并导致给予利妥昔单抗后临床疗效的提高。为了实现这项建议的目标，我们将进行CT-011联合利妥昔单抗治疗复发性滤泡性淋巴瘤患者的第二阶段临床试验。本研究提出三个具体目标：1)确定CT-011联合利妥昔单抗治疗复发性滤泡性淋巴瘤的安全性和临床疗效；2)确定CT-011对滤泡性淋巴瘤患者肿瘤特异性T细胞频率和功能的影响；3)确定CT-011对滤泡性淋巴瘤患者自然杀伤细胞功能的影响。CT-011和利妥昔单抗联合应用有望在不增加毒性的情况下提高临床疗效。鉴于FL患者确诊时的中位年龄为60岁，开发这种无毒但有效的免疫治疗方法是非常必要的。 公共卫生相关性：CT-011和利妥昔单抗这两种抗体疗法的联合使用可能是互补的，甚至可能是协同的，在不增加滤泡性淋巴瘤患者毒性的情况下提高临床疗效。由于滤泡性淋巴瘤在老年人中最常见，因此开发这种有效但无毒的免疫治疗方法对于滤泡性淋巴瘤的治疗是非常必要的。由于使用这种方法激活了免疫系统的多个手臂，它可能会最大限度地减少逃脱免疫系统的肿瘤变异的出现，因此可以提高我们找到这种疾病的根治疗法的机会。

DESCRIPTION (provided by applicant): The observation of spontaneous clinical remissions, correlation of gene expression signatures of infiltrating nonmalignant immune cells in the tumor with survival, and the high response rates following administration of rituximab, an anti-CD20 monoclonal antibody suggest that follicular lymphomas are particularly immune responsive. However, immunosuppressive factors in the tumor microenvironment may render the endogenous anti-tumor immune responses ineffective. Recently, the inhibitory receptor programmed death 1 (PD-1), a negative regulator of activated T cells and natural killer cells, was demonstrated to be markedly upregulated on intratumoral CD4+ and CD8+ T cells in patients with follicular lymphoma. PD-1 expression was associated with impaired function of CD4+ and CD8+ T cells and blockade of the PD-1/PD-ligand pathway with antibody against PD-1 significantly enhanced proliferation of intratumoral CD4+ and CD8+ T-cells and induced production of TH1 but not TH2 cytokines in response to autologous tumor cells obtained from patients with follicular lymphoma. In the current proposal, we intend to reverse the inhibitory effects of the PD-1/PD-ligand pathway in patients with follicular lymphoma. The central hypothesis of this proposal is that blockade of the interaction of PD-1 with its ligands by using CT-011, an anti-PD-1 blocking antibody, will enhance the endogenous antitumor T-cell and natural killer-cell immune responses in patients with follicular lymphoma and lead to clinical regression of the tumors. Furthermore, we hypothesize that CT-011 will enhance the antibody-dependent cell-mediated cytotoxicity mediated by natural killer cells and lead to increased clinical efficacy following administration of rituximab. To accomplish the objectives of this proposal, we will conduct a phase 2 clinical trial of CT-011 combined with rituximab in patients with relapsed follicular lymphoma. Three Specific Aims are proposed: 1) determine the safety and clinical efficacy of CT-011 administered in combination with rituximab in patients with relapsed follicular lymphoma, 2) determine the effects of CT-011 on the frequency and function of tumor-specific T cells in patients with follicular lymphoma, and 3) determine the effects of CT-011 on the function of natural killer cells in patients with follicular lymphoma. The combination of the two drugs, CT-011 and rituximab is expected to improve the clinical efficacy without increasing the toxicity. Given that the median age of FL patients at diagnosis is 60 years, developing such nontoxic but efficacious immunotherapeutic approaches is highly desirable. PUBLIC HEALTH RELEVANCE: The combined use of the two antibody therapies, CT-011 and rituximab is likely to be complementary and may be even synergistic and lead to enhanced clinical efficacy without increasing the toxicity in patients with follicular lymphoma. Development of such efficacious but nontoxic immunotherapeutic approaches is highly desirable for the treatment of follicular lymphoma since it is most commonly diagnosed in the elderly population. Due to activation of multiple arms of the immune system using this approach, it can potentially minimize the emergence of tumor variants that escape the immune system and therefore can improve the chance of our goal to find a curative therapy for this disease.