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

描述（由申请方提供）：观察到自发性临床缓解、肿瘤中浸润性非恶性免疫细胞的基因表达特征与生存期的相关性以及利妥昔单抗（一种抗CD 20单克隆抗体）给药后的高应答率，表明滤泡性淋巴瘤特别具有免疫应答性。然而，肿瘤微环境中的免疫抑制因子可能使内源性抗肿瘤免疫应答无效。最近，抑制性受体程序性死亡1（PD-1），活化的T细胞和自然杀伤细胞的负调节剂，被证明是显着上调肿瘤内的CD 4+和CD 8 + T细胞在滤泡性淋巴瘤患者。PD-1表达与CD 4+和CD 8 + T细胞的功能受损相关，并且用抗PD-1抗体阻断PD-1/PD-配体途径显著增强了肿瘤内CD 4+和CD 8 + T细胞的增殖，并诱导了响应于从滤泡性淋巴瘤患者获得的自体肿瘤细胞的TH 1而非TH 2细胞因子的产生。在目前的提案中，我们打算逆转PD-1/PD-配体通路在滤泡性淋巴瘤患者中的抑制作用。该提议的中心假设是，通过使用CT-011（一种抗PD-1阻断抗体）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细胞和天然巨噬细胞免疫应答，并导致肿瘤的临床消退。此外，我们假设CT-011将增强由自然杀伤细胞介导的抗体依赖性细胞介导的细胞毒性，并导致利妥昔单抗给药后临床疗效增加。为了实现本提案的目标，我们将在复发性滤泡性淋巴瘤患者中进行CT-011联合利妥昔单抗的2期临床试验。提出了三个具体目标：1）确定CT-011与利妥昔单抗联合给药在复发性滤泡性淋巴瘤患者中的安全性和临床功效，2）确定CT-011对滤泡性淋巴瘤患者中肿瘤特异性T细胞的频率和功能的影响，3）检测CT-011对滤泡性淋巴瘤患者NK细胞功能的影响。CT-011和利妥昔单抗两种药物的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患者诊断时的中位年龄为60岁，开发这种无毒但有效的免疫方法是非常可取的。 公共卫生相关性：两种抗体疗法CT-011和利妥昔单抗的联合使用可能是互补的，甚至可能是协同的，并导致临床疗效增强，而不会增加滤泡性淋巴瘤患者的毒性。开发这种有效但无毒的免疫治疗方法对于治疗滤泡性淋巴瘤是非常理想的，因为它最常在老年人群中诊断。由于使用这种方法激活了免疫系统的多个臂，它可以潜在地最大限度地减少逃避免疫系统的肿瘤变体的出现，因此可以提高我们找到这种疾病的治愈性疗法的目标的机会。

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.