Assessing the effect of anti-PD-1/PD-L1 agents on tumoricidal efficacy of secretory TRAIL-armed NK cells

摘要 黑色素瘤是一种严重的皮肤癌，发生在肤色细胞(黑素细胞)中。当黑色素瘤 进展到晚期，治疗选择有限，并与显著的发病率和 死亡率。在这项赠款申请中，我们建议开发一种组合免疫疗法来治疗转移瘤。 黑色素瘤。多项研究表明，细胞因子TRAIL(肿瘤坏死因子相关的细胞凋亡- 诱导配体)可诱导多种肿瘤细胞的凋亡，但对大多数正常细胞没有毒性 细胞。用TRAIL治疗这种疾病有很大的希望，但它并不简单，因为可能的药物 治疗这种疾病的重组TRAIL在体内持续的时间不够长，无法奏效。我们发现了一个 让TRAIL驻留在另一个细胞中的方法，如自然杀伤(NK)细胞；该细胞然后在 长期的基础上。重要的是，NK细胞有一个额外的优势--他们寻找黑色素瘤细胞，所以他们 将TRAIL直接带到肿瘤部位，在那里发挥其深刻的杀瘤作用。最近的临床试验 研究表明，抗PD-1(程序性细胞死亡-1)和抗PD-L1(程序性细胞死亡配体1) 药物在转移性黑色素瘤中有令人印象深刻的抗肿瘤效果。因此，我们假设这个组合 分泌TRAIL的NK细胞与抗PD-1/PD-L1联合应用将有效增强对肿瘤的杀伤力 NK细胞的疗效。为了验证这一假设，(1)我们将评估分泌型武器的生物学效应 NK细胞和抗PD-1/PD-L1药物对转移性黑色素瘤细胞的影响，以及(2)我们将检测临床前 分泌型TRAIL介导的NK细胞与抗PD-1/PD-L1联合免疫治疗的疗效观察 转移性黑色素瘤的异种移植小鼠模型。第一个目标的拟议研究将研究 分泌型TRAIL介导的NK细胞与抗PD联合治疗对黑色素瘤细胞的杀伤作用 1/PD-L1制剂。在第二个目标中，我们将使用小鼠异种移植模型来评估治疗效果。 分泌TRAIL的NK细胞联合抗PD-1/PD-L1药物对人卵巢癌生长和消退的影响 转移性黑色素瘤。我们相信，这项研究的成功结果将支持这一应用 晚期恶性黑色素瘤患者的联合免疫治疗。

ABSTRACT Melanoma is a serious form of skin cancer that develops in skin color cells (melanocytes). When melanomas progress to an advanced stage, treatment options are limited and are associated with significant morbidity and mortality. In this grant application, we propose to develop a combinatorial immunotherapy to treat metastatic melanoma. Several studies have revealed that the cytokine TRAIL (tumor necrosis factor-related apoptosis- inducing ligand) induces apoptosis in a wide variety of tumor cells, but does not cause toxicity to most normal cells. Treating this disease with TRAIL holds great promise, but it is not simple, because the likely agent to treat the disease, recombinant TRAIL, does not last long enough in the body to be effective. We have found a way to have TRAIL reside in another cell such as the natural killer (NK) cell; that cell then secretes TRAIL on a long-term basis. Importantly, NK cells have an additional advantage--they seek out melanoma cells, so they bring TRAIL directly to tumor sites, where it can exert its profound tumor-killing effects. Recent clinical trials have shown that anti-PD-1 (programmed cell death-1) and anti-PD-L1 (programmed cell death-ligand 1) agents have impressive antitumor effects in metastatic melanoma. Thus, we hypothesize that the combination of secretory TRAIL-armed NK cells with anti-PD-1/PD-L1 agents will effectively enhance the tumoricidal efficacy of NK cells. To test the hypothesis, (1) we will assess the biological effect of secretory TRAIL-armed NK cells and anti-PD-1/PD-L1 agents on metastatic melanoma cells, and (2) we will examine the preclinical efficacy of combinatorial immunotherapy with secretory TRAIL-armed NK cells and anti-PD-1/PD-L1 agents in a xenograft mouse model of metastatic melanoma. The proposed studies for the first aim will examine the cytotoxicity of melanoma cells during combined treatment with secretory TRAIL-armed NK cells and anti-PD- 1/PD-L1 agents. In the second aim, we will employ a mouse xenograft model to assess the effect of treatment with secretory TRAIL-armed NK cells in combination with anti-PD-1/PD-L1 agents on growth and regression of metastatic melanoma. We believe that the successful outcome of this study will support the application of this combinatorial immunotherapy to patients with advanced malignant melanoma.