Targeting the Chemokine System to Sensitize Tumors to Immunotherapy

修订后的P01 CA 234212测试了促进选择性CTL进入肿瘤微环境的新策略。 在免疫治疗中，TME可以增强肿瘤的免疫功能，并使“冷”肿瘤对免疫治疗敏感。我们的临床前和早期临床数据 证明了靶向Toll样受体-3（TLR 3）、1型 干扰素（IFN）和PGE 2系统，选择性地增加CTL数量，但减少调节性T（reg）细胞 在TME中，对PD-1阻滞剂的治疗有效性和专门的肿瘤敏感性一致， 树突状细胞疫苗（α DC 1）在黑色素瘤、结直肠癌（CRC）和卵巢癌（OvCa）中的应用。我们现在将： 1)确定全身或局部应用的CKM在癌症患者中的局部免疫功效; 2）识别 使用CKM增强抗肿瘤作用的最有效方法DC疗法和PD-1阻断;以及3） 评估由此产生的疗法在PD-1耐药癌症患者中的临床活性， 临床获益的相关TME相关性。 项目1组合佐剂促进均匀和选择性的肿瘤内CTL浸润将测试 在IIa期试验NCT 03403634中，是否全身施用由林他托莫德（TLR 3- IFNα和塞来昔布促进转移性结直肠癌（CRC）TME中的局部CTL积聚。 效应的大小、肿瘤选择性（相对于周围组织）和小鼠研究将指导药物的设计。 第二项试验将评估CMK/抗PD-1序贯应用于CRC患者的临床疗效。 项目2局部免疫疗法纠正OvCa中的趋化因子模式将完成II期部分， 试验NCT 02432378，旨在检测局部CKM在吸引CTL（而非TMEs）至TME方面的特异性， 接种载有自身肿瘤细胞的α DC 1（α DC 1 [肿瘤]）并识别“继发性”的OvCa患者 机制或治疗抗性。这些结果将为临床前研究和第二个实验室的设计提供信息。 确定DC[肿瘤]/CKM序贯治疗随后PD-1阻断的临床活性的试验。 项目3趋化因子调节增强TME中CD 8 + TIL募集和交叉致敏 基于我们对α DC 1疫苗57%的客观应答率（ORR）的最新观察结果（NCT 01876212） 靶向肿瘤血管（α DC 1 [TBVA]在7例原发性PD 1耐药的黑色素瘤患者中的4例中， 总体客观临床获益为46%（6/13例患者）。我们现在将进行II期试验，以评估临床 α DC 1 [DBVA]联合全身性CKM（BB-IND 16，704）在IV期黑色素瘤患者中的活性 主要的PD 1抗性。利用相关研究和小鼠体内模型，我们将开发优化的， 潜在的简化疫苗，以补充CKM和PD-1阻断，从而获得持久的治疗益处。 影响：我们将测试广泛适用的补充方法，以促进治疗药物的选择性进入 CTL进入肿瘤。由于肿瘤内CTL数量预测了检查点的生存率和治疗优势， 阻断剂在多种癌症类型中的应用，结果可能会使广泛的癌症患者受益。

The revised P01CA234212 tests novel strategies to promote selective CTL entry into tumor micro- environments (TME) and sensitize “cold” tumors to immunotherapy. Our preclinical and early clinical data demonstrate that the chemokine-modulating (CKM) regimen targeting toll-like receptor-3 (TLR3), type-1 interferons (IFN) and the PGE2 system, selectively enhances CTL numbers but reduces regulatory T(reg) cells in TME, uniformly sensitizing tumors for the therapeutic effectiveness of PD-1 blockers and specialized dendritic cell vaccines (αDC1) in melanoma, colorectal cancer (CRC) and ovarian cancer (OvCa). We will now: 1) Determine local immunologic efficacy of systemically- or locally applied CKMs in cancer patients; 2) Identify the most effective ways of using CKM to enhance antitumor effects DC therapies and PD-1 blockade; and 3) Evaluate the clinical activity of the resulting therapies in PD-1-resistant cancer patients, and identify the most relevant TME correlates of clinical benefit. Project 1 Combinatorial adjuvants promote uniform and selective intratumoral CTL infiltration will test in a Phase IIa trial NCT03403634 whether systemic administration of CKM composed of rintatolimod (TLR3- ligand) IFNα and celecoxib promotes local CTL accumulation in TME of metastatic colorectal cancer (CRC). Magnitude of effects, tumor-selectivity (vs surrounding tissues) and mouse studies will guide the design of the second trial which will evaluate the clinical efficacy of sequential CMK/anti-PD-1 application in CRC patients. Project 2 Local immunotherapy corrects chemokine patterns in OvCa will complete the phase II portion of trial NCT02432378 to test the specificity of local CKM in attracting CTLs (rather than Tregs) to the TME of OvCa patients vaccinated with αDC1 loaded with own tumor cells (αDC1[tumor]) and identify “secondary” mechanisms or treatment resistance. The results will inform preclinical studies and the design of the second trial to determine the clinical activity of sequential treatment with DC[tumor]/CKM followed with PD-1 blockade. Project 3 Chemokine modulation to enhance CD8+ TIL recruitment and cross-priming in the TME is based on our latest observations (NCT01876212) of 57% objective response rate (ORR) to αDC1 vaccine targeting tumor blood vessels (αDC1[TBVA] in the 4 of 7 melanoma patients with primary PD1 resistance and 46% objective clinical benefit overall (6/13 patients). We will now perform phase II trial to evaluate the clinical activity of αDC1[DBVA] combined with systemic CKM (BB-IND16,704) in stage IV melanoma patients with primary PD1 resistance. Using correlative studies and mouse in vivo models, we will develop optimized and potentially simplified vaccines to complement CKM and PD-1 blockade for durable therapeutic benefit. Impact: We will test widely-applicable complementary approaches to promote selective entry of therapeutic CTLs into tumors. Since intratumoral CTL numbers predict survival and therapeutic advantage of checkpoint blockers in multiple cancer types, the results are likely to benefit a broad range of cancer patients.