Enhancing the efficacy of immunotherapy in DLBCL using rational combination approaches

项目摘要/摘要 虽然小分子抑制剂对人类弥漫性大B细胞淋巴瘤(DLBCL)有影响， 免疫疗法，特别是使用基于抗CD20的方法，对治疗产生了最深远的影响 战略和长期成果。尽管取得了这一进展，高达40%的患者最终将死于他们的 疾病。此外，即使治疗成功，细胞毒性化疗也有很高的长期- 影响生活质量的病症。最近靶向治疗和免疫检查点的成功 淋巴瘤环境中的抑制物显示了在长期疾病中取得额外进展的潜力 控制DLBCL，毒性小。对犬DLBCL的分子遗传表型进行了研究 它通常类似于激活的B细胞(ABC)类别，通常与人的侵袭性DLBCL有关。 此外，现在有大量数据表明，特定的遗传变化和通路异常是保守的。 在狗和患有DLBCL的人中支持犬病可以被用作相关的 人类模型的自发大动物模型。为此，这项建议的目的是 利用自发性幼稚DLBCL犬快速评估合理的小分子/免疫治疗 组合方法，最终目标是确定最有效的组合以向前迈进 人类DLBCL患者。具体地说，我们假设抗CD20、抗CD20和抗CD20的最佳组合 抑制PD1、XPO1、NAMPT/PAK4和PI3K Delta抑制将比阿霉素有更好的结果 以化疗为基础，为未来的人体试验制定了一份“无化疗”的蓝图。使用自适应 小型试点试验方法，那些被认为具有对抗性和/或与不可接受的不良反应相关的组合 事件可以很快被排除在考虑之外，而那些有明确治疗承诺的事件可能是大多数 有效地学习了在一线的设置和提升。我们将通过首先确定最优的 小分子/抗CD20组合的非化疗方案，然后确定最佳的非化疗方案 小分子/抗PD1联合化疗方案，最后通过评估一种一线非化疗新药 联合方案治疗犬DLBCL优于标准R-CHOP方案化疗。 此外，我们将根据所获得的肿瘤样本的rna测序来询问相关的生物标志物。 从登记参加预期试验的狗身上提取并开发出不仅可以用来预测 对治疗的反应，但更重要的是长期无进展生存。总而言之，生成的数据 将创建一个框架，以便有效地利用从 对DLBCL患者的免疫治疗试验，以开发最终改善的非化疗策略 人类的结果。

Project Summary/Abstract While small molecule inhibitors have made an impact in human diffuse large B-cell lymphoma (DLBCL), immunotherapy, specifically using anti-CD20 based approaches, has had the most profound effect on treatment strategies and long-term outcomes. Despite this progress, up to 40% of patients will ultimately succumb to their disease. Furthermore, even when treatment is successful, cytotoxic chemotherapy carries a high risk of long- term morbidities that impact quality of life. The recent success of targeted therapies and immune checkpoint inhibitors in the setting of lymphoma demonstrates the potential for additional progress in long-term disease control of DLBCL, with less toxicity. The molecular and genetic phenotype of canine DLBCL has been studied and it often resembles the activated B cell (ABC) category typically associated with aggressive DLBCL in people. Moreover, there is now substantial data that specific genetic changes and pathway aberrations are conserved across dogs and people with DLBCL supporting the notion that the canine disease can be used as a relevant spontaneous large animal model of the human counterpart. Toward this end, the purpose of this proposal is to use dogs with spontaneous naïve DLBCL to rapidly evaluate rational small molecule/immunotherapy combination approaches, with the ultimate goal of identifying the most effective combination to move forward in human patients with DLBCL. Specifically, we hypothesize that optimal combinations of anti-CD20, anti- PD1, XPO1 inhibition, NAMPT/PAK4 and PI3Kdelta inhibition will have better outcomes than doxorubicin based chemotherapy, resulting in a “chemo-free” blueprint for future human trials. Using an adaptive mini-pilot trial approach, those combinations deemed antagonistic and/or associated with unacceptable adverse events can be rapidly removed from consideration, while those with clear therapeutic promise can be most effectively studied in the front-line setting and enhanced. We will accomplish this by first determining the optimal chemo-free regimen with small molecule/ anti-CD20 combinations, then identifying the optimal chemo-free regimen with small molecule/anti-PD1 combinations and finally, by evaluating a frontline chemo-free novel combination regimen in canine DLBCL to demonstrate superiority to standard R-CHOP-based chemotherapy. Additionally, we will interrogate correlative biomarkers based on RNA sequencing of tumor samples obtained from dogs enrolled into the prospective trials and develop signatures that can be used to predict not only response to therapy, but more importantly long-term progression-free survival. Together, the data generated from this proposal will create a framework for effectively leveraging information gained from integrated immunotherapeutic trials in canine patients with DLBCL to develop chemo-free strategies that ultimately improve human outcomes.