Enhancing the efficacy of immunotherapy in DLBCL using rational combination approaches

项目总结/摘要 虽然小分子抑制剂对人弥漫性大B细胞淋巴瘤（DLBCL）产生了影响， 免疫疗法，特别是使用基于抗CD 20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，但高达40%的患者最终将死于他们的疾病。 疾病此外，即使治疗成功，细胞毒性化疗也具有长期- 影响生活质量的长期发病率。最近成功的靶向治疗和免疫检查点 抑制剂在淋巴瘤背景下显示出在长期疾病中额外进展的潜力 控制DLBCL，毒性较小。对犬DLBCL的分子遗传表型进行了研究 并且它通常类似于通常与人的侵袭性DLBCL相关的活化B细胞（ABC）类别。 此外，现在有大量的数据表明，特定的遗传变化和途径畸变是保守的 在狗和DLBCL患者中，支持犬科疾病可以作为相关的 人类的自发大型动物模型。为此，本提案的目的是 使用自发性未处理DLBCL犬快速评价合理的小分子/免疫治疗 组合方法，最终目标是确定向前推进的最有效组合， DLBCL的人类患者。具体地说，我们假设抗CD 20、抗CD 20和抗CD 20抗体的最佳组合， PD 1、XPO 1抑制、NAMPT/PAK 4和PI 3 K δ抑制的结局优于阿霉素 基于化学疗法，为未来的人体试验提供了一个“无化学疗法”的蓝图。使用自适应 小型试点试验方法，这些组合被视为拮抗和/或与不可接受的不良反应相关 事件可以迅速从考虑中删除，而那些具有明确治疗前景的事件可能是最重要的。 在前线环境中有效地学习和提高。我们将通过首先确定最佳的 使用小分子/抗CD 20组合的无化疗方案，然后确定最佳无化疗方案 方案与小分子/抗PD 1组合，最后，通过评估一线化疗免费的新的 在犬DLBCL中的联合方案，以证明优于基于标准R-CHOP的化疗。 此外，我们将根据获得的肿瘤样品的RNA测序来询问相关的生物标志物， 从参加前瞻性试验的狗身上，并开发出不仅可用于预测 对治疗的反应，但更重要的是长期无进展生存。总之，生成的数据 将建立一个框架，有效利用从综合 在患有DLBCL的犬患者中进行免疫试验，以开发最终改善 人类成果。

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.