Rao Kirthana, Rao Zechuan, Huang Angelina, Heston Scott, Wang Max, Yildiz-Altay Ümmügülsüm, Qutab Fatima, Kwong Danny A, Gardner Heather L, Richmond Jillian M, London Cheryl A
UMass Chan Medical School.
Tufts University.
Res Sq. 2025 Aug 19:rs.3.rs-7110482. doi: 10.21203/rs.3.rs-7110482/v1.
Pet dogs spontaneously develop a form of diffuse large B cell lymphoma (DLBCL) that recapitulates many of the features of double hit () human DLBCL. We recently completed a clinical trial in dogs with DLBCL using a combination of canine anti-CD20 antibody and low dose doxorubicin followed by one of three small molecule immune-modulating agents (KPT-9274, TAK-981 or RV1001). Clinical outcomes and tumor specific biomarkers of response from these dogs have been previously reported. In this study, we used the NanoString Canine IO panel to assess dynamic changes in gene counts from peripheral blood mononuclear cells (PBMCs) collected longitudinally from these from dogs over the course of their treatment to identify immune correlates associated with early relapse versus long-term survivorship. Increases in interferon-stimulated gene (ISG) signatures and immune skewing genes [ (DC-SIGN), and (RIG-I)] were associated with shorter (<400 day) survival times and early relapse. In contrast, and were elevated post-immunotherapy in long-term (>400 day) survivors, suggesting that these may be associated with protective immune signatures. Examining genes that were expressed in short- versus long-term survivors early on in the treatment regimen identified , and as elevated in dogs with shorter survival times at day 7. To facilitate point-of-care PBMC gene expression testing that could be used to distinguish those dogs likely to require more intensive treatment regimens in advance of relapse, we developed qPCR assays for , and . Together these data provide proof of principle that biomarker interrogation in PBMCs can help predict early relapse and poor responders to inform clinical management of DLBCL.
宠物狗会自发发展出一种弥漫性大B细胞淋巴瘤（DLBCL），它概括了许多双打击（）人类DLBCL的特征。我们最近完成了一项针对患有DLBCL的犬类的临床试验，使用犬抗CD20抗体和低剂量阿霉素联合三种小分子免疫调节剂之一（KPT-9274、TAK-981或RV1001）。这些犬类的临床结果和肿瘤特异性反应生物标志物此前已有报道。在本研究中，我们使用NanoString犬类免疫肿瘤学检测板评估从这些犬类治疗过程中纵向收集的外周血单核细胞（PBMC）的基因计数动态变化，以确定与早期复发和长期存活相关的免疫相关性。干扰素刺激基因（ISG）特征和免疫偏向基因[（DC-SIGN）、和（RIG-I）]的增加与较短（<400天）的生存时间和早期复发相关。相比之下，和在长期（>400天）存活者免疫治疗后升高，表明这些可能与保护性免疫特征相关。检查在治疗方案早期短期和长期存活者中表达的基因，发现、和在第7天存活时间较短的犬类中升高。为了便于进行即时护理PBMC基因表达检测，以用于在复发前区分那些可能需要更强化治疗方案的犬类，我们开发了针对、和的qPCR检测方法。这些数据共同提供了原理证明，即PBMC中的生物标志物检测有助于预测早期复发和低反应者，为DLBCL的临床管理提供信息。
