Subcutaneous and systemic preclinical modeling of A20 murine B cell lymphoma

淋巴瘤是一组淋巴细胞恶性肿瘤，范围从惰性到侵袭性不等。B细胞源性淋巴瘤，特别是非霍奇金淋巴瘤（NHL），是最常见的，但这种疾病也可以起源于T细胞。2018年，估计美国将有74680例新的非霍奇金淋巴瘤病例被确诊，19910例患者死亡。虽然非霍奇金淋巴瘤的5年生存率相对较高，为71%，^[1]recurrence is common, so continued discovery of improved treatments for lymphoma is important for long term survival of these patients.

Researchers use preclinical mouse modeling of lymphoma to explore novel combination strategies of conventional chemotherapy or radiation and immunomodulatory agents. To support these efforts, Covance has developed the murine B cell lymphoma model,答20。A20 was derived from a spontaneous reticulum cell sarcoma from an aging Balb/c mouse.^[2]A20 tumors are reported to express PD-L1,^[3]which is consistent with our RNAseq profile (data not shown) and concordant with several human lymphoma subtypes,^[4]making it attractive for use in immunotherapy drug development.

In a2017 Model Spotlight，我们介绍了最初的生长数据以及皮下植入后不久开始的治疗反应。2018年，我们继续努力扩大该模型的特征描述。在这里，我们介绍了已建立的皮下A20肿瘤的初始抗肿瘤反应数据，以及一个系统性荧光素酶激活的A20模型的生长动力学，该模型的肿瘤进展由生物发光成像(BLI).

Treatment of A20 with immunotherapy agentsin vivois extremely effective against early stage disease, resulting in several complete responses. However, as expected, initiating treatment once tumors are established results in a much more limited response. Figure 1 illustrates individual (A-F) growth of control tumors and those treated with anti-mPD-1 or anti-mPD-L1 as monotherapy or in combination withfocal radiationdelivered by SARRP (XStrahl). Combination therapy produced a better than additive anti-tumor response, indicating that these strategies can be readily assessed in the A20 model once the tumors are established. Additionally, efficacy of anti-mGITR and anti-mCD137 against established A20 tumors was minimal to moderate, allowing for a broad dynamic range to assess improvement in combination of these antibodies and investigational agents (Figure 2 A-C).

为了进一步提高A20淋巴瘤模型的实用性，我们利用荧光素酶建立了A20细胞系，用于监测系统性疾病的肿瘤进展。模型的平均加倍时间为2.7天，治疗窗口约为3周。

Figure 3 shows individual tumor progression determined by BLI (A) and overall survival (B) which indicates favorable growth kinetics, and Figure 4 illustrates representative BLI imaging over time. Upon necropsy, a 100% incidence of liver lesions and 70% incidence of hindlimb paralysis and/or lesions on other organs (i.e., spleen, ovary, pancreas) were recorded. Abdominal distension was a common clinical sign manifesting between Days 30-32 and correlates well to the timing of strong BLI signal in Figures 3 and 4. A follow up study to investigate response to checkpoint blockade and costimulatory molecules is ongoing using this systemic model.

The A20 model provides robust preclinical means by which to study B cell lymphoma both by subcutaneous and systemic methods. Please联系人Covanceto speak with our scientists about how A20 or one of our othersyngeneic modelscan be used for your next immuno-oncology study.

Download