.png){kind=icon}
MB49-膀胱癌小鼠肿瘤模型
AUTHOR:
Erin Trachet | Director, Scientific Development
DATE:
April 2019
Bladder cancer is one of the most frequent cancers of the urinary tract, accounting for about 80,000 new cases and 18,000 deaths in the United States in 2018, according to the National Cancer Society. Typically, patients with bladder cancer have limited surgical or treatment options. Traditional chemotherapeutics are ineffective, and surgery is often used to diagnose bladder cancer and to determine whether the cancer has spread into (invaded) the muscle layer of the bladder wall. When bladder cancer is invasive, all or part of the bladder may need to be removed, leaving the patient with long term adverse effects. In an effort to meet the need for advances in bladder cancer treatment, in 2018 the FDA accelerated the approvals for two checkpoint inhibitors, Keytruda and Tecentriq.
The steady growth, and interest in immunotherapy has required continual development and optimization ofsyngeneic mouse tumor modelswith desirable growth kinetics and response to immunomodulatory agents. One of these bladder cancer models,MB49型, has been characterized by Covance to support development of these agents. MB49 cells (urothelial carcinoma) were derived from a C57BL/6 mouse following exposure of primary bladder cells to DMBA (7,12-dimethylbenz[a]anthracene) for 24 hours followed by culturing.[1]
MB49型Baseline Tumor Immune Profile
As described below, MB49 is considered to have a cold tumor phenotype with very low levels of CD8+ and CD4+ T cell infiltration (<3%) and significant presence of immunosuppressive myeloid populations (~65%), see Figure 1. The preliminary immunomodulatory treatment data shows mild responses, further supporting a cold tumor phenotype, and indicating that this model has the potential to respond to immune stimulants, perhaps best in combination with other agents. Thus, MB49 is well positioned to be a powerfulimmuno-oncologymodel with significant utility in drug development.
MB49肿瘤的平均和个体生长
Thein vivo皮下MB49肿瘤的倍增时间约为4天，这是一个中等增长率，可以促进长达三周的剂量窗口，供试药物激发其抗肿瘤活性（图2A）。图2显示了与同型对照组（图2C）相比，未治疗对照组（图2B）的平均肿瘤体积（图2A）和单个肿瘤体积。未观察到差异。
MB49型Response to Checkpoint Inhibitor Therapy
The model was evaluated for response to commonly utilized checkpoint inhibitor antibodies, anti-mCTLA-4, anti-mPD-L1, or anti-mPD-1 (Figure 3). Dosing with all test agents began once tumors were established (~100mm3). Treatment with anti-mPD-L1, anti-mPD-1, and anti-mCTLA-4 demonstrated similar, mild anti-tumor activities, with approximately 2.5-days tumor growth delay compared to the isotype control group. However, treatment with anti-mPD-L1, anti-mPD-1 and anti-mCTLA-4 did produce 20%, 20%, and 40% putative responders, respectively. The clear effect of these treatments can allow for additive or synergistic improvement in combination with candidate molecules.
MB49型Response to Costimulatory Antibody Therapy
MB49对共刺激分子抗mCD137和抗mGITR的反应也进行了评估，发现与图3所示的反应相比，MB49具有相似的活性水平（见图4A-D）。抗mCD137治疗产生轻微的抗肿瘤活性，肿瘤生长延迟3.5天，假定有20%的应答。抗-mGITR治疗的抗肿瘤活性最低，肿瘤生长延迟0.9天，预期有20%的应答者。然而，有限的活动提供了显着的改善空间与联合治疗。
The MB49 murine bladder carcinoma model can be employed as a robust preclinical immuno-oncology model. Our data supports the use of this tool in investigating novel treatment combinations with checkpoint inhibitors or costimulatory molecules. Please联系人Covanceto speak with our scientists about how MB49, or one of our other syngeneic models, can be used for your next immuno-oncology study.
[1]White-Gilbertson S, Davis M, Voelkel-Johnson C, Kasman LM. Sex differences in the MB49 syngeneic, murine model of bladder cancer. Bladder (San Franc). 2016;3(1):e22.
Note: Studies were performed in accordance with applicable animal welfare regulations in an AAALAC-accredited facility