Radiation and CSPG4-specifc CAR T cell based combinatorial therapy for the in vivo treatment of TNBC

项目总结/摘要 三阴性乳腺癌（TNBC）的有效治疗选择由于化疗和化疗而缺乏。 新靶向疗法的辐射抗性和低治疗功效。由于这些令人失望的 临床结果，我们已经评估了CSPG 4特异性嵌合体的潜在治疗临床应用， 抗原受体（CAR）T细胞为基础的治疗TNBC。CSPG 4已被选为目标， 因为这种肿瘤抗原（TA）在约70%的原发性和转移性TNBC肿瘤中表达。此外，委员会认为， CSPG 4在TNBC癌症起始细胞（CIC）上表达，其被认为在肿瘤的转移中起作用。 传播和疾病复发是患者发病和死亡的两大原因。最后，CSPG 4 除了肿瘤微环境（TME）中的活化周细胞外，在正常细胞上检测不到。 我们已经表明，CSPG 4 CAR T细胞在消除分化的TNBC细胞和TNBC CIC中是有效的。 在体外，它们不能完全根除移植在免疫缺陷小鼠中的TNBC肿瘤。这种差异 可能反映了TME对CSPG 4特异性CAR T细胞-TNBC细胞相互作用的负面影响以及TME对CSPG 4特异性CAR T细胞-TNBC细胞相互作用的不良影响。 肿瘤的T细胞浸润。为了消除这些阻碍CAR T细胞疗法成功应用的障碍， 我们将联合收割机CSPG 4特异性CAR T细胞与辐射结合。这种组合策略是基于我们的 结合文献中的信息，初步结果表明，肿瘤放射可以 增强CSPG 4特异性CAR T细胞与TNBC细胞的抗肿瘤活性。这种影响似乎是 通过多种机制介导，其中，TNBC细胞上CSPG 4表达的显著上调， 调节参与细胞凋亡的分子以及增加T细胞浸润和持续性似乎是 涉案该提案的具体目的是i）评估肿瘤放射是否增强了 CSPG 4特异性CAR T细胞根除在NRG小鼠中原位移植的人TNBC细胞，和ii）评估 CSPG 4特异性CAR T细胞与CSPG 4特异性CAR T细胞的组合的能力增加的分子机制 放射以根除在NRG小鼠中原位移植的人TNBC细胞。这些结果将有助于 优化用于治疗TNBC的组合辐射和基于CSPG 4特异性CAR T细胞的策略。

Project Summary/Abstract Effective treatment options for triple negative breast cancer (TNBC) are lacking due to chemotherapy and radiation resistance and low therapeutic efficacy of novel targeted therapies. Because of these disappointing clinical results, we have assessed the potential therapeutic clinical application of a CSPG4-specific chimeric antigen receptor (CAR) T cell-based therapy for the treatment of TNBC. CSPG4 has been selected as the target, since this tumor antigen (TA) is expressed in about 70% of primary and metastatic TNBC tumors. Furthermore, CSPG4 is expressed on TNBC cancer initiating cells (CICs), which are believed to play a role in metastatic spreading and disease recurrence, the two major causes of patients' morbidity and mortality. Lastly, CSPG4 is not detectable on normal cells with the exception of activated pericytes in the tumor microenvironment (TME). We have shown that CSPG4 CAR T cells are effective in eliminating differentiated TNBC cells and TNBC CICs in vitro, but are not able to completely eradicate TNBC tumors grafted in immunodeficient mice. This discrepancy may reflect the negative impact of TME on CSPG4-specific CAR T cell-TNBC cell interactions as well as poor T cell infiltration of the tumor. To counteract these obstacles to the successful application of CAR T cell therapy, we will combine CSPG4-specific CAR T cells with radiation. This combinatorial strategy is based on our preliminary results, which in combination with the information in the literature show that tumor radiation can enhance the antitumor activity of CSPG4-specific CAR T cells with TNBC cells. This effect appears to be mediated by multiple mechanisms, of which, a significant upregulation of CSPG4 expression on TNBC cells, modulation of molecules involved in cell apoptosis and increased T cell infiltration and persistence seem to be involved. The specific aims of this proposal are to i) evaluate whether tumor radiation enhances the ability of CSPG4-specific CAR T cells to eradicate human TNBC cells orthotopically grafted in NRG mice and ii) assess the molecular mechanism(s) underlying the increased ability of CSPG4-specific CAR T cells in combination with radiation to eradicate human TNBC cells orthotopically grafted in NRG mice. These results will contribute to optimize a combinatorial radiation and CSPG4-specific CAR T cell-based strategy for the treatment of TNBC.