Abstract

Background

Glioblastoma (GBM) is a highly malignant brain tumour with no curative treatments. Immunotherapies, including immune checkpoint inhibitors (ICI) are under clinical evaluation, but have not yet been proven to have major impact. The low immune infiltration and modest mutational load of most GBM suggest that combination therapies will be required to improve sensitivity to immunotherapies.

Methods

Two mouse GBM models were used, the immunogenic GL261 and the stringent, less mutated SB28. A novel, brain-penetrant, microtubule-targeting agent, BAL101553 (BAL) which induces tumour cell death through activation of the spindle assembly checkpoint, and an agonistic anti-CD40 antibody were combined with ICI (antibodies targeting PD-1 and CTLA-4) to evaluate potential therapeutic synergy. Tumours were analyzed molecularly (mutations, transcriptional profiling) and immunologically (immune infiltration, therapy response in T/B-cell deficient mice).

Results

Well-tolerated combination therapies that significantly enhanced survival were identified in both SB28 and GL261 GBM models. The aggressive SB28, most representative of untreated human GBM, was most responsive to BAL combined with anti-CD40 (median survival in days: vehicle=27, anti-CD40=29, BAL=42, BAL/CD40=49); this effect was found to be T-cell independent as a similar result was observed in SB28 glioma-bearing immunodeficient (RAG1 KO) mice. The immunogenic GL261 model was, as predicted, responsive to ICI; it was relatively insensitive to BAL and anti-CD40 monotherapies but responsive to a combination of these two treatments (median survival in days: vehicle=28, anti-CD40=30, BAL=33, BAL/CD40=40).

Conclusion

Combination GBM therapies that include immunomodulation will likely require selection of patients according to immunological characteristics. Most clinical exploration of immunomodulators focusses on enhancing T-cell mediated anti-tumour immunity but our data suggest that synergistic combination of a tumour checkpoint controller and immunostimulation can be appropriate for poorly immunogenic GBM that is refractory to T-cell control.

Legal entity responsible for the study

The authors.

Funding

Basilea Pharmaceutica Ltd.

Disclosure

P. McSheehy: Shareholder / Stockholder / Stock options, Full / Part-time employment: Basilea Pharmaceutica Ltd.. F. Bachmann: Shareholder / Stockholder / Stock options, Full / Part-time employment: Basilea Pharmaceutica Ltd.. H. Lane: Shareholder / Stockholder / Stock options, Full / Part-time employment: Basilea Pharmaceutica Ltd.. P.R. Walker: Advisory / Consultancy, Research grant / Funding (self): Basilea Pharmaceutica Int. Ltdtd. All other authors have declared no conflicts of interest.

中文翻译：

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115P结合肿瘤检查点控制器BAL101553（利沙万星）和免疫调节在两种免疫状态不同的小鼠神经胶质瘤模型中的治疗功效

抽象的

背景

胶质母细胞瘤（GBM）是一种高度恶性的脑肿瘤，无需治疗。包括免疫检查点抑制剂（ICI）在内的免疫疗法正在临床评估中，但尚未证明有重大影响。大多数GBM的低免疫浸润和适度的突变负荷表明，将需要联合疗法来提高对免疫疗法的敏感性。

方法

使用了两种小鼠GBM模型，即免疫原性GL261和严格的，突变少的SB28。一种新型的脑渗透微管靶向剂BAL101553（BAL）通过激活纺锤体装配检查点诱导肿瘤细胞死亡，并将激动性抗CD40抗体与ICI结合（靶向PD-1和CTLA-4的抗体）以评估潜在的治疗协同作用。对肿瘤进行分子分析（突变，转录谱分析）和免疫学分析（免疫浸润，T / B细胞缺陷小鼠的治疗反应）。

结果

在SB28和GL261 GBM模型中均发现了耐受性良好的联合疗法，可显着提高生存率。侵略性SB28，最能代表未治疗的人GBM，对BAL与抗CD40联合治疗最有反应（中位生存期：媒介物= 27，抗CD40 = 29，BAL = 42，BAL / CD40 = 49）；发现这种作用与T细胞无关，因为在带有SB28胶质瘤的免疫缺陷（RAG1 KO）小鼠中观察到了相似的结果。如预期的那样，具有免疫原性的GL261模型对ICI有反应；它对BAL和抗CD40单一疗法相对不敏感，但对这两种疗法的组合有反应（中位生存期：媒介物= 28，抗CD40 = 30，BAL = 33，BAL / CD40 = 40）。

结论

包括免疫调节在内的GBM联合治疗可能需要根据免疫学特征选择患者。免疫调节剂的大多数临床研究都集中在增强T细胞介导的抗肿瘤免疫力上，但我们的数据表明，肿瘤检查点控制器和免疫刺激的协同组合可适用于难治性T细胞控制的免疫原性较差的GBM。

负责研究的法人实体

作者。

资金

Basilea Pharmaceutica Ltd.

揭露

P. McSheehy：股东/股东/股票期权，全职/兼职：Basilea Pharmaceutica Ltd.。F. Bachmann：股东/股东/股票期权，全职/兼职：Basilea Pharmaceutica Ltd .. H. Lane：股东/股东/股票期权，全职/兼职：Basilea Pharmaceutica Ltd.。PR Walker：咨询/顾问，研究补助金/资金（自己）：Basilea Pharmaceutica Int。Ltdtd。所有其他作者都声明没有利益冲突。