Abstract

Background

Cancer immunotherapy has revolutionized treatment options for patients suffering from immunogenic tumors, among them melanoma, bladder and lung cancer. In the context of colorectal cancer (CRC), the administration of checkpoint inhibitors (CPIs) was shown to induce durable clinical responses in patients with mismatch repair deficient and microsatellite instable tumors, a though very small fraction of all CRC subtypes. To ameliorate response rates in metastatic CRC, various therapeutic strategies are currently being investigated to increase the immunogenicity of mismatch repair proficient (pMMR)/ microsatellite stable (MSS) CRC tumors and to set the ground for immunotherapy. Several conventional therapies approved for treating CRC patients are classified as immunogenic cell death inducers and may aid in priming cytotoxic T cells to the patient’s tumor.

Methods

At 2cureX, we aim to pre-therapeutically measure the potential responsiveness of a CRC patient to various drug therapy options to support the oncologists in identifying the best suitable treatment regimen. Our functional IndiTreat® assay system allows for testing of chemotherapeutic agents, targeted therapies and combinations thereof against micro-tumors (tumoroids), which we derive from CRC tissue or liver metastases. To broaden the applicability of the IndiTreat® test, the present study aims to adapt the assay system to functional testing of checkpoint inhibitors in the context of pMMR/MSS CRC, subsequent to standard of care therapy.

Results

To assess the potential efficacy of IO interventions for individual patients, we co-culture tumoroids and (in vitro expanded) autologous PBMCs and monitor immune-mediated killing of tumoroids in the presence of CPIs. Tumoroids recapitulate the highly individual disease of cancer patients and constitute a valuable platform for evaluating different aspects of immune-mediated tumor cell recognition and killing.

Conclusion

In vitro testing of individual responses to CPIs will be of key relevance for stratifying pre-treated pMMR/MSS CRC patients according to their likelihood to benefit from IO therapy and holds the potential to make these powerful drugs available to more patients suffering from CRC.

Legal entity responsible for the study

The authors.

Funding

2cureX, BMBF KMU-innovativ.

Disclosure

T. Sturmheit: Full / Part-time employment: 2cureX. T. Sutus Temovski: Full / Part-time employment: 2cureX. J. Thastrup: Full / Part-time employment: 2cureX. W. Fiedler: Advisory / Consultancy, Research grant / Funding (self), Licensing / Royalties: Amgen; Advisory / Consultancy: ARIAD/ Incyte; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Jazz Pharmaceuticals; Research grant / Funding (self): Pfizer. J. Wellbrock: Licensing / Royalties: Amgen. J. Kupper: Full / Part-time employment: 2cureX. A. Block: Research grant / Funding (self): 2cureX . All other authors have declared no conflicts of interest.

中文翻译：

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165P对结肠直肠癌患者免疫检查点抑制的患者特异性反应的治疗前评估

抽象的

背景

癌症免疫疗法彻底改变了患有免疫原性肿瘤（包括黑素瘤，膀胱癌和肺癌）的患者的治疗选择。在结直肠癌（CRC）的情况下，显示出检查点抑制剂（CPIs）的使用可在错配修复缺陷和微卫星不稳定肿瘤（尽管占所有CRC亚型的一小部分）中诱导持久的临床反应。为改善转移性CRC的应答率，目前正在研究各种治疗策略，以提高错配修复熟练（pMMR）/微卫星稳定（MSS）CRC肿瘤的免疫原性，并为免疫治疗奠定基础。

方法

在2cureX，我们的目标是预先治疗性评估CRC患者对各种药物治疗方案的潜在反应性，以支持肿瘤科医生确定最佳的治疗方案。我们功能强大的IndiTreat®检测系统允许针对源自于CRC组织或肝转移瘤的微肿瘤（类肿瘤）测试化学治疗剂，靶向疗法及其组合。为了扩大IndiTreat®检测的适用性，本研究旨在使检测系统适应pMMR / MSS CRC背景下的检查点抑制剂的功能检测，随后成为护理治疗标准。

结果

为了评估IO干预对个别患者的潜在疗效，我们共培养类肿瘤和（体外扩增的）自体PBMC，并在存在CPI的情况下监测免疫介导的类肿瘤杀灭。拟态肿瘤概括了癌症患者的高度个体化疾病，并构成了评估免疫介导的肿瘤细胞识别和杀伤的不同方面的宝贵平台。

结论

根据CPI治疗的可能性，对个体对CPI的反应进行体外测试对于分层治疗的pMMR / MSS CRC患者至关重要，这有可能使更多的CRC患者可以使用这些有力的药物。

负责研究的法人实体

作者。

资金

2cureX，BMBF KMU创新。

揭露

T. Sturmheit：全职/兼职：2cureX。T. Sutus Temovski：全职/兼职：2cureX。J. Thastrup：全职/兼职：2cureX。W. Fiedler：咨询/顾问，研究补助金/资金（自己），许可/特许权使用费：Amgen；咨询/顾问：ARIAD / Incyte；咨询/顾问：诺华；咨询/顾问：辉瑞；咨询/顾问：爵士药业；研究资助/资助（个体经营）：辉瑞公司。J. Wellbrock：许可/特许权使用费：Amgen。J. Kupper：全职/兼职：2cureX。A.部门：研究资助/资助（自己）：2cureX。所有其他作者都声明没有利益冲突。