Pre-therapeutic Evaluation of Patient-Specific Responses to Immune-Checkpoint Inhibition in Colorectal Cancer

Abstract

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.