gms | German Medical Science

Introduction: Patient stratification for therapeutic response mainly focus on biomarker expression on cancer cells. Contrary, the tumor micromileu is less considered, although stromal cells and leukocytes play a crucial role in tumor progression and drug resistance. The present study investigates the impact of tumor infiltrating lymphocytes on Catumaxumab efficacy in CRC.

Material and methods: Fresh tumor samples from 27 CRC patients were used to prepare tumor spheroids. Autologous PBMCs were isolated by ficoll density gradient. Tumor spheroids co-cultured with or without PBMCs were treated with Catumaxumab for 96h. The cellular composition of the spheroids and the therapeutic impact on epithelial cells and leukocytes were measured by FACS analysis. The metabolic activity of the co-cultures was determined by the ATP assay.

Results: Similar to their original cancers all spheroid models consisted of a sufficient high fraction of EpCAM positive tumor cells indicating CRC an appropriate cancer type for Catumaxumab therapy. In contrast, the fraction of CD45 positive leukocytes in spheroids was low mimicking the parental tumors. The effector cell to target cell (E:T, CD45 : EpCAM) ratio ranged from 0,05:1 to 1,92:1. Treatment of these spheroids with Catumaxumab revealed no significant therapeutic effect. Addition of patient specific PBMCs changed the E:T ratio up to 7:1 and had a significant impact on antibody efficacy. Catumaxumab induced cell death was found up to 52% (p=0,015) depending on the individual E:T ratio. After Catumaxumab treatment co-cultures demonstrated metabolic stimulation underlining the functionality of the leukocytes.

Conclusion: A dual biomarker system is required to select appropriate CRC patients for Catumaxumab treatment. EpCAM expression on cancer cells is required, but the leukocyte infiltrate is the key predictor for the therapeutic response of Catumaxumab. Both extent and functionality of the tumor infiltrating leukocytes have to be determined in the individual tumor sample for targeted therapy using Catumaxumab.