Accurately evaluating immuno-oncology therapeutics in pre-clinical models presents a significant technological challenge in translational oncology. Both human organoid models and humanized mouse models fail to recapitulate the complexity of the cancer tumor microenvironment found in the patient. Multiple stromal components such as immune cells, fibroblasts, blood vessels, and even bacteria have been shown to affect tumor response to treatment, suggesting the need for their inclusion and faithful reconstruction in pharmacological development.
To overcome these challenges, we have made use of a recently developed novel immune-competent ex vivo organ culture (EVOC) assay to evaluate the activity of CD3-based T-Cell Bispecific Antibodies (TCBs). In particular, we assessed the anti-tumor effects of a CEACAM5 TCB, which is designed to simultaneously bind CEA-expressing cancer cells and CD3-expressing T cells, activating the latter. Fresh tissues obtained during resection of NSCLC, CRC and PDAC tumors, were sliced and cultured ex vivo. The cancer tissue and microenvironment, including endothelial and immune cells, was preserved at high viability for 5 days. We then evaluated cytokine secretion in the assay after 24 and 48 hours.
We found robust expression of T-Cell specific activation markers in response to treatment with CEACAM5 TCB antibodies. NSCLC and CRC tissues with abundant T-cells showed significant cytokine over-expression, while PDAC with low T-Cell presence showed none. Notably, comparing the histology of the fresh sample with the treated sample after 5 days, showed T-Cell infiltration from the tissue periphery into the cancer foci, demonstrating the efficacy of the bispecific antibody to recruit T-cells to tumor cells.
These results show the applicability of our ex vivo organ culture to evaluate immune activating compounds and suggests the ability to use EVOC, in the future, as a predictive biomarker for TCB therapy.
The authors.
Curesponse Ltd. & F. La-Hoffman Roche.
A. Zundelevich, B. Ibrahim, L. Turovsky, S. Aharon, V. Bar: Financial Interests, Personal, Member: Curesponse. S. Salpeter, G. Neev: Financial Interests, Personal, Leadership Role: Curesponse. R. Straussman: Financial Interests, Personal, Advisory Board: Curesponse. I. Silva, S. Li, S. Herter, M. Bacac, S. Sadok, N. Gjorevski: Financial Interests, Personal, Member: Roche.