9P - Primary NSCLC patient-derived microtumors (PMTs) for clinical-relvant prediction of immunotherapy efficacy

Background

Although the establishment of checkpoint inhibitors (CPIs) has shown great success in the treatment of cancer patients, a significant number of patients do not respond to it. This demonstrates the highly individualized nature of patient response to therapy, highlighting the need of a more tailored therapeutic approach. To this end, we have developed a functional 3D in vitro model, generated directly from primary tumor to evaluate personalized therapy options in a clinically relevant manner to improve outcome prediction.

Methods

Freshly resected NSCLC tumor material from 20 patients with different TPS Scores was mechanically and enzymatically digested to obtain a single cell suspension. PMTs were then generated by seeding the suspension into ultra-low attachment plates, preserving the original cell composition, which was characterized prior to drug administration after six days of tissue maturation. In addition to treating PMTs with CPIs, combinations with chemotherapies were applied. The dynamic drug response was monitored over 14 days, using bright field imaging. Further analysis of the drug response was performed by cytokine release as well as bulk RNA sequencing.

Results

To test immune modulators in vitro, it is necessary to preserve the immune compartment of the original tumor. FACS data confirmed, that during the maturation process of the NSLCL microtumors and beyond, the original cell compartments, including the various immune cell populations were largely preserved. Overall, the clinical routine categorized objective response rates reflected the clinical outcome distribution. In addition, immunotherapy treatment resulted in characteristic cytokine release and gene-pathway up/down regulation as a proof of concept to build a HUMAN LUNG CANCER RESPONSOME database linking a wide range of patient-specific functional outcomes with in-depth changes in individual pathways.

Conclusions

The present PMT model in combination with a clinically relevant drug response analysis is one of the first to show the typical immunotherapy-dependent alteration of TME as well as immunotherapy-induced cancer cell death in a scalable long-term in vitro assay.

Legal entity responsible for the study

A. Amann.

Funding

PreComb Therapeutics AG.

Disclosure

All authors have declared no conflicts of interest.