85P - Mechanistic divergence of immune checkpoint inhibition by an ex vivo platform derived from patient tumors where tumor and immune microenvironment i...

Date 08 December 2017
Event ESMO Immuno-Oncology Congress 2017
Session Lunch & Poster Display session
Topics Bioethics, Legal, and Economic Issues
Personalised Medicine
Presenter Manjusha Biswas
Citation Annals of Oncology (2017) 28 (suppl_11): xi6-xi29. 10.1093/annonc/mdx711
Authors M. Biswas1, N. Brijwani2, B. Balakrishnan3, O. Muthusamy1, S. Thiyagarajan4, D.G. Mehrotra1, B. Majumder4, P. Radhakrishnan5, P.K. Majumder5
  • 1Department Of Molecular Pathology, MITRA RXDX, 560099 - BENGALORE/IN
  • 2Department Of Cancer Biology Cancer Biology, MITRA RXDX, 560099 - BENGALORE/IN
  • 3Department Of Cancer Biology, MITRA RXDX, 560099 - BENGALORE/IN
  • 4R&d, Mitra RxDx, 560037 - Bangalore/IN
  • 5R&d, Mitra RxDx, 01801 - Woburn/US

Abstract

Background

In the rapidly changing landscape of immuno-oncology, matching right drugs with patients remains a critical challenge for informed treatment decision. Colorectal cancer (CRC) is one of the few cancers that maintain a robust tumor immune phenotypic signature, therefore, making the targeting with checkpoint inhibitors (CPI) more tractable. Although high mutational load usually orchestrates a successful response to multiple CPIs, the immune phenotypic underpinning of response profile needs further delineation of complex and dynamic microenvironment.

Methods

We evaluated thirty-one clinically advanced CRC in CANScriptTM platform that preserves the heterogeneity of dynamic tumor-immune interface in a personalized ex vivo setting (Majumder B et al Nature Commun, 2015). Freshly collected tumors from CRC patients were cultured in this platform for 3 days in presence of autologous PBMC. Tumor slices were treated with anti CTLA4 and PD1 inhibitors either as single agents or in combination. Comparative efficacy was evacuated based on a predictive score that informs response status using a panel of kinetic (viability, glucose, LDH release) and phenotypic changes. Modulation of critical markers like CD8, CD4, CD68, ICOS, PD1, PDL1, FOXp3, Ki67, IFN-g & granzymes were measured by IHC. The 3D mechanistic profiling of the On-Tx phenotypic modulation was performed using 7 color multispectral imaging technology.

Results

The mechanistic learning of tumor response to CPI revealed a preferential modulation of multiple effector functions and linked phenotypes, of which, increase in CD8 in tumor core and augmentation of granzymes were found to be more profound. M1 (CD8, Granzyme, IFN-g) and M2 paradigms (FOXP2, CD68) at baseline and post treatment also showed interesting shift, explaining the underlying response to specific inhibitors at individual levels.

Conclusions

Development of immune driven ex vivo functional phenotypic platforms that preserve clinical landscape of drug efficacy in multiple mechanistic fronts may redefine the selection of rational combinations based on individual profile of a complex, dynamic immune milieu in clinically challenging CRC.

Clinical trial identification

Not applicable

Legal entity responsible for the study

Mitra RxDx India Pvt Ltd

Funding

Mitra RxDx India Pvt Ltd

Disclosure

All authors have declared no conflicts of interest.