Projects

Dr. Doug Hanahan at the Ludwig Branch at Lausanne and the Swiss Cancer Center Leman is leading a project to better understand determinants of therapeutic response in melanoma. These studies focus on genetically-engineered mouse models (GEMM) of melanoma and human samples from clinical trials. Melanomas carrying mutations in the BRAF kinases are initially responsive to treatment with BRAF/MEK inhibitors but resistance frequently arises both in human patients and mouse models. In GEMMs resistance is driven by a specific modification in a transmembrane receptor. Understanding the mechanisms of resistance may provide new avenues for increasing the durability of response to existing therapies.

This project, led by Dr. George Coukos at the Ludwig Branch at Lausanne and the University of Lausanne, focuses on understanding how ovarian cancers evade detection by the immune system. The goal is to develop new drugs, combination of existing drugs, and predictive biomarkers that enable the use of immunotherapy in ovarian cancer and achieve long-term remission in patients. In the first phase of this work we have found that tumor infiltrating lymphocytes engaged by cognate antigen upregulate PD-1, which restrains their effectiveness. These cells receive CD28 co-stimulation in distinctive intraepithelial niches where they express a range of TCR-engaged and exhausted states. Following PD-1 blockade (with therapeutic antibodies), activation of TILs still requires CD28 co-stimulation. Exhausted TILs, in a state of TCR engagement but without proper CD28 co-stimulation by antigen presenting cells do not fully benefit from PD-1 blockade.

Dr. Tyler Jacks at the Ludwig Center at MIT is leading a project using multiplexed tissue imaging to develop high-definition spatial maps of tumor-immune interactions in genetically-engineered mouse models of lung and pancreatic cancer. These innovative experimental models recapitulate the type of crosstalk that is common in tumor formation, with tumor cells under pressure to develop avoidance strategies that permit evasion from immune cell attack. In-depth analysis of murine models of cancer is needed to develop an understanding of the mechanisms that shape the tumor microenvironment; only animal models have the necessary manipulability and reproducibility for causal, mechanistic studies.

Dr. Akash Patnaik at the Ludwig Center at the University of Chicago is focused on understanding why only ~10-25% of metastatic, castrate-resistant prostate cancer (mCRPC) patients respond to therapies targeting immune checkpoint proteins such as CTLA-4, PD-1 and PD-L1. The reasons for this are thought to lie in the composition and organization of the tumor immune microenvironment. The properties of the tumor micro-environment primary versus in metastatic prostate cancer are therefore being studied to better understand how tumor-immune interactions change as a function of disease progression. We hope that this will lead to discovery of new resistance mechanisms and targets for therapeutic intervention.

Over a dozen investigators at the Ludwig Center at Harvard are using spatial profiling methods to study the molecular and cellular determinants of drug resistance in solid tumors. Despite extraordinary advances in cancer therapeutics, most patients eventually relapse and succumb to disease due to the development of drug resistance. The problem of resistance is complicated by tumor heterogeneity both within an individual tumor and among tumors located at different sites in the same patient. Tumors and their microenvironments are also plastic, changing through the course of disease and in response to drugs. Spatial profiling of human specimens acquired in the course of patient care and research clinical trials provides a unique opportunity to better understand how heterogeneity at different spatial scales promotes drug resistance.