Biomarkers and Therapeutic Targets in Tumor Microenvironment and Metastasis

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Cancer is a complex multicellular process that involves both genetic alterations leading to unique clonal populations and key interactions with its local and distant microenvironment to allow for growth and survival. Metastasis the process of cancer cell spread and growth at sites distant from the primary tumor is particularly dependent on microenvironmental changes. We have uncovered the essential changes in the microenvironment during metastatic progression. The processes we identified are recruitment of bone marrow derived myeloid cells that suppress anti-tumor immunity and the preceding vascular changes, stromal cell activation and extracellular matrix remodeling. The myeloid cell recruitment is localized to specific sites based on changes in vascular permeability and extracellular matrix that create angiocrine signals and a repair response that provide growth and survival signals that elicit myeloid cell recruitment. Our lab has identified key microenvironmental events in metastatic murine models. We have used this timeline and mapping of key microenvironmental changes essential for metastatic progression to use these models to test cell therapy based on microenvironmental modulation. More recently we have begun investigations in human metastatic microenvironment. We have performed single cell sequencing on metastatic lung and liver and tissue from lung and liver without obvious cancer in patients with metastatic cancers. These studies have provided new insights into pivotal microenvironmental changes that are a result of systematic changes coordinated across multiple cell types to promote cancer progression. This coordinated process with changes across cell compartments was conserved across multiple cancer types and across metastatic sites. Using new machine learning technologies, we have found a core set of genes that can predict metastasis based on changes in tumor free tissues that are near to these cancers. These results were intriguing because the changes in the microenvironment including immune cells, stromal cells and endothelial cells we found was more pronounced in these tissues that were free to tumor cells than those in the primary tumor or metastatic cancer. These gene score is highly predictive of outcome and can help to prevent patients at lower risk for metastasis to receive unnecessary treatment or patients that are deemed at high risk for metastasis at risk of getting insufficient or ineffective therapy and therefore opens the door to improving stratification for patients at risk for cancer and also opportunity to develop therapies that can reverse these coordinated changes essential to metastasis to improve clinical outcomes. Current investigations in our laboratory are focused on examining the mechanisms of inducing this coordinated program and developing cell therapy based microenvironmental modulation that can be effectively reverse these changes by activating a shift from an immune suppressive program to an immune activated one to induce anti-tumor immunity as well as remodel the extracellular matrix improving drug efficacy and cell trafficking. Myeloid cells are abundant in cancers and yet their functional role remains underappreciated and not well understood. Our research program is delineating the behavior and function of myeloid cells in cancer. Utilizing both quantification and functional assays, including flow cytometry and immune suppression and phagocytosis/trogocytosis assays, we are assessing the circulating bone marrow-derived myeloid cell populations in pediatric and adult patients with malignancies. We have recently performed genetic screens of myeloid functional assays to determine the key drivers of these myeloid functional processes. We have recently leveraged the data we have generated from our first clinical trial of chimeric antigen receptor T cells targeting GD2 in patients with osteosarcoma and neuroblastoma. This collaboration with Dr. Lynn Hedrick and team now at University of Georgia and Dr. Mackall and team at Stanford has allowed deep transcriptomic, mass cytometry and epigenetic investigations into immune response in patients on CART trial. We found that myeloid cells are key regulators of the CART cells. We have found that myeloid cells depending on the subpopulations and their receptors can be helpful in promoting effective anti-tumor immunity and conversely myeloid subpopulations can also limit CART expansion. These studies speak to the diversity of myeloid populations and their functions and importance of studying these aspects. These investigations are shaping a new understanding of myeloid mediators of CART expansion and may ultimately impact efficacy and serve as a path to combine myeloid and T cell based therapies. Furthermore, myeloid markers of CAR efficacy will be further explored in our current GD2 CART PERSIST trial. Capitalizing on the findings of CXCR3 on myeloid cells and epigenetic markers of T cell and myeloid cells will be investigated in our current correlative studies in solid tumor CART cell trials. We have on-going investigations to explore circulating monocytes and monocyte function and the impact on metastatic risk. Our new on-going multisite clinical trial of GD2 CART PERSIST trial provides new investigations into myeloid biology and its impact on CART cell function in solid tumors. We are actively examining CART cell efficacy and the combination with myeloid modulating therapies to improve responses in metastatic solid tumors. Our recent studies have highlighted the role of both tumor cell and microenvironmental cell plasticity whereby changes promote cancer progression. We also now have evidence that tumor associated fibroblast activation and extracellular matrix deposition are essential for tumor recurrence. We are using different investigational agents to determine their specific impact on each microenvironmental cell. We have preclinical studies that harness mesenchymal cell plasticity and function to modulate metastatic microenvironment. We have developed using genetic engineering to modify extracellular matrix remodeling in mesenchymal cells that have matrix remodeling as the main functionality. We use our established models of metastasis that have an intact immune system. These studies have shown efficacy alone and in combination with chemotherapy highlighting strategies to rebalance the altered cancer microenvironment hold promise as an adjunct therapeutic approach. On the clinical research side, we have several active clinical trials open and in development and have been working hard on correlative studies with reverse engineering to understand which patients respond and which do not and why in order to make our therapies better. We have the only pediatric study for tenosynovial giant cell tumor and have learned a great deal about this sarcoma through the trial and the correlative studies. We are also investigating many T cell based therapies in solid tumors and in myeloid malignancies. We have recently developed a new trial to modulate the myeloid mediated immune suppressive environment. We have developed a new cell therapy based on genetically engineering myeloid cells (GEMys) that can serve as delivery vehicles given their propensity to accumulate in tumor and metastatic sites. These cells can be engineered to deliver Il12 into the tumor milieu and reprogram multiple cell types, change gene transcriptional signatures and reverse immune suppression and enhance anti-tumor immunity. We have developed humanized murine systems to examine human cell therapy with advanced human tumors. We developed a new human cell therapy and show these therapies can have curative effects in preclinical models. Recently we have developed an IND package for human IL12 GEMys for FDA submission and are planning to open a clinical trial by end of year.