OUR RESEARCH
Our laboratory is focused on translational immunotherapy research for primary liver cancers, including hepatocellular carcinoma (HCC), cholangiocarcinoma, and fibrolamellar hepatocellular carcinoma (FLC). Progress in liver cancer has lagged some other tumor types, and the prognosis of liver cancers remains poor. Until we eliminate suffering and death due to liver cancer, we are 100% dedicated to studying the diverse aspects of liver cancers in the lab and in the clinic. Using preclinical models and human clinical trial biospecimens, we are developing novel therapeutic combinations to overcome resistance to immune checkpoint inhibitor therapy in liver cancers. Our research is translational and highly collaborative: We work closely with Drs. Elizabeth Jaffee and Dan Laheru (co-leaders of the GI cancer program at Johns Hopkins), Nilo Azad (an expert in early stage clinical trials and cholangiocarcinoma immunotherapy), Elana Fertig and Luciane Kagohara (bioinformatics), Neeha Zaidi (neoantigen vaccines), and Won Jin Ho (novel technologies to interrogate the tumor immune microenvironment).
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B CELL BIOLOGY
Novel immunotherapies that modulate T cell function are firmly established as a pillar of cancer therapy, whereas the potential for B cells in the anti-tumor immune response is not well established. We and others have observed that B cell activation and trafficking to the tumor microenvironment is a feature of response to immune checkpoint inhibitor therapy. We are studying how B cells contribute to the antitumor immune response, and whether they can be directly targeted to augment antitumor immunity.
EPIGENETIC THERAPIES
We seek to understand the mechanisms through which epigenetic therapies modulate the immune system’s interaction with liver cancers, and to investigate the potential for synergy between epigenetic therapies and other treatments that work on the immune system. This work is done collaboratively with Dr. Nilo Azad M.D., an expert in epigenetic therapies and cholangiocarcinoma immunotherapy who currently leads multiple clinical trials of epigenetic therapy in patients.
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MOLECULARLY TARGETED THERAPIES
Molecular targeted therapies have complex effects on tumor cells as well as direct effects on immune cell populations. Understanding the diverse effects of molecularly targeted therapies can enable the development of rational combination therapy between targeted therapies and systemic immunotherapies. A major focus of this work has been to determine the effects of RAS pathway activation or inhibition on the tumor immune microenvironment.
NEOANTIGEN FEATURES AND NEOANTIGEN-SPECIFIC VACCINES
Neoantigens are abnormal proteins not found on normal host cells, and their selective expression on tumors may allow them to be recognized as “non-self” by the host immune system, thereby inducing anti-tumor immunity. In 2014, a chimeric transcript between DNAJB1, a homolog of the molecular chaperone DNAJ, and PRKACA, the catalytic domain of protein kinase A, was identified as the signature genetic event of FLC, providing new opportunities for therapeutic development. We are investigating whether it is possible to target the DNAJB1-PRKACA chimeric transcript in FLC using a vaccine specific for the abnormal protein resulting from this fusion event. We are also studying the use of neoantigen-specific vaccines for other forms of liver cancer, and identifying genomic features of neoantigens that make them more or less suitable for immune targeting.