Dr. Bakalar is developing new methods to discover the millions of interactions between T-cell receptors and foreign antigens that trigger an immune response. In many cancers, such as metastatic melanoma, immunotherapy depends on the ability of T cells to recognize and respond to tumor-specific neoantigens—new proteins found on cancer cells, which let the immune system know that these are not normal cells. Collecting the data on this relationship can help create computational models to predict the antigen-target of a patient’s individual T cell receptor, which could then guide the design of patient-specific cancer vaccines and engineering of new, tumor-targeting T cells.

Immunotherapies that rely on reinvigorating T cells to patrol the body, detect cancerous cells and eliminate them have shown the potential for long-lasting cures. Despite their initial success, immunotherapies have been effective only for some cancers and for some patients. To improve outcomes, Dr. Birnbaum has developed a new method to match T cells with their antigen targets on cancer cells by engineering viruses to use T cell recognition as a means of cell entry. This technology will be applicable to a wide range of cancers, including ones for which immunotherapy is not currently effective.

Squamous cell carcinoma (SCC) can occur on a number of epithelial surface tissues ranging from the skin and lung to the esophagus and oropharynx, and collectively, are the most common form of cancer in the world. Recent sequencing studies have found that mutations in epigenetic regulators that control gene expression frequently occur in all forms of SCC. Dr. Capell aims to harness the great accessibility of human skin to understand how altered epigenetics promotes cutaneous SCC. Given that epigenetic changes are inherently reversible and numerous epigenetic drugs are currently in development, he hopes that by understanding these mechanisms he will identify better therapies for these incredibly common and potentially deadly cancers.

Dr. Chudnovskiy studies “antigen presentation,” an immune process by which dendritic cells capture antigens at the tumor site, migrate to the tumor-draining lymph nodes, and present tumor antigens to the effector CD4 and CD8 T cells that are responsible for anti-tumor responses. This is the first crucial step in successful cancer immunotherapy.

Immunotherapy has resulted in positive outcomes for patients with melanoma, lung cancer, and other malignancies; however, most patients do not have meaningful responses to this treatment strategy. Tumors that fail to respond to immunotherapy have effectively hidden themselves from detection by the host immune system. Understanding how cancers create an immune-excluded environment promises to lead to the development of more highly effective immunotherapies. Dendritic cells (DCs) play a central role in orchestrating the immune response to cancers by enabling T cells to “see” and destroy cancerous cells. Previous work has shown that melanomas secrete a protein called Wnt5a that potently suppresses DC function and ultimately contributes to the development of immunotherapy resistance. Dr. DeVito will examine certain tumor signaling pathways that have been implicated in driving Wnt5a production and facilitating cancer spreading by suppressing DC function within nearby draining lymph node tissues, which are critical for generating immune responses capable of destroying developing cancers. These studies will further investigate the ability of Wnt5a inhibition to sensitize cancers that are typically resistant to immunotherapy strategies. In addition, he is conducting a clinical trial to determine if the activation of these pathways correlates with immunotherapy failure in melanoma patients. He anticipates that better characterization of pathways that cancers utilize to suppress DC function to thus shut down the immune response will lead to the discovery of novel, more effective immunotherapy strategies, and may identify biomarkers that will improve selection of tailored immunotherapies for specific cancer patients.

Dr. Dong studies how injury and pathogen invasion trigger a chain of inflammatory and repair responses that restore the damaged tissue. Defects in wound repair result in painful, non-healing ulcers that frequently affect aged individuals and diabetes patients. Malignant tumors are particularly severe complications, which often occur at sites of repetitive irritation and chronic wounds. She is investigating the roles of anti-microbial peptides during inflammation and wound healing, and hopes that these studies will provide insights about the cause and prevention of various carcinomas.

Immunotherapy drugs, which spur the body's own immune system to attack tumors, hold great promise but still fail in many patients. Dr. Griffin aims to identify therapeutic targets that can enhance the efficacy and scope of immunotherapy in melanoma and other cancer types. His unique approach focuses on retrotransposons, repetitive sequences of DNA that are evolutionary remnants of viruses and comprise upwards of 50% of the human genome. These genetic elements are usually silenced via DNA methylation but can activate an immune response at certain times. Dr. Griffin’s research will characterize the epigenetic pathways that silence these repetitive elements in cancer cells, thus helping tumors evade surveillance by the immune system. This basic understanding may guide the development of epigenetic therapies capable of triggering anti-tumor immunity.

Dr. Insco studies advanced melanoma. Melanoma initiation and drug resistance rely heavily on factors that control gene expression. Proteins called Cyclin Dependent Kinases (CDKs) show promise as drug targets in multiple difficult-to-treat cancers and are enabling a method to “drug” the previously “undruggable” process of gene expression. She aims to determine whether any of the transcriptional CDKs could be an effective drug target in advanced melanoma. 

Squamous cell skin cancer or cutaneous squamous cell carcinoma (cSCC) is the second most common cancer in the United States. In cases when the tumor cannot be surgically removed, treatment options are limited. Dr. Ji is focusing on intratumoral heterogeneity, the diversity of cell types and tumor cell subpopulations that characterize these tumors. Current cSCC treatments do not effectively target all subpopulations within a tumor, which leads to survival of some cancer cells and therapeutic resistance. He aims to understand how intratumoral heterogeneity arises within cSCC tumors, focusing on how cell-cell communication within the tumor microenvironment influences this process. This research may guide the development of improved treatment strategies.

Immune checkpoint inhibitors, a standard of care for metastatic melanoma, release the brakes on a patient's T cells, so they can attack a tumor. Some patients, however, relapse when resistance to treatment occurs. Dr. Kalbasi will lead a clinical trial to test a new immunotherapy treatment approach for patients with this deadly skin cancer, who did not respond to standard therapies. He will identify patients whose melanoma tumor cells express a protein called IL13R2. He will then collect the patient's immune T cells, engineer them to identify tumor cells that express the protein and reinfuse the T cells to kill tumor cells inside the patient. In contrast to immune checkpoint inhibitors that require regular intravenous doses, these engineered chimeric antigen receptor (CAR) T cells are a one-time treatment that theoretically protect the body for life. This clinical trial may also offer insights on how CAR T therapy overcomes tumor resistance mechanisms to treat patients with metastatic melanoma.