Unraveling the mechanisms of immune checkpoint dysfunction in cutaneous T cell lymphoma
Christiane Querfeld
PhD, MDBeckman Research Institute of the City of Hope
Project Term: July 1, 2018 - June 30, 2023
Cutaneous T-cell lymphoma (CTCL) is a disfiguring, incurable malignancy profoundly affecting patients’ appearances, quality of life, and relationships. Standard treatments only benefit 30% of patients with limited duration. Rather than focusing on the tumor alone, we target the adjacent tumor microenvironment, which nourishes tumor growth. We have begun a clinical trial of durvalumab, which is an inhibitor of the checkpoint protein receptor PD-L1. We are currently investigating how immune checkpoint proteins together with the immune booster lenalidomide affect CTCL growth. This research will benefit not only those with CTCL but many other cancers.
Cutaneous T-cell lymphoma (CTCL) is a type of non-Hodgkin lymphoma that originates in the skin. It is a disfiguring, incurable malignancy that also causes severe itching, profoundly affecting patients’ appearance, quality of life, and relationships. Those with advanced disease face a poor prognosis. Current therapies may prolong survival and improve outcomes for patients, but none constitutes a cure. Existing treatments for progressive disease are only helpful for about 30% of patients for a short duration (<6 months). As opposed to current standard treatment strategies, which focus on the tumor cells alone, my research addresses the complex network within the tumor microenvironment. The tumor microenvironment consists of the blood vessels, immune cells, and connective tissue cells that surround the tumor cells. An important part of that microenvironment are T cells, some of which normally attack tumor cells. However, in CTCL, the T cells become exhausted and can’t fight the tumor cells, because of the expression of inhibitory immune checkpoint proteins. These proteins are normally used by the body to prevent an overactive immune system. In CTCL, however, immune checkpoint proteins are out of balance and hamper the immune response, allowing the disease to persist. My laboratory is devoted to dissecting the critical components of immune suppression and developing novel therapies to enhance the immune response against the patient’s tumor. Our institution has begun a clinical trial for CTCL patients, which I direct, to test durvalumab, which is an inhibitor of the checkpoint protein PD-L1. Some trial participants will also receive lenalidomide, a drug known to boost the immune system. Thus, durvalumab will release the breaks on the immune system, while lenalidomide will increase the acceleration. The team has witnessed impressive results in the patients enrolled in the trial so far. I am also interested in learning more about the underlying biology of patients, which will help predict response and provide insights into next-generation treatments. For example, my group has learned that in addition to PD-L1, another immune protein known as ICOS is also highly expressed in patients with advanced disease. My laboratory is currently investigating how ICOS may be involved in T cell exhaustion, and this knowledge may be leveraged in the near future to develop novel treatments. I expect that discoveries arising from these laboratory and clinical investigations will have relevance not only to CTCL but to other T cell lymphomas and potentially other malignancies.