Identification of Effector and Suppressive T-Cell Clones in Graft-vs-Host Disease

Fiscal Year 2017 (FY17) Peer Reviewed Cancer Research Program (PRCRP) Topic Area: Immunotherapy

FY17 PRCRP Military Relevance Focus Area: Gaps in treatment of hematologic malignancies that have a profound effect on the health and well-being of active duty Service members, Veterans and their beneficiaries.

Allogeneic stem-cell transplantation (SCT), a procedure where bone marrow stem cells and immune cells are transferred from a donor to a recipient, is performed in 30,000 patients with blood cancers each year, including many active duty Service men and women. Allogeneic SCT is the oldest form of cancer immunotherapy, where the donor's immune system is harnessed to attack and destroy the recipient's cancer cells, a process known as the graft-versus-tumor (GvT) response. Graft-versus-host disease (GvHD) is one of the most common complications of allogeneic SCT, where the donor immune system targets normal recipient organs and causes severe inflammation and damage, primarily in skin, liver and gut. GvHD can be life-threatening, and requires aggressive therapy with drugs that suppress the immune system, leading to infections, cancer relapse, and poor quality of life. GvHD is the most frequent cause for treatment-related death after SCT. The current approach to prevention and treatment of GvHD, which includes the administration of drugs that suppress the immune system, is only partially effective, and 30%-70% of transplant patients still encounter significant GvHD and at least 15% of deaths after allogeneic SCT are a direct result of GvHD. Better strategies that prevent or treat GvHD efficiently without suppressing the immune system are a major unmet need, and their development will allow us to extend allogeneic SCT to older and sicker patients who are currently ineligible for this procedure due to this devastating complication.

GvHD is caused by donor lymphocytes, specifically a subset called T cells that identifies recipient tissues as foreign and attacks them. T cells form clones of identical T cells in the body that are trained to attack only a specific tissue or target. The majority of T cells are effector cells that are capable of attacking and destroying their target, but there are subtypes of T cells with suppressive properties and their role is to control the immune response and dampen the activity of effector cells. Regulatory T cells (Tregs) are a well-characterized type of suppressive T cells. Tregs are very potent in suppressing an uncontrolled immune response such as GvHD; however, infusing large numbers of unselected Tregs to GvHD patients has shown limited benefit so far and the lack of specificity may weaken the immune system globally, suppress responses against bacteria and other infectious pathogens, and weaken the effectiveness of effector T cells against cancer.

We hypothesize that Tregs and other suppressive T cells that are found inside GvHD tissues are selective and have been programmed to migrate into and suppress inflammation in a particular tissue or organ. Identifying these T-cell clones will make it possible to develop better targeted cell therapies. Ultimately the goal is to develop a strategy that rapidly and accurately identifies specific T-cell clones that suppress GvHD in tissues, allowing us to isolate them, grow them in the lab, and infuse them back into patients in large numbers for therapeutic benefit. This can be particularly useful in chronic GvHD, which is an indolent chronic process that significantly impairs quality of life for many years after SCT and currently has very few therapeutic options with limited efficacy.

We also hypothesize that identifying the specific clones of T cells in the diseased tissue and characterizing the ratio between suppressive and effector T cells will help make the diagnosis of GvHD more accurately and help determine its potential severity before a patient develops severe symptoms or stops responding to therapy. In this proposal, we suggest to use a novel strategy that characterizes the identity and function of T cells taken out of fresh tissue biopsies. Because GvHD patients undergo biopsies routinely for the diagnosis of GvHD, the development of our method is highly feasible and the resources and collaborators that we have at Columbia University are highly appropriate for this study.

This strategy is ultimately designed to mitigate the toxicity of allogeneic SCT, reduce the number of patients who die or become severely ill after transplantation, and by that extend these treatments to a greater number of patients with a larger variety of diseases. Of the 8,000 allogeneic SCT procedures conducted each year in the US, a significant proportion is done in Service personnel or their beneficiaries. If this proposal is successful and leads to advancement in the efficacy or safety of SCT, it will also be extended to older individuals with blood cancers, which frequently occur in Veterans. Finally, allogeneic SCT is the only lifesaving procedure for severe radiation injuries, and therefore it has been a long-standing priority for the military to develop better and safer strategies to perform these transplants.