Chemokine Receptor Signatures in Allogeneic Stem Cell Transplantation

Allogeneic stem-cell transplantation (SCT) is performed in 28,000 patients with blood cancers each year, including many servicemen and women. The success of allogeneic SCT relies in part on the ability of the donor's immune system to attack and destroy the recipient's cancer cells, a process known as graft-versus-leukemia (GvL). However, this process works as a double-edged sword because the donor immune system can also target normal recipient tissues and cause severe damage, a complication called graft-versus-host disease (GvHD). Acute GvHD is a deleterious process that primarily causes damage in the skin, liver, and gut. GvHD can be life-threatening and requires aggressive therapy with drugs that suppress the immune system, leading to infections and poor quality of life. Second only to cancer relapse, GvHD is a frequent cause for morbidity and mortality 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. Interventions that prevent GvHD efficiently but preserve the function of the immune system and permit effective GvL are a major unmet need, and breakthroughs in this field have not occurred since the 1980s.

GvHD is caused by donor lymphocytes, specifically a subset called T cells; it is dependent on the ability of these lymphocytes to migrate from the blood into specific tissues to cause damage. The migration of donor lymphocytes into organs is a well-orchestrated and highly regulated process, governed by certain chemicals called chemokines, which attract cells into sites of inflammation by binding to chemokine receptors. These chemokine receptors are present on the lymphocyte surface and act as a 'ZIP code' to guide each lymphocyte to its own specific 'address' in the body. Chemokine receptors offer us an opportunity to inhibit lymphocyte migration using drugs that block these receptors. I have previously shown in a clinical trial that blocking the chemokine receptor CCR5 decreased rates of GvHD without impairing lymphocyte function, i.e., without increasing the risk for infections or cancer relapse. It appeared that the beneficial effect of CCR5 blockade was unique to the liver and gut and did not affect the skin, implying that CCR5 blockade affected a trafficking pattern that is specific to those organs. This trial showed that the detrimental process of GvHD could be modulated by blocking a single chemokine receptor, similar to removing a digit from the ZIP code on an envelope.

I now propose to study the role of CCR5 and other chemokine receptors in the migration of T cells after allogeneic SCT, hypothesizing that there are specific combinations ('signatures') of receptors that guide T cells into specific organs. The discovery phase of this proposal will use a tissue bank, which currently contains more than 850 blood, marrow, and biopsy samples from allogeneic SCT recipients at Penn. The validation phase will include the study of similar samples from patients who underwent allogeneic SCT and received the drug maraviroc, a CCR5 antagonist, as part of a clinical trial.

In order to demonstrate the role of specific chemokine receptors in trafficking into tissues, I will use an advanced genomic method called T-cell receptor sequencing. This novel technology allows me to identify specific groups (clones) of T cells in tissue biopsies and in peripheral blood. By sorting a patient's blood into groups of cells that carry specific chemokine receptors (the 'ZIP code') and then comparing their T-cell receptor sequences to the ones that are found in a specific organ, I can assess which chemokine receptors determined the migration into a specific organ. The identification of specific chemokine receptor signatures that have a critical role in GvHD can further propel the development of targeted medications that control cell migration and improve the outcome of allogeneic SCT without suppressing the immune system.

Personally, I am a physician scientist specializing in cellular therapy and SCT for blood cancers. I completed my training in hematology and oncology at the University of Pennsylvania, and conducted lab and clinical research at Penn under the guidance of Dr. David Porter and Dr. Robert Vonderheide, who serve as mentors for this research proposal as well. Together, we pioneered the use of the chemokine receptor blocker maraviroc in allogeneic SCT. I was recently appointed a co-chair of a multicenter clinical trial that will further test this strategy. I aspire to continue my work in the exciting realm of cancer research and transplantation. The Career Development Grant will provide me a unique opportunity to advance the field of allogeneic SCT by introducing novel genomic methods and identifying new targets that will improve survival and quality of life for transplant patients.