Vaccine-enhanced DLI to prevent cancer recurrence after stem cell transplantation

DESCRIPTION (provided by applicant): Delayed reconstitution of antigen-specific immunity following allogeneic hematopoietic stem cell transplantation (HSCT) predisposes patients to opportunistic infections and tumor recurrence. To address these problems, we are developing a vaccination methodology using a non-replicating but highly immunogenic Listeria monocytogenes (Lm) vector. When an Lm vaccine expressing murine cytomegalovirus (MCMV) antigen was administered immediately after bone marrow transplantation (BMT) in mice, protective anti-MCMV CD8+ CTLs expanded to 10% of total CD8+ cells within 7 days. The vaccine-driven immune response was durable, demonstrating profound MCMV antigen-specific cytolytic activity up to 200 days after transplantation. We now propose to develop similar Lm vaccines that can reduce recurrence of leukemia/lymphoma by raising durable cellular immunity against minor histocompatibility antigens (miHA) that are differentially expressed on malignant cells. First (Aim 1) optimized parameters will be determined for effective vaccination against the model tumor miHA ovalbumin (OVA) in BMT mice. These studies will be facilitated by the ability to accurately track anti- OVA effector/memory T-cells, and to serially monitor growth of a subcutaneous OVA-expressing tumor. Next (Aim 2), we will extend this work by vaccinating against a clinically-relevant endogenous murine miHA, B6dom1, in allogeneic BMT mice. These studies will focus on raising miHA-specific immunity and eradicating B6dom1-positive EL4 leukemia cells following allogeneic BMT without therapy-limiting GvHD. Since the Lm vector has been demonstrated to be safe for human use, successful completion of the proposed studies will lay the foundation for a Phase II STTR application leading directly to translational clinical trials. Implications and relevance to public health: In patients who undergo HSCT/BMT as treatment for leukemia/lymphoma, the return to normal immune function can be greatly delayed. During this period, transplant recipients can experience complications including life-threatening infections and recurrence of their cancer. Development of effective methods to prevent these complications, such as the immunization approach proposed in this application, would significantly improve the survival and quality of life for patients that undergo transplantation to treat blood cancers.