Breaking B-Cell Tolerance to Produce Antibodies that Eradicate Leukemias and Lymphomas
Abstract
This research proposal addresses two Fiscal Year 2017 Peer Reviewed Cancer Research Program (PRCRP) Topic Areas: (1) Immunotherapy and (2) Lymphoma. Our previous major objective has been to solve the problem called chronic graft versus host disease (cGVHD) that limits success of donor bone marrow transplant (also known as allogeneic stem cell transplantation or allo-HCT). Allo-HCT confers important anti-tumor reactivity, and it is the only known curative therapy for many patients afflicted with life-threatening blood, bone marrow, and lymph gland cancers. The proposed work will benefit active duty Service members, Veterans, and other military beneficiaries because evidence supports the fact that blood-borne cancers are more common among military personnel. In part, this is due to frequent exposure to benzene and petroleum products that are linked to deadly leukemia development. Our objective is to develop safe, effective cell immunotherapies for patients with blood, bone marrow, and lymph gland cancers. B cells are specialized cells that produce proteins called antibodies (or immunoglobulins, Ig). The problem of why B cells mount ineffectual tumor response in patients remains poorly studied. Antibodies are able to bind with high specificity to target cells. In the healthy state, antibody targets are typically foreign invaders of the host like microbes or tumor cells. Host cells are also targets of destructive antibody responses in patients who receive allo-(donor)-HCT. Our previous work led to the understanding that antibody-producing B cells after allo-HCT are involved in the immune pathology found in cGVHD. Our preliminary studies have entailed use of a tumor vaccine system that allows exposure of B cells to high amounts of protein in a safe way without producing immune toxicity. The premise is that by first administering agents that incite immune signaling through so-called tissue damage/danger receptors, we are inducing increases in high levels of a B cell survival factor called BAFF. We previously injected mice with BAFF protein and showed increased anti-tumor antibody production. Since BAFF injection is possible in the clinic, we are now proposing to add back B cells during the immediate post-HCT period when BAFF is high inside the patient. BAFF at high levels along with nucleic acids and glycoproteins in the vaccine promotes anti-tumor antibody responses, capable of binding tumor. Further funds are needed in order to continue this project, so we can determine the timing of how to induce and/or administer the components we now know are critical for the anti-tumor antibody response. Thus, our previous PRCRP pilot funding allowed us to learn how we might capitalize on the mechanisms that cause B cells to lead to host tissue destruction after allo-HCT and move them into the setting of less toxic autologous HCT (auto-HCT) in which cancer patients receive their own stem cells and do not ever suffer from cGVHD. We have now compiled the required tools and expertise, and we believe we are now well poised to move our findings forward to a clinical trial within 3 years. Specific Aim 1: Our research team at Duke has now developed tools and sufficient expertise to be able to conduct focused and highly translational studies that will lead to the development of cellular therapy strategies that will result in anti-tumor B cell antibody responses in patients. Specific Aim 2: We have now elucidated the B cell subsets in patients after allo-HCT that will yield anti-tumor antibodies. At Duke we are fortunate to have collaborators (Dr. Bart Haynes) with expertise in high-throughput human antibody engineering who can help us realize the potential of the allo-HCT patient B cells’ capacity to produce therapeutically viable antibodies. Summary: Production of monoclonal antibodies to human tumor-associated antigens has been difficult for both technical and biological reasons. Our previous PRCRP grant enabled
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810239
Entities
People
- Stefanie Sarantopoulos
Organizations
- Duke University
- United States Army