Multiple myeloma (MM) is a bone marrow plasma cell cancer with a mortality rate greater than 50%1. According to the National Program of Cancer Registries United States Cancer Statistics, both incidence and death rates among African-Americans were approximately twice that seen in the other ethnic populations2. It is therefore important to examine those factors unique to this population which may contribute to the unequal rates of morbidity and mortality associated with this disease. Of the available treatments for MM, remission has primarily been observed following autologous and allogeneic hematopoietic stem cell transplantation3,4. Immunotherapy strategies have also been developed. For example, the human leukocyte antigen (HLA)-A2 restricted MM-associated protein HM1.24, which is overexpressed in Multiple myeloma cells, has been shown to stimulate interferon gamma expression by myeloma-specific cytotoxic T lymphocytes (CTLs)7. However, at present, these therapeutic approaches alone do not consistently elicit antitumor cytotoxic effects in in vitro or in vivo studies8,9. This is due, in part, to the lack of understanding of te factors which contribute to T cell activation in the largely tolerizing tumor setting, such as allogenicity. However, the greater diversity of HLA polymorphisms in African-Americans provides a unique resource for interrogating the biophysical underpinnings of HLA restriction in targeted tumor immunotherapies for diseases such as MM. The general objective of the project detailed in this proposal is to determine the effect of allogeneic variation in HLA-A2 on the induction of CTLs to immunodominant peptides of the HM1.24 antigen. The prevalence of certain HLA-A2 alleles may differ between African-Americans and Caucasians, and it is possible that these differences contribute to different responses against HLA-A2-restricted tumor associated antigens. Thus, in Aim 1, the most prevalent HLA-A class I alleles within the African-American population will be identified. Immunogenic peptides of MM HM1.24 specific for those alleles will be determined by in silico analysis. This will be used in Aim 2 to design and construct structurally allogeneic variants of HLA-A2-HM1.24 complexes by molecular modeling and molecular biology techniques. Finally, in Aim 3, to investigate the impact of allogeneic variation on CTL responses, the complexes will be delivered to antigen presenting cells using a novel application of the lentiviral vector system. The APCs will then be co-cultured with HLA-A2-restricted, HM1.24-specific CTLs in CTL effector assays. The hypothesis being tested is that allogeneic variants of this MM associated HLA-peptide complex can be engineered to augment CTL responses. This project utilizes bioinformatics, molecular biology, and tissue culture techniques to address how biophysical and genetic components of HLA-A2-peptide complexes contribute to the allogeneic responses of T cells. Ultimately, this project seeks to contribute to the knowledge base currently being used to develop immunotherapies for diseases such as MM, specifically in populations which demonstrate well-documented health disparities.
Multiple myeloma is a destructive plasma cell cancer which disproportionately affects African-Americans and for which no definitive cure exists. This project may contribute a putative model for designing and optimizing vectors which uses the genetic variation within the African-American population to promote anti-cancer immune responses. This model could perhaps be used to develop personalized therapies for diseases such as Multiple myeloma, which exhibit health disparities in unique populations.
