Epistatic Effects of Fcgamma (GM) and FcgammaR Genes on the ADCC of EGFR-Overexpressing Osteosarcoma Cells
Abstract
Fiscal Year 2023 (FY23) Rare Cancers Research Program (RCRP) Focus Areas: Biology and Etiology; Therapy Currently available immunotherapies do not help patients with osteosarcoma. It is relevant to note that about two-thirds of the human population remains cancer free. Presumably in these people their own immune system eradicates precancerous lesions before they can develop into full-blown cancer. This suggests that a better understanding of how our natural immune system reacts to cancer cells is likely to enhance our ability to devise therapeutic strategies that would be beneficial to the majority of the patient population. In this proposal, we will investigate the immunology of a protein called EGFR, which is overexpressed on osteosarcoma cells. Its overexpression correlates with worse survival. In some cancers, a gene of the immune system – called GM allotypes – influences natural antibody responses to EGFR and these antibodies are associated with enhanced survival. To further understand the mechanisms underlying the beneficial effects of anti-EGFR antibodies, we will characterize osteosarcoma specimens stored at Children’s Oncology Group (COG) Biospecimen Bank. DNA will be used to type for GM genes and another gene of the immune system called FCGR. Plasma samples will be used to measure antibodies to EGFR. We will use statistical tests to determine whether people expressing particular genes are more or less likely to make antibodies to EGFR. Most importantly, we will determine whether a particular combination of these genes is more potent in killing osteosarcoma tumor cells. Encouraging results from this Concept grant will lead to large-scale studies to conclusively show the influence of GM allotypes on natural immunity to EGFR. Results from these large-scale studies could lead to the development of immunotherapy for patients who already have osteosarcoma and also those who are likely to develop this malignancy. Results obtained here could potentially divide the population into naturally high or low responders to EGFR. Subjects with the high responder genotype are more likely to make therapeutic responses to EGFR-based vaccines (active immunotherapy). In individuals with the low responder genotype EGFR could be fused with appropriate adjuvants (immune enhancers) to overcome the genetic restriction in immune responsiveness. Our experiments involving cytotoxicity (killing) of tumor cells could identify the most potent combination of genes for killing osteosarcoma tumors. This knowledge would be instrumental in manufacturing antibodies for treating patients with osteosarcoma (passive immunotherapy). Anti-tumor antibodies could be manufactured whose Fc (GM) region has high affinity for a given FCGR molecule expressed on immune killer cells. After determining their FCGR genotype, the patients could be given anti-tumor antibodies carrying the GM variant having the highest affinity for that FCGR molecule. It is also important that the patient and the therapeutic antibody share the same GM variant, thus preventing the generation of anti-allotype antibodies in the host, which could eliminate the therapeutic antibody from the system. Current approaches to immunotherapy do not take into account the inherent variability of GM genes. Designing antitumor antibodies – taking into account the natural variability in Fc (GM) and FCGR – that have a high potential for killing tumor cells is commercially feasible and could be done in just few years. These markers are variable, but not too variable to make the manufacturing of antibodies commercially prohibitive. Only a few different kinds of antibodies need to be manufactured, and typing for the patient’s FCGR genotype can be easily automated. For a disease with no cure, these efforts are worth trying. A patient-related outcome could be achieved within 2-3 years after the completion of the large-scale studies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310504
Entities
People
- Janardan P Pandey
Organizations
- Medical University of South Carolina
- United States Army