Genetic Mutation in Immune Cells for Infectious Disease and Cancer Therapy

Application

Conditional epigenetic mutation in CD8+ memory T cells as potential cell therapy for chronic viral infection and personalized cancer treatment.

Key Benefits

• Blocks DNA methylation in T cells, prolonging the life and enhancing the function of these cells.
• Results in faster CD62L re-expression during effector to memory cell conversion.
• Delays or eliminates T cell exhaustion.
• Reduces side effects of currently approved treatments by patient specific autologous cell-based therapy.

Market Summary

Infectious diseases are a leading cause of death worldwide and pose an increasing threat due to ease of transmission, lack of effective therapeutics, and emerging drug resistance. At the onset of a viral infection, CD8+ T cells initiate clonal expansion, expression of effector molecules, and down regulation of lymphoid homing molecule L-selectin (CD62L), allowing the cells to traffic to sites of infection and kill infected cells. The lack of success in generating vaccines for chronic viral infections such as HIV and HCV emphasize a need for new targets that mediate the specialization of memory CD8 T cells, which is essential to generate effective vaccines. By blocking DNA methylation, CD8+ T cells would be resistant to T-cell exhaustion and improve viral control during infection.

Technical Summary

Emory University inventors have developed a cell therapy for chronic viral infection and personalized cancer treatment. This therapy conditionally deletes the DNA methyltransferase 3a (Dnmt3a) gene from L-selectin (CD62L) promoter in CD8+ T cells. Dnmt3a deletion enhances highly functional cellular immune response during chronic infections or cancer in humans. The genetically engineered cellular therapy utilizes the patients own isolated naïve CD8 T cells. This therapy resolves a major obstacle in current autologous T cell transfer therapies, preventing T cells from acquiring a heritable exhausted fate and allowing them to mediate better anti-viral or anti-tumor functions.

Developmental Stage

• Dnmt3a deficient antigen-specific CD8 T cells were able to control a chronic viral infection in LCMV mice.
• Dnmt3a deletion enhances the efficacy of Immune Checkpoint Blockade in a preclinical animal model of T cell exhaustion.

Publications

Youngblood, B. et al. (2017). Nature, 552(7685), 404-409.
Ghoneim, H.E. et al. (2017). Cell, 170(1), 142-157.
Ahn, E. et al. (2016). J Virol, 90(19), 8934-46.