Highlights
- HLA-A*1101 restriction makes this LMP2-TCR transduction therapy especially applicable to the Chinese population
- Targeting the LMP2 viral epitope removes concern over on-target toxicity associated with most cell-based therapies
- Gene transfer approach for TCR clones enables significantly faster (48 h) preparation of patient derived T cells compared to alternative co-culture methods (9 weeks)
- The technology demonstrates in vivo efficacy with no observed toxicities
- Cancer Research Horizons is prosecuting a patent for the technology and the relevant sequences
The opportunity
Cancer-targeting cell therapies are being widely developed and taken into the clinic where they are proving to be potent treatment modalities to accompany or replace current standard of care. Nasopharyngeal carcinoma (NPC) is unusually common throughout China and Southeast Asia, where it accounts for 63% of the 87,000 NPC cases worldwide. In southern China it is the third most common cancer in men. While radiotherapy is the first-line treatment for NPC, this cancer is often diagnosed late. 60%-90% of patients present with late stage disease, dramatically reducing survival rates. In high incidence regions, relapse following primary treatment occurs in nearly 80% of patients and is the leading cause of death from NPC. Consequently, there is a real need for novel approaches to treat NPC.
Epstein Barr Virus (EBV) is detected in almost all malignant cells from NPC patients and is strongly associated with NPC pathogenesis. Of all the EBV-specific antigens, latent membrane protein 2 (LMP2) induces the largest immunogenic response. Researchers at the University of Birmingham have developed an optimised T-cell receptor (TCR) clone for NPC-associated EBV protein LMP2 which has demonstrated in vivo efficacy. Rational selection of HLA subtype restriction makes this therapy uniquely applicable to the Chinese NPC population.
Reactivated EBV-specific T-cells from a healthy Chinese donor were screened for reactivity to the EBV protein LMP2 restricted by the HLA-A*1101 allele. The most reactive TCR was cloned into a GMP-compliant retroviral vector and subjected to multiple rounds of optimisation to improve expression and reduce receptor mispairing. The HLA-A*1101 allele is found in over 50% of the Chinese population, making this optimised T-cell therapy particularly applicable to this demographic group. The TCR transfer modality provides a significant efficiency improvement over existing adoptive T-cell co-culture approaches. Using a retroviral vector enables a patient’s T cells to be re-engineered to express the target TCR and tumour antigen within 24 – 48 hours. This therapy demonstrates promising in vivo efficacy in a surrogate xenograft model. Targeting the viral epitope also removes concern over on-target toxicity associated with most cell-based therapies.