Adoptive transfer of TCR-gene-transduced T cells
First-in-man use of the TCR gene for the MAGE-A4-peptide for refractory esophageal cancer
The technology used to engineer antigen receptor genes presents opportunities for novel T cell-based therapies. We previously reported the establishment of a CTL clone that recognizes the MAGE-A4143-151 peptide in an HLA-A*24:02-restricted fashion. Using receptor engineering, we constructed a retrovirus vector, MS-bPa, for transduction of T cells with the TCR-alpha and -beta chains derived from the MAGE-A4143?151-specific T-cell clone. Then, we investigated whether these TCR-engineered T cells had the capacity to survive in hosts. Next, we performed a first-in-man clinical trial of TCR gene therapy for recurrent esophageal cancer, targeting MAGE-A4, which was the first developed TCR-gene T cell therapy for esophageal cancer. By monitoring the in vivo kinetics of the transferred cells by sensitive, quantitative PCR and specific tetramers, we demonstrated that the transferred T cells persisted for more than 5 months, trafficked to tumor sites, and maintained tumor-specific reactivity in patients (Clin Cancer Res. 2015; 21(10):2268?2277).
Technology for specific silencing of endogenous TCR (siTCR)
Adoptive T-cell therapy using lymphocytes genetically engineered to express tumor antigen-specific TCRs is an attractive strategy for treating patients with malignancies. However, there are potential drawbacks to this strategy, including mispairing of the introduced TCR alpha/beta chains with endogenous TCR subunits and competition between the introduced and endogenous TCRs for CD3 molecules, which can impair cell surface expression of the transduced TCR, resulting in insufficient function and potential generation of autoreactive T cells. In addition, the risk of tumor development following infusion of cells with aberrant vector insertion sites increases with vector copy number in the transduced cells. We developed retroviral vectors encoding both small interfering RNA (siRNA) constructs that specifically downregulate endogenous TCR and a codon-optimized, siRNA-resistant TCR specific for human tumor antigens (Cancer Res. 2009; 69(23):9003?9011).
siTCR-MAGE-A4 and siTCR-NY-ESO-1 TCR-T cell transfer for refractory malignant tumors
We are conducting two clinical trials using TCR-MAGE-A4 and TCR-NY-ESO-1 for refractory tumors. MAGE-A4 is expressed in 50% of esophageal squamous cell carcinomas and is broadly expressed in various other tumors. NY-ESO-1 is expressed in 30% of esophageal cancers and other malignant tumors. For example, synovial sarcoma cells frequently express NY-ESO-1 (in 60% or more cases).
In these trials, we tested safety and transferred-cell survival in patients who were treated with the preconditioning regimens shown in the figure (ClinicalTrials.gov: NCT02096614, NCT02366546).