T cell receptor-engineered T cell (TCR-T) therapy is a form of adoptive cell therapy in which genetically modified immune effector cells are used as direct anti-cancer therapeutics. TCR-T therapies are generated by inducing the expression of modified TCRs on the surface of T cells, enabling their endogenous cell killing activity to be redirected against cancerous cells. Our lead TCR-T program, CVT-TCR-01, targets an intracellular cancer-testis antigen called NY-ESO-1.
TCR-T Represents Potential Best Cell Therapy Approach For Solid Tumors
∙ Targets cell surface proteins;
∙ Higher risk of side effects given engineered chimeric antigen receptor construct;
∙ Current antigens of interest do not differentiate between healthy and malignant cells.
∙ Targets both intracellularly and extracellularly expressed antigens;
∙ Potential to treat solid tumors as well as hematologic tumors;
∙ Lower risk of side effects due to greater specificity against unique cancer targets;
∙ Lower risk of immunogenicity and related issues if TCRs are natural, non-mutated structures.
Discovering TCR Therapeutics For Asian Patients
TCR-T therapies have shown great promise in targeting solid tumors; however, end-to-end development of TCR-Ts suited to Asian patients has its own scientific and logistical challenges. TCR-T is a personalized therapy, and it requires the transgenic TCR to recognize tumor antigen in complex with self HLA (“the target”). Compared with the Caucasians, Asian populations have unique immunological characteristics and specific disease burdens. For example, a number of cancer types, e.g., nasopharyngeal carcinoma, esophageal cancer, and hepatocellular carcinoma, have high annual incidence rates in China but are much less prevalent in the West. Consequently, the solid tumor burden in Asian patients, which represent a huge unmet medical need, is largely not addressed by TCR-T therapies currently in development, as most of them have a focus on the HLA-A*02:01-positive population.
At Cytovant, we choose tumor antigens that are differentially expressed in highly prevalent diseases in Asia and choose HLA alleles that are overexpressed in Asian populations. Tumor antigen epitopes restricted by a selected HLA allele are identified by in silico analysis and further validated by different methods such as immunoprecipitation-mass spectrometry. T cell clones specifically recognizing a selected target are generated using Medigene's proprietary allo-priming strategy, which is thought to enable the identification of highly functional TCRs more rapidly and efficiently than affinity enhancement through random mutagenesis, the industry standard.
TCR-T Therapy Flowchart
As shown in the figure above, personalized cancer treatment with a TCR-T therapy comprises six steps:
(1) Isolation of T cells from a patient’s peripheral blood
(2) Ex vivo transfer of tumor-specific TCR genes into patient T cells using viral vectors or non-viral transposon systems
(3) Ex vivo expansion of TCR-engineered T cells
(4) Purification, formulation and freezing of TCR-T cells and Quality Control testing of drug products
(5) Shipment of drug product from manufacturing center to clinical site
(6) Thawing and infusion of genetically modified T cells back to into in human subject