Enhanced TCR Discovery Technology Improves Personalized Cancer Immunotherapy
A new high-throughput platform identifies tumor-specific TCR genes from diagnostic biopsies, facilitating engineered T cell therapy for cancer treatment.
Adoptive cell therapy using tumor-infiltrated lymphocytes (TIL) has proved ability to mediate tumor regression and achieve durable responses across various solid cancers, particularly melanoma. Yet, the wider applicability and effectiveness of TIL therapies have faced considerable restrictions due to challenges such as the need for invasive procedures to access viable tumor material and the limited proliferative ability of TILs themselves. Researchers from Neogene Therapeutics, together with leading institutions including NKI-AVL (Amsterdam), LUMC (Leiden), and Moffitt Cancer Center (Tampa), have developed an innovative platform capable of identifying specific T-cell receptor (TCR) genes efficiently from diagnostic tumor biopsies, including non-viable core-needle biopsies. This platform promises to extend effective treatments to more patients, paving the way for engineered T cell therapies.
The breakthroughs made possible by this new TCR discovery technology stem from its ability to employ genetic screening techniques for the identification of antigen-reactive TCRs with unprecedented sensitivity and specificity. This method allows for analysis of even complex tumor specimens, generating high complexity TCR libraries directed at multiplexed antigen targets. The results indicate significant potential not only for melanoma but also for solid tumors with low mutational burdens, including microsatellite-stable colorectal cancers. Here, TCRs have been identified from fresh, frozen, non-viable samples. One of the significant advances of this platform is its ability to work with tumor biopsy samples rather than requiring extensive surgical intervention to collect viable TILs, thereby overcoming previous limitations.
The core design aspects of this screening platform prioritize efficacy and clinical relevance by assessing the TCRs based on their activation potential without restricting the analysis to specific HLA classes. By concentrating on functional readouts, the technology accounts for the natural processes of antigen processing and presentation by the TILs. When tested on diverse cancers, the platform facilitated the identification of TCRs from non-synonymous mutations linked to tumor-specific antigens, showcasing its broad utility. 738 tumor-specific mutations were documented, allowing the identification of 563 candidate neoantigens which could successfully target TCR responses.
"We developed technology to extend the proven clinical activity of TIL to larger patient groups, eliminating the need for large quantities of viable tumor material," stated the research team. Their optimistic findings included the successful identification of TCRs across several tumor types, which indicated the technology’s vast applicability. This is particularly promising for cancers like colorectal carcinoma, typically characterized by low tumor response rates to current immunotherapies.
By establishing evidence of efficacy across various cancer types, the research team contributes to the growing foundation of knowledge geared toward personalized carcinoma immunotherapy. The platform introduces the ability to pool multiple antigen-specific TCRs, providing comprehensive targeting capabilities which could mitigate the risks of challenges such as antigen escape typically faced by single-target therapies. "The individualized TCR-T cell therapies we propose could significantly reduce the risk of antigen escape compared to single-target engineered therapies," the authors highlighted.
The continuous expansion of personalized cancer therapies driven by technologies such as this high-throughput TCR discovery platform demonstrates the promise of targeted treatments. With breakthroughs like these, the potential for highly individualized, more effective treatment approaches becomes increasingly reachable, questing toward the goal of developing personalized medicine’s capabilities against cancer.