Selective Expansion of Engineered TCR-T Cells for Use in Adoptive Cell Immunotherapy

Summary:

The National Cancer Institute (NCI) seeks capable licensees interested in commercializing T cell receptor (TCR)-engineered T cells expressing murine/human hybrid receptors.

Description of Technology:

TCR-T therapies, particularly those targeting patient-specific neoantigens, remain a promising approach to the treatment metastatic cancers. Contemporary gene engineering techniques permit both the targeted integration of the exogenous receptor(s) and further genetic manipulation of the host cells to enhance persistence and performance following adoptive transfer (e.g., through disruption of immune checkpoints such as CISH or PD1). However, these techniques often suffer from low transduction efficiencies and may result in the generation of infusion products with sub-optimal percentages of targeted cells.

NCI scientists designed a new method that enables the selective expansion of T lymphocytes, under GMP conditions, that have been engineered to stably express a murine-human hybrid TCR. These hybrid TCRs consist of human variable regions and murine constant regions. The inventive approach uses irradiated feeder cells and an anti-mouse TCR beta constant region antibody (e.g., H57) to provide stimulation, enabling the specific activation and expansion of T cells transduced with the hybrid TCRs. Critically, replacement of the OKT3 activating antibody from the standard rapid expansion protocol with one specific for the TCR murine constant region prevents the outgrowth of non-transduced cells. Consequently, the new method produces a cell population highly enriched for the desired engineered cells.

NCI seeks to market this method, which is analogous to an antigen-specific stimulation of the T cell, to companies interested in developing personalized ACT.

Potential Commercial Applications:

• Enables the GMP production of personalized T cell therapy products targeting tumor specific mutations with a high percentage of engineered cells

Competitive Advantages:

• Increased therapeutic benefit due to enhanced persistence and performance following adoptive T cell transfer
• Increased therapeutic benefit due to improved surface expression of the therapeutic TCR αβ
  • TCR alpha/beta chains substantially eliminate the risk of mis-pairing with the endogenous alpha/beta chain sequences expressed by the host cell
• Improved manufacturing since the population is highly enriched for the desired engineered cells
  • Greatly increases the frequency of tumor-specific T cells following expansion, exceeding what is achieved using alternative methods to generate mutation- or tumor-specific T cells