Generation of antigen-specific mature T cells from RAG1(-/-)RAG2(-/-)B2M(-/-) stem cells by engineering their microenvironment.
Publication Year:
2024
PubMed ID:
38062131
Public Summary:
It is estimated that each year, over 170,000 Californians will be diagnosed with cancer and approximately 60,000 will die of this disease. Exciting successes have been seen by harnessing the immune system to kill cancer using T cell therapy. However, not all patients who could benefit are able to access this therapy because of the cost and logistical challenges associated with the need to manufacture each product from the patients’ own blood. We will address a major current bottleneck for T cell immunotherapy: the limited access to cancer treatment that relies on patient-specific T cells due to the cost and delay of these therapies. In the manuscript Chang et al, NBME 2023, we showed that we could combine a novel method to produce T cells from pluripotent stem cells with CRISPR-based gene editing tools, to create stem cells that can serve as a universal source of T cells for cancer immunotherapy.
Scientific Abstract:
Pluripotent stem cells (PSCs) are a promising source of allogeneic T cells for off-the-shelf immunotherapies. However, the process of differentiating genetically engineered PSCs to generate mature T cells requires that the same molecular elements that are crucial for the selection of these cells be removed to prevent alloreactivity. Here we show that antigen-restricted mature T cells can be generated in vitro from PSCs edited via CRISPR to lack endogenous T cell receptors (TCRs) and class I major histocompatibility complexes. Specifically, we used T cell precursors from RAG1(-/-)RAG2(-/-)B2M(-/-) human PSCs expressing a single TCR, and a murine stromal cell line providing the cognate human major histocompatibility complex molecule and other critical signals for T cell maturation. Possibly owing to the absence of TCR mispairing, the generated T cells showed substantially better tumour control in mice than T cells with an intact endogenous TCR. Introducing the T cell selection components into the stromal microenvironment of the PSCs overcomes inherent biological challenges associated with the development of T cell immunotherapies from allogeneic PSCs.