A single, master genetic regulator can improve the effectiveness of T cells in cancer therapy and could extend their use for other diseases, researchers have discovered.
A member of the BAF chromatin remodeling complex was able to reprogram T-cell genes to improve their cancer-killing abilities and reduce the chances of them becoming exhausted. The CRISPR-based, gene-editing technology could be another step toward off-the-shelf T-cell therapies for cancer. It could also lead to the use of T-cell therapies in clinical areas such as autoimmune diseases. The research is published in the journal Nature Genetics.
“In some cases, T-cell therapy works like a miracle drug, but in most others, it hardly works at all,” explained senior researcher Charles Gersbach, PhD, a professor of biomedical engineering at Duke University.
“We are looking for generic solutions that can make these cells better across the board by reprogramming their gene regulation software, rather than rewriting or damaging their genetic hardware. This demonstration is a crucial step toward overcoming a major hurdle to getting T-cell therapy to work in more patients across a greater range of cancer types.”
Currently, there are six T-cell therapies approved by U.S regulators for particular leukemias, lymphomas, and multiple myeloma. However, they tend to be less effective for solid tumors due to the quantity of cancer cells, which can lead to “T-cell exhaustion” where they are unable to have an anti-tumor response.
The researchers developed a form of CRISPR that did not involve its use in cutting genes but instead modulated their activity through altering the packages and storage of DNA.
Orthogonal, CRISPR-based screening approaches were deployed to discover regulators of complex T-cell phenotypes in order to speed the engineering of T cells with improved durability and therapeutic potential.
Specifically, the team developed compact epigenome editors based on Staphylococcus aureus Cas9 molecular scissors to target gene regulation in primary human T cells. These tools were then used to investigate the effects of activating and repressing 120 genes transcription factors and epigenetic modifiers on human CD8+ T cell states.
The screens revealed that BATF3 overexpression could be harnessed to promote particular features of memory T cells such as increased IL7R expression and glycolytic capacity, while countering gene programs associated with cytotoxicity, regulatory T-cell function, and T-cell exhaustion.
CAR T cells overexpressing BATF3 significantly outperformed control CAR T cells in both in vitro and in vivo tumor models. In addition, BATF3 programmed a transcriptional profile that correlated with positive clinical response to adoptive T-cell therapy.
CRISPR knock-out screens with or without BATF3 overexpression identified co-factors and downstream targets of BATF, in addition to other therapeutic targets.
“This study suggests many strategies for applying this approach to enhance T-cell therapy, from using a patient’s own T cells to having a bank of generalized T cells for a wide variety of cancers,” said Gersbach. “We hope that these technologies can be generally applicable across all strategies.”
