Using genetic engineering, physician and scientist Christopher Klebanoff, has led a team of researchers to create a “cloak” that protects cancer-fighting T white blood cells, such as chimeric antigen receptor T cells from self-destructing.
During cancer immunotherapy, immune cells often undergo a form of cellular suicide – termed apoptosis, which can limit the therapy’s effectiveness.
The use of “genetic cloaking” prevents immune cell apoptosis, enhancing the effectiveness of cellular immunotherapies for liquid and solid cancers in mouse models.
This new technique is also effective in protecting human cancer-fighting immune cells.
These findings are published in the Journal of Clinical Investigation and lay the groundwork for a potentially universal gene-engineering strategy to safely increase the potency of cellular immunotherapies for a broad range of cancers.
Dr Klebanoff and colleagues hypothesised that the disruption of pathways that impair T white blood cell survival might represent exploitable targets for improving outcomes following a form of cancer immunotherapy known as adoptive immunotherapy.
This type of immunotherapy uses genetically engineered T cells for individuals with refractory B cell malignancies, but responses to this therapy have been comparatively modest in patients with solid malignancies.
In this study, the team analysed gene expression data from many tumour types to identify the potentially actionable molecules in the tumour microenvironment that were capable of compromising the longevity of T cells following transfer into patients.
The researchers found that the major pathway involved in apoptosis – the FasL/Fas pathway is poised to be activated in many people receiving adoptive immunotherapy.
Specifically, Dr Klebanoff and his colleagues found that FASLG (the gene encoding the death-signalling ligand FasL) was over-expressed in 73 percent of the human tumour types evaluated.
This over-expression was found to be highly correlated to the expression signatures of immune regulation and activation.
Death-signalling (or apoptosis-inducing) ligands can cause immune cells to kill themselves, potentially resulting in poorer outcomes following adoptive immunotherapy treatments.
Based on these findings, the team went on to develop a series of decoy receptors, termed dominant negative receptors (DNRs), which wrap around T white blood cells to protect them from receiving the kill signal delivered by FasL – in effect, creating a genetic cloak.
The Fas DNR-modified engineered T cells exhibited superior persistence in tumour-bearing animals, resulting in significantly improved cancer regression and survival in both solid and liquid cancer models.
The researchers concluded that the Fas DNR-modified T cells can cloak both mouse and human T cells from FasL-induced cell death, providing a new method to protect adoptively transferred T cells in the human tumour microenvironment.
“Cellular therapy has now entered the standard of care for certain kinds of blood cancers. However, new strategies that enhance the potency of transferred T white blood cells without increasing side effects are desperately needed if cell therapy is to serve a broader role in the treatment of solid malignancies, collectively the leading cause of cancer-related deaths,” explained Dr Klebanoff.
He also added: “These initial promising results have shown that ‘genetic cloaking’ can disrupt the factors that negatively regulate T white blood cell survival. In turn, the greater survivability of the cancer-fighting white blood cells results in superior cancer regression in multiple difficult-to-treat cancer models. We look forward to continuing to advance this research forward into human clinical trials in the coming years.