UCL, Autolus Develop New Strategy to Treat T cell Malignancies
Mature T cell cancers are typically aggressive, treatment-resistant and associated with poor prognosis. Clinical application of immunotherapeutic approaches has been limited by a lack of target antigens that discriminate malignant from healthy (normal) T cells. Unlike B cell depletion, pan–T cell aplasia is prohibitively toxic.
And now, Autolus, a young biotech spun from University College London (UCL), has revealed a new strategy to treat T-cell lymphoma without harming healthy, protective T cells. The therapy is expected to start human tests soon.
T-cells recognize and remove germs using a molecule on their surface called the T-cell receptor. This receptor is made using one of two duplicated copies of the T-cell receptor gene, called C1 or C2, at random. As a result, the T-cells we use to fight off viruses and other germs are a near equal mixture of cells using either the C1 or C2 genes. When a T-cell becomes cancerous all cancer arises from a single cell so that the cancer is either all C1 or C2.
In the study, UCL and Autolus researchers leveraged the mutually exclusive expression of two versions of the T cell receptor beta chain (TCRB) constant domain
— T cell receptor beta constant 1 (TRBC1) and TRBC2 — to deplete a portion of the T cell repertoire including malignant cells, while leaving the other, non-malignant portion intact.The researchers identified an mAb that bound TRBC1 with ten-thousandfold greater affinity than TRBC2, despite the high similarity between the two proteins. They showed TRBC1- and TRBC2-positive cells comprised about 35% and 65% of all T cells in healthy volunteers, respectively. Both TRBC1- and TRBC2-positive cells were present in all T cell subsets including anti-viral repertoires, suggesting functional T cell immunity might be preserved if only one of the subsets were depleted.
In samples from T cell leukemia patients, each malignancy was mostly TRBC1 or TRBC2-positive, indicating that targeting one subset alone would eliminate most of the malignant cells.
They developed a CAR based on the anti-TRBC1 mAb and showed normal human T cells transduced with the CAR killed TRBC1-positive, but not TRBC1-negative, T cells in samples from patients with TRBC1-positive malignancies or healthy volunteers. In xenograft mice transplanted with a mix of TRBC1-positive and TRBC2-positive leukemia cells, anti-TRBC1 CAR T cells eliminated the former but not the latter.
In a xenograft model of TRBC1-positive T cell leukemia co-transplanted with normal human peripheral blood mononuclear cells (PBMCs), anti-TRBC1 CAR T cells decreased tumor burden but left behind similar numbers of normal T cells as CAR T cells targeting an unrelated antigen.
Professor Andrew Sewell from Cardiff University’s School of Medicine said: “We wouldn’t last a week without the essential job our T-cells perform by protecting us from infection. The devastating effects of low numbers of just one type of T-cell are all too evident in HIV/AIDS.”
“T-cell lymphomas are particularly difficult to treat without damaging essential, healthy T-cells that are vital to the immune system. The new and innovative approach that Autolus have developed now allows the potential for removal of all cancer cells without causing any damage to half of our T-cells. Since T-cells select use of the C1 or C2 gene at random, this remaining half of T-cells are capable of providing immunity to the pathogens we encounter every day.”
Dr. Justine Alford from Cancer Research UK, said: “This study has demonstrated it’s possible to kill cancerous T-cells but importantly spare some healthy ones, opening up exciting new treatment possibilities. T cells are a vital part of our immune system and our survival; that’s why when a patient has cancer in these cells, it would cause serious harm to use a therapy that targets both healthy T cells and cancerous ones.”
“This research is still in the experimental phase though, so researchers will need to do further studies to prove the method is safe and effective before starting clinical trials in people.“
