The global race for a T cell receptor that zeros in on—and annihilates—solid tumors

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Immunobiologists in China have designed a synthetic T-cell receptor for anti-cancer therapy, which not only allows this protein to detect and destroy solid tumors, but also gives this cancer-fighting weapon a powerful stamina to get the job done.

So far, the Beijing-based research has only been conducted in animal models, but the research is a tempting step towards a new form of CAR T cell therapy for solid tumors, the subject of a global race in recent years.

The current form of treatment is composed of specially endowed cells designed to destroy cancers of the blood. The emerging form of therapy promises the same powerful action: killing cancer cells, but this time solid tumors while leaving healthy tissue unharmed.

The abbreviation – CAR – stands for chimeric antigen receptor. T cells are isolated from a patient’s blood and a gene for a special receptor is inserted into the T cells in the laboratory to produce the chimeric antigen receptor. Large numbers of these specially modified T cells are propagated in the laboratory, with the gene expressing the receptor on the T cell surface. The receptor is vital because it binds to a specific protein on patients’ cancer cells to destroy the cancer.

Once equipped with the receptor, the T cells – now chimeric antigen receptor T cells – are reintroduced into the patient as a formidable combat unit of millions. Some doctors call these specially-armed T cells “living drugs” because they fight cancer around the clock. Still others have cited CAR T cell treatment as cell, gene and immunotherapy in one.

Regardless of how the treatment is defined, CAR T cell therapy is a breakthrough form of treatment for B cell lymphomas and certain leukemias. Children were among the largest beneficiaries because the therapy was especially successful in young people compared to adults.

Still, for both age groups, solid tumors have eluded the ability of CAR T therapy to stop cancer in its path. Brain, breast, colon, lung and prostate malignancies are insensitive to the stimulated T cells. For these types of cancer, scientists say the encouraged T cells don’t last long enough to destroy tumor cells.

Immunobiologists from a Beijing-based biotechnology company and several academic centers have collaborated on a new approach that differently adds potency to T cells, promising promising efficacy against solid tumors. By addressing two glaring weaknesses in CAR T therapy, the team of collaborators has reimagined how T cells can be recharged. The resulting therapeutic, they say, is able to target cancer cells more efficiently.

The emerging technology has also been given a new name for the treatment of solid tumors. It’s called STAR T cell therapy, and differs from its predecessor in the way it was developed – with a synthetic receptor – and how it targets cancer antigens by taking advantage of strong cell signaling activity. As with CAR T, STAR T cells are primed to find tumor cells and kill the cancer.

“Chimeric antigen receptor T cell therapies have demonstrated high response rates and durable disease control for the treatment of B cell malignancies. However, in the case of solid tumors, CAR T cells have shown limited efficacy, attributed in part to intrinsic defects in CAR. signaling, ”wrote Drs Yue Liu, Xin Lin and colleagues in the journal Science Translational Medicine.

Two CAR T cell products have been approved by the U.S. Food and Drug Administration: Kymriah (tisaglenlecleucel), a Novartis drug, was approved in August 2017, followed by Yescarta (axicabtagene ciloleucel) in October of the same year. Yescarta was developed by Kite Pharmaceuticals in California, a division of Gilead Sciences, Inc.

The Beijing team has not adapted CAR T treatments to produce STAR T cell therapy. The researchers instead developed a synthetic T cell receptor and an antigen receptor that combine features of CAR T cells, but with the added internal signaling mechanisms to mimic a natural T cell.

The name STAR T cell is an abbreviation – in a roundabout way – for the process and the components: Synthetic T (cell receptor and) antigen receptor – or in shorthand – STAR.

In the Beijing study reported in Science Translational Medicine, STAR T cells outperformed their CAR T counterparts by controlling multiple solid tumor types in animal models, in this case mice.

In these experiments, STAR T cells were not fatigued as is often the case when their CAR T cell counterparts have been used against solid tumors. Depletion and ineffectiveness of CAR T cells, Liu and Lin report, are due to a phenomenon called tonic signaling, an uncoordinated and sustained activation – irreversibly erroneous – T cell signals.

In addition to the work of the Beijing scientists, researchers have shown additional problems when CAR T cells have been used to treat solid tumors. They are suppressed by molecules in and around the solid tumor, dampening their effectiveness and weakening their signaling.

In the Beijing studies, STAR T cells showed potent activity against solid tumor cells by rapidly inducing tumor regression in test mice with glioblastoma and mice with liver and lung cancer. None of the mice in the study showed signs of side effects, the scientists reported.

“STAR mediates strong and sensitive T cell receptor-like signaling, and STAR T cells show less susceptibility to dysfunction and better proliferation than traditional CAR T cells,” wrote Liu and Lin. “In addition, STAR T cells exhibit a higher antigen sensitivity than CAR T cells, which may reduce the risk of antigen loss and induced tumor recurrence in clinical use.”

The animal study reported by Liu and Lin is part of an ongoing study of the potential of STAR T cell therapy conducted by four centers in Beijing. Participating institutions include: The Institute for Immunology and School of Medicine, Tsinghua University; Tsinghua-Beijing Life Sciences Center; China Immunotech Biotechnology Co., and Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University.

While medical researchers at those institutions are targeting solid tumors in mouse models as targets for their STAR T cell research, another Beijing-based team of researchers is exploring STAR T cell therapy as a new form of treatment. People are involved in their work.

Scientists from Beijing Lu Daopei Institute of Hematology were not involved in the animal research as reported by Liu and Lin. But the institute is in the midst of early-phase studies to determine how well humans tolerate supercharged T cells.

Dr. Penhua Lu and his colleagues conducted a Phase 1 human trial reported at the American Society of Hematology’s annual virtual meeting in December. The study did not analyze the efficacy of STAR T as a treatment for solid tumors, but tested the cell infusion as a treatment for recurrent B-cell acute lymphoblastic leukemia.

Lu called the study “a first study in humans to determine the technical feasibility, clinical safety and efficacy of the therapy.” But she is also well aware of the dedicated T cell treatment for solid tumors. Lu spoke during the discussion period of the meeting about the prospects of STAR T cell therapy for these types of cancer. “It can potentially better recognize and target the tumor’s intracellular antigen than a conventional CAR T. It is easier to construct – and holds great promise for the treatment of solid tumors,” said Lu.

A leap forward in CAR T cell therapy research

More information:
Yue Liu et al. Chimeric STAR Receptors Using TCR Machines Provide Robust Responses Against Solid Tumors, Science Translational Medicine (2021). DOI: 10.1126 / scitranslmed.abb5191

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