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Engineered T-cells show promise

Chimeric antigen receptor (CAR)-T-cells are a concept in development for treating cancer. Seattle researchers have published a new approach for developing CAR-T-cells. This new strategy could eventually lead to better outcomes for people living with HIV.

What is a CAR-T cell?

T-cell receptors help trigger immune responses. T-cell receptors are found on the surface of T cells, extending inside the cell to signal to other molecules. CAR-T cells have an engineered T-cell receptor. In a CAR-T-cell, the outer and inner segments of the receptor come from different molecules.

Why develop this approach for HIV?

Antiretroviral drugs don’t completely get rid of HIV infection. Natural immune responses are also not able to clear lingering virus. CAR-T-cells might be able to do what regular T cells can’t — kill HIV-infected cells remaining in the body during therapy. This is because CAR-T-cells recognise a broad range of HIV-infected cells, are potent and may be less affected by the blocks limiting regular T cells. CAR-T-cells have already been developed and tested in people living with HIV. Clinical trials of first-generation CAR-T-cells showed that the cells stay in the body for more than ten years, but do not reduce the amount of virus.

What’s different this time?

In the recent study, the outer segment of the T-cell receptor included parts of broadly neutralising antibodies (bNAbs) which effectively target multiple HIV strains. The researchers used an inner segment of the T-cell receptor from normal T cells, with co-stimulatory components that weren’t included in the first-gen CAR-T-cells. The researchers made the CAR-T-cells resistant to HIV infection by directing the T-cell receptor genes to the middle of the CCR5 gene. The engineered cells specifically targeted HIV-infected cells, and were resistant to HIV infection.

What exactly did the researchers do?

First, the researchers created CAR-T-cells from healthy human T cells using five different bNAbs. The researchers then tested the cells in a range of experiments. The CAR-T-cells became activated in the presence of HIV-infected cells, and could kill HIV-infected cells.

Secondly, the researchers selected the most potent CAR-T variant (PGT145-CAR) to test CCR5 disruption. Similar to the first lot of CAR-T-cells, the CCR5-edited CAR-T-cells were activated and could kill HIV-infected cells. In addition, the CCR5-edited CAR-T-cells were better at dealing with active virus replication.

What does this all mean?

This work shows the potential for engineered T-cells based on broadly neutralising antibodies that are themselves resistant to HIV infection.

These cells are specifically switched on when they encounter HIV antigens. They are able to kill HIV-infected cells even when there is a lot of HIV around because they don’t get infected and can maintain their potent function.

This work is still at an early stage. All of the experiments in this study were done in laboratory models of disease. The CCR5-edited CAR-T-cells haven’t been tested in humans yet. Recent funding announcements suggest that there is a lot of preclinical exploration of this promising strategy to come.

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