16 July 2019

Scientists have successfully ‘super-charged’ CAR-T cell therapy so that it can be used effectively on solid tumours in mice.

Researchers at the Massachusetts Institute of Technology, USA, have developed a vaccine that dramatically boosts the CAR‑T cell population, thus allowing the cells to invade solid tumours. They found that solid tumours were eliminated in 60% of the mice that were given T-cell therapy along with the booster vaccination, while engineered T cells on their own had almost no effect.

The study, which appears in the journal Science, could also prove to be promising for preventing tumour recurrence, according to senior author Professor Darrell Irvine, associate director of MIT's Koch Institute for Integrative Cancer Research.

Two CAR-T cell therapies have been approved by the FDA, both used to treat leukaemia. However, CAR‑T cell therapy has not worked as well for solid tumours because the tumours generate an immunosuppressive environment that disarms the T cells before they can reach their target.

To address this issue, the MIT researchers gave a vaccine that goes to the lymph nodes to stimulate the CAR-T cells there. “Our hypothesis was that if you boosted those T cells through their CAR receptor in the lymph node, they would receive the right set of priming cues to make them more functional, so they'd be resistant to shut down and would still function when they got into the tumour,” said Prof Irvine.

They were able to deliver vaccines more effectively to the lymph nodes by linking them to a fatty molecule which binds to albumin and therefore allows the vaccine to go directly to the lymph nodes. The vaccine also contained an antigen that stimulates the CAR-T cells once they reach the lymph nodes.

In mice, the researchers showed that their vaccines dramatically enhanced CAR T-cell response. When mice were given about 50,000 CAR-T cells but no vaccine, the CAR-T cells were nearly undetectable in the animals’ bloodstream. However, when the booster vaccine was given the day after the T-cell infusion, and again a week later, CAR-T cells expanded until they made up 65% of the animals’ total T cell population, two weeks after treatment.

This huge boost in the CAR-T cell population translated to complete elimination of glioblastoma, breast, and melanoma tumours in many of the mice. CAR-T cells given without the vaccine had no effect on tumours, while CAR-T cells given with the vaccine eliminated tumours in 60% of the mice.

The researchers add that human cells coated with CAR antigens also stimulated human CAR-T cells, suggesting that the same approach could work in human patients.

Source: Ma, L., Dichwalkar, T., Chang, J.Y.H., Cossette, B., Garafola, D., Zhang, A.Q., Fichter, M., Wang, C., Liang, S., Silva, M., Kumari, S., Mehta, N.K., Abraham, W., Thai, N., Li, N., Wittrup, K.D., Irvine, D.J. (2019) “Enhanced CAR–T cell activity against solid tumors by vaccine boosting through the chimeric receptor”, Science, available from doi: 10.1126/science.aav8692


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