Engineering T cells to destroy cancer cells has shown success in treating some types of cancer, such as leukaemia and lymphoma.

However, it hasn’t worked as well for solid tumours.

One reason for this lack of success is that the T cells target only one antigen (a target protein found on the tumours); if some of the tumour cells don’t express that antigen, they can escape the T cell attack.

MIT researchers have now found a way to overcome that obstacle, using a vaccine that boosts the response of engineered T cells, known as chimeric antigen receptor (CAR) T cells, and also helps the immune system generate new T cells that target other tumour antigens.

 In studies in mice, the researchers found that this approach made it much more likely that tumours could be eradicated.

“This vaccine boosting appears to drive a process called antigen spreading, wherein your own immune system collaborates with engineered CAR T cells to reject tumours in which not all of the cells express the antigen targeted by the CAR T cells,” says Darrell Irvine, the Underwood-Prescott Professor with appointments in MIT’s departments of Biological Engineering and of Materials Science and Engineering, and a member of MIT’s Koch Institute for Integrative Cancer Research and the Ragon Institute of MGH, MIT, and Harvard.

Irvine is the senior author of the study, which appears today in Cell.

The lead author of the paper is Leyuan Ma, a former postdoc at the Koch Institute and currently an assistant professor of pathology and laboratory medicine at the University of Pennsylvania School of Medicine.

Engineered T cells

The U.S. Food and Drug Administration has approved several types of T cell treatments for blood cancers. These treatments are based on CAR-T cells, which are engineered to display receptors that can recognise a specific antigen found on cancer cells.

To try to adapt this kind of treatment to glioblastoma, a type of brain cancer, researchers have designed CAR-T cells that target a mutated version of the EGFR receptor.

However, not all glioblastoma cells express this antigen, and when attacked by CAR-T cells, some glioblastoma cells respond by halting production of the target antigen.

In a 2019 study, Irvine and his colleagues enhanced CAR-T cells’ effectiveness against glioblastoma by delivering a vaccine to mice shortly after the engineered T cells were administered.

This vaccine, which carries the same antigen targeted by the CAR-T cells, is taken up by immune cells in the lymph nodes, where the CAR-T cells are exposed to it.

In that study, the researchers found that this vaccine boost not only helped the engineered CAR-T cells attack tumours, but it had another, unexpected effect: It helped to generate host T cells that target other tumour antigens.

This phenomenon, known as “antigen spreading,” is desirable because it creates populations of T cells that, working together, can fully eradicate tumours and prevent tumour regrowth.

“That would be exactly the kind of thing that could help you deal with the antigen heterogeneity of solid tumours, because if you primed host T-cells to attack other antigens, they may be able to come in and kill the tumour cells that your CAR-T cells cannot,” Irvine says.

An immune boost

In their new study, the researchers wanted to explore how that additional T-cell response becomes activated.

They used the same type of CAR-T cells from their 2019 study, which are engineered to target mutant EGFR, and the same vaccine.

The mice in the study were given two doses of the vaccine, one week apart.

The researchers found that in these boosted mice, metabolic changes occurred in the CAR-T cells that increased their production of interferon gamma, a cytokine that helps stimulate a strong immune response.

This helps the T cells to overcome the immunosuppressive environment of the tumour, which normally shuts down any T cells in the vicinity.

As the CAR-T cells killed tumour cells expressing the target antigen, host T cells (not the engineered CAR-T cells) encountered other antigens from those tumour cells, stimulating those host T cells to target those antigens and help destroy tumour cells.

Without that host T cell response, the researchers found, tumours would regrow even if the CAR-T cells destroyed most of the original tumour cells.

This happens because tumour cells treated with CAR-T cells often stop producing the antigen targeted by the engineered cells, allowing them to evade those cells.

Tumour eradication

The researchers then tested their approach in mice with tumours that had different levels of the target antigen.

They found that even in tumours where only 50 percent of the tumour cells expressed the target antigen, about 25 percent of the tumours could still be eradicated, by a combination of CAR-T cells and host T-cells.

The success rate was higher for tumours with greater levels of the target antigen.

When 80 percent of the tumour cells expressed the antigen targeted by CAR-T cells, tumours were eliminated in about 80 percent of the mice.

The technology used in this study has been licenced to a company called Elicio Therapeutics, which is working on developing it for potential testing in patients.

In this study, the researchers focused on glioblastoma and melanoma, but they believe it could potentially be used to combat other types of cancer as well.

“In principle, this should apply to any solid tumour where you have generated a CAR T-cell that could target it,” Irvine says.

The researchers are also working on ways to adapt CAR-T cell therapy so that it can be used to attack tumours for which no targetable antigens have been identified.

Source: Massachusetts Institute of Technology