Cancer treatments boosted by immune-cell hacking

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A CAR T cell (orange) attacks a cancer cell (green).Credit: Eye of Science/Science Photo Library
Elaborately engineered immune cells can not only recognize cancer cells, but also evade defences that tumours use to fend off attacks, researchers have found.
Two studies published today in Science¹^,² build on the success of chimeric antigen receptor (CAR)-T cancer therapies, which use genetically altered T cells to seek out tumours and mark them for destruction. These treatments have the potential to lead to long-lasting remission, but are not successful for everyone, and have so far been effective against only a small number of cancers.

Last-resort cancer therapy holds back disease for more than a decade

Last-resort cancer therapy holds back disease for more than a decade
To bolster the power of CAR-T therapies, researchers have further engineered the cells to contain switches that allow control over when and where the cells are active. The hacked cells produce a protein that stimulates T cells, to counteract immunosuppressive signals that are often released by tumours.
Both studies are a tour de force in T-cell engineering and highlight the direction that researchers want to push CAR-T-cell therapy, says systems immunologist Grégoire Altan-Bonnet at the US National Cancer Institute. “We know a lot of the parts, now it’s being able to put them together and explore,” he says. “If we engineer the system well, we can really put the tumours into checkmate.”
T cells typically patrol the body, looking for foreign proteins displayed on the surface of cells. Such cells could be infected with a virus, for example, or they could be tumour cells that are producing abnormal, cancer-associated proteins. A class of T cells called killer T cells can then destroy the abnormal cells.
CAR-T therapies involve genetically engineering T cells from a person with cancer to produce CARs, which are proteins that recognize the proteins displayed by tumour cells.
The approach has been approved to treat some leukaemias, lymphomas and myelomas. But researchers have been pursuing ways to make the treatments safer and more effective, and to expand their use to other diseases.

Highly mutated cancers respond better to immune therapy

Highly mutated cancers respond better to immune therapy
In one of the new studies, Ahmad Khalil, a synthetic biologist at Boston University in Massachusetts, and his colleagues wired a complex system of 11 DNA sequences into CAR T cells. The resulting genetic circuits can be switched on and off using already-approved drugs, which allows researchers to control when and where the hacked T cells are active, as well as their production of a protein called IL-2, which stimulates immune responses.
The other group of researchers, led by synthetic biologist Wendell Lim at the University of California, San Francisco, programmed CAR T cells to produce IL-2 only when the engineered T cell encounters a cancer cell. The team found that this IL-2 production was most efficient at fighting tumours in mice with pancreatic cancer when it was activated through a pathway that was separate from the one used to recognize the cancer cell — a detail that could help in shaping future therapies, says Andrea Schietinger, a tumour immunologist at Memorial Sloan Kettering Cancer Center in New York City.
Both approaches could be particularly useful in crafting CAR-T therapies that can target solid tumours, Schietinger says. Solid tumours have posed a particular challenge to CAR-T approaches because the engineered cells have difficulty infiltrating the tumours and, once there, can be disabled by signals that cancer cells use to suppress the immune response. “These engineered T cells overcome both roadblocks,” she says. “They find their way in and then, once they’re in, get the signals in the right space and at the right time to be really effective in killing the cancer cell.”
The ability to turn the T cells on and off could also help to reduce a phenomenon called T-cell exhaustion, in which T cells become inactive after a prolonged period of stimulation, says Evan Weber, a cancer immunologist at the Children’s Hospital of Philadelphia in Pennsylvania. Some studies have found that giving T cells a ‘rest period’ can reduce T cell exhaustion and boost their overall effectiveness against tumours³.

Building better CAR-T therapies

Building better CAR-T therapies
Lim plans to further develop the system for testing in clinical trials, and to tweak it to explore the effects of producing other molecules that, like IL-2, stimulate immune cells. There has been a growing realization that such molecules, called cytokines, could be pivotal to the success of CAR-T therapies, says Weber. “We know we need smarter ways of tapping into them,” he says, “rather than just turning on a receptor all the time or secreting a cytokine constitutively.”
Khalil hopes that the system that he and his colleagues have developed will be usable in other cell types, including another type of immune cell called macrophages, which are better than T cells at penetrating solid tumours. His genetic circuits were designed with adaptability in mind, so that researchers who specialize in cancer immunotherapies — or fields such as gene therapy or stem-cell biology — can tweak them to suit their needs. “I hope this will capture the imagination of a lot of researchers out there,” he says.
doi: https://doi.org/10.1038/d41586-022-04465-y
Li, H.-S. et al. Science 378, eade0156 (2022).
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Allen, G. M. et al. Science 378, eaba1624, 2022.
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Weber, E. W. et al. Science 372, eaba1786 (2021).
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Last-resort cancer therapy holds back disease for more than a decade
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University College London (UCL)
London, United Kingdom
Technische Universität Dresden (TU Dresden)
01069 Dresden, Germany
Francis Crick Institute
London, United Kingdom
The University of British Columbia (UBC)
Vancouver, Canada
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