CRISPR used to engineer precision in vivo CAR T cells

Hello Nature readers,
This week, we discover a more precise way to engineer in vivo CAR T cells, hear that ageing drives the spread of lung cancer and learn how metastatic breast cancer cells resist attack from immune cells.

Greater precision for in vivo CAR T

Researchers have invented a two-vector system that uses CRISPR–Cas9 gene editing to create in vivo cancer-fighting CAR T cells without accidentally targeting other cells. Leukaemia and multiple myeloma were eliminated in the mice treated with these precision in vivo CAR T cells, while more than half of mice with sarcoma went into remission. Biotech company Azalea Therapeutics is testing the approach in monkeys and hopes to trial the treatment in people by the end of next year.

Ageing drives metastasis in lung cancer

As mice age, their cells become stressed, and levels of a protein called ATF4 increase, helping lung cancer to spread. Targeting this pathway using genetic edits or drugs limits the spread of tumours. Lung cancer is most commonly diagnosed in older people aged 65-75 but researchers typically rely on young mice to develop therapies for the disease. “This age disconnect between experimental models and patients may explain why many cancer therapies that perform well preclinically, such as with glutaminase inhibitors, have failed to translate their efficacy in clinical trials,” write the authors.

How breast cancer blocks immune cells

Breast cancer cells can spread to the lungs by resisting attack from immune cells — a process that involves a stress response that activates the glucocorticoid receptors. In mice with triple-negative breast cancer, researchers found that blocking these receptors using a drug called mifepristone in combination within immunotherapy reduced the spread of breast cancer and extended the lifespan of mice. Stress hormones can be chronically elevated in people with advanced breast cancer, either because of prolonged stress and pain associated with the diagnosis or because of use of synthetic glucocorticoids as anti-inflammatory treatments. This study suggests that both of these factors could drive cancer progression.

Tumour cells in the blood guide treatment

People with head and neck cancer are around 40% more likely to survive without a relapse over three years if the frequency and dosage of their chemoradiotherapy is guided by their circulating tumour DNA levels than if it is not. This dynamic therapy “could be a promising strategy to improve survival, challenging the conventional fixed-course, static treatment approach,” report the authors.

Herding is hoarding

The money and time invested in clinical trials for cancer drugs called TIGIT inhibitors would be better spent investigating a broad range of drug types, argue health-policy researchers Emily Zhang and Leeza Osipenko and biologist John Hickman. More than US$3 billion has been spent by 21 competing companies on TIGIT inhibitor clinical trials, involving nearly 49,000 people. But it is unlikely that these medications will receive approval, given that 95% of oncology drugs fail in clinical trials. This race to develop TIGIT inhibitors is a case of ‘herding’, where conformity is preferred to diversification, they write. “The risks of drug toxicity in ineffective clinical trials of this magnitude have raised moral questions concerning the role of patients in such trials,” write the authors.