Study finds low secondary cancer risk with CAR-Ts

Study finds low secondary cancer risk with CAR-Ts

There’s no doubt that CAR-T therapies have transformed the treatment of many blood cancers, but a risk of secondary malignancies has cast a pall over the class. Now, a study has suggested those concerns may be overblown.

Last November, the FDA issued a warning about a risk of secondary cancers – particularly T-cell cancers – and earlier this year it requested a change to safety labelling to include a ‘black box’ warning on all six of the BCMA-directed and CD19-directed CAR-T therapies approved in the US.

The agency said that T-cell malignancies had occurred in patients treated with ‘several products’ in the CAR-T class. Meanwhile, in Europe, the EMA also started a safety review of the six EU-approved CAR-T therapies.

To explore the risk more closely, researchers at Stanford Medicine in the US sifted through the records and a large biobank of tissue and blood samples from around 700 patients who received CAR-T therapies in the Stanford Health Care network and found that the risk of a secondary cancer was around 6.5% in the three years after therapy.

They found only one fatal case, but concluded that it was likely due to the immunosuppression caused by CAR-T therapy, rather than the CAR-T cells themselves. They believe the compromised immune system allowed pre-existing, but undetected, cancer cells to grow in the patient. 

“We wanted to understand this one rare case, so we analysed all the patients treated with CAR-T cell therapy at Stanford with wide breadth and studied this single case in extraordinary depth,” said Prof Ash Alizadeh, professor of medicine at the Stanford Cancer Institute. 

“We compared protein levels, RNA sequences, and DNA from single cells across multiple tissues and time points to determine that the therapy didn’t introduce the lymphoma into this patient; instead it was already brewing in their body at very low levels.”

It has previously been hypothesised that the cancers could result from the mis-insertion of the gene for the chimeric antigen receptor (CAR) during the genetic engineering of the T-cell therapy.

“These results may help researchers focus on the immune suppression that can precede and often follows CAR-T cell therapy,” said David Miklos, chief of bone marrow transplantation and cellular therapy at Stanford Cancer Institute.

“Understanding how it contributes to cancer risk is particularly important as the CAR-T cell field pivots from treating high-risk, refractory blood cancers to lower risk, but clinically important, disorders including autoimmune diseases.”

The study has been published in the New England Journal of Medicine.