Some CAR-T may very rarely cause new cancers

The FDA issued a statement this week that there have been reports of new cases of blood cancer after patients received CAR-T therapies. The FDA specifically mentions T cell malignancies.

CAR-T, CAR-T cancer
Killer T cells (green and red) surrounding a cancer cell. “Credit: Alex Ritter, Jennifer Lippincott Schwartz, and Gillian Griffiths, National Institutes of Health.” CAR-T cells work in this way too, but could they sometimes rarely lead to new cancers?

New cancers in rare cases?

In the announcement, FDA Investigating Serious Risk of T-cell Malignancy Following BCMA-Directed or CD19-Directed Autologous Chimeric Antigen Receptor (CAR) T cell Immunotherapies, the agency reported that the benefits of CAR-T still appear to greatly outweigh possible risks of new cancers.

Gina Kolata at the New York Times covered this development: Innovative Cancer Treatment May Sometimes Cause Cancer, F.D.A. Says. Angus Chen at STAT also has coverage on the possible CAR-T new cancer risk.

Open questions on cancer CAR-T connection

There isn’t a whole lot of information or specifics on this new development so that leaves many open questions.

Are all of the new cancers T-cell malignancies as might be expected? Are the malignancies found in patients who received specific kinds of CAR-T therapies? How often are the CAR transgenes found in the new cancers? Are specific endogenous genes activated or inactivated?

One previously reported case of a patient implicated TET2 inactivating variants in clonal expansion. While that may have actually helped that particular patient, such cells could be a step closer to oncogenic transformation in some contexts.

One thing that seems clear is that these are very rare events.

From the NYT:

“While the hypothetical risk was known, “we haven’t observed it” in patients, Dr. Marcela V. Maus, director of cellular immunotherapy at Massachusetts General Hospital, said.

Dr. John DiPersio, director of the center for genetic and cellular immunotherapy at Washington University School of Medicine in St. Louis, said his center had treated 500 to 700 patients. And, he said, “I haven’t seen a single one” develop a new T cell cancer.

CAR-T therapy has been reserved for patients who would die without it, he added.

“They are all going to die and they are all going to die quickly without this treatment. It saves their life,” Dr. DiPersio said. “It works in a substantial portion of patients. The benefit is enormous.”

Some thoughts from Bruce Levine

I also asked leading cell and gene therapy researcher Bruce Levine from his thoughts on this development.  He reiterated what others have said that in talking with colleagues that these events seem extremely rare. In fact, many researchers and clinicians have never had CAR-T patients develop such new malignancies. He also noted:

“No information is available that I can find on in how many patients the CAR transgene was actually present in the T cell lymphomas. FDA says “some”. This is very important as lineage switch in hematologic malignancies is a not uncommon occurrence.”

and

“While we wait for the results of the FDA investigation, we will continue, based on diligence and our considerable cell therapy expertise at Penn Medicine, to: (i) make commercial CART products available to patients when this appears to be the best option possible (based on the most up to date and confirmed safety information) and (ii) lead, develop, and conduct research in this area based on (based on the most up to date and confirmed safety information)”

This makes good sense.

On the whole, CAR-T therapies have saved thousands of lives. However, if some CAR-T therapies do very rarely cause new cancers we need to understand exactly how that happens and in which cases.

Perhaps such rare events can then be prevented in some cases by new research as Bruce noted.

The FDA now suggests following CAR-T recipients have follow-up for life instead of just 15 years after getting the therapy.

What CAR-T therapies are approved?

Here are the CAR-T therapies currently approved by the agency.

  • Abecma (idecabtagene vicleucel)
  • Breyanzi (lisocabtagene maraleucel)
  • Carvykti (ciltacabtagene autoleucel)
  • Kymriah (tisagenlecleucel)
  • Tecartus (brexucabtagene autoleucel)
  • Yescarta (axicabtagene ciloleucel)

Some of the manufacturers have started making announcements related to the news. According to NCI, all these CAR-T products use viruses, which could contribute to risks in some cases.

You can also see my wider list of FDA-approved stem cell, cell therapy, and gene therapy products.

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1 thought on “Some CAR-T may very rarely cause new cancers”

  1. CAR-T also described as a – living drug- involves targeting cancer cells. T cells are collected from a patient blood sample- re-engineered in a lab to identify and kill cancer cells. But to cure cancer and avoid any recurrence – we need to target cancer stem cells in addition to cancer cells. I am not surprised by the recent FDA findings.

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