Oncologists Defend CAR-T After FDA Advisory | BioSpace

Illustrated: concept of cell therapy / iStock, Meletios Verras

Last month, the FDA announced that BCMA- or CD19-directed autologous CAR T cell therapies were under review after the agency received reports of several secondary blood cancers in patients it treated. But the leading oncologists say that the cancers seem to be rare and the therapy saves lives in the context of deadly malignancies that have already won chemotherapy and radiation.

“I doubt you’ll find a CAR-T treating physician who will change their practice because of this warning,” said Rahul Banerjee, a physician researcher specializing in multiple myeloma at Fred Hutchinson. Cancer Center of Seattle, Wash. He added that although CAR-T can put myeloma into a lasting remission, for most patients the cancer will return sooner or later, and that is a bigger concern. In addition, There is something called immortal time bias, he explained. If you get CAR-T and live longer, your risk of another cancer increases.

Biopharma companies in the CAR-T space appear to be stagnant for now. A spokesperson for Novartis, whose Kymriah was the first CAR T therapy approved in 2017, said BioSpaceNovartis found no causal relationship between Kymriah and secondary malignancies and remains confident in [its] favorable benefit/risk profile. A spokesperson for Gilead Sciences offered similar reassurance: After conducting an analysis of our data, we are not aware of any evidence to date that treatment with Yescarta or Tecartus plays a role in the development of these T-cell malignancies. cell of origin. Yescarta is approved for large B-cell lymphoma and high-grade B-cell lymphoma, Tecartus for relapsed or refractory B-cell acute lymphoblastic leukemia.

To be fair, Banerjee said, the FDA has never said CAR T therapy caused these cancers, but they are investigating it. It is the lay press that sometimes misses that nuance.

The Multiple Causes of Secondary Cancers after CAR-T

According to Bruce Levine, a specialist in cell and gene therapies at the University of Pennsylvanias Perelman School of Medicine, about 35,000 patients worldwide have been treated with CAR T therapies, including those in clinical trials. If there are secondary cancers, a very small percentage will be induced by therapy,” he said BioSpace.

The risk of a secondary cancer after CAR-T has long been known, said Brian Skorney, a Baird senior research analyst who coauthored a research note with fellow senior analyst Jack Allen. Is it a surprise that an engineered aggressive treatment with a viral vector results in secondary malignancies in rare cases? It’s not surprising, Skorney said BioSpace.

CAR-T involves taking blood from patients, isolating immune cells called T cells and using an engineered virus to genetically modify the cells to display cancer-targeting chimeric antigen receptors (CARs). Once infused back into the patient, the CAR T cells lock onto the malignant cells and kill them. On rare occasions, however, the engineered virus can insert the CAR code into a location in the genome that disrupts the function of a gene or activates a gene that promotes cancer. This is known as insertional mutagenesis. This is one reason the FDA requires 15 years of follow-up for each CAR-T patient.

Levine lists several questions that need to be answered to contextualize the rare cancers: Are the cancers CAR positive? If so, was the CAR a passenger in what happened to be a secondary evil, or did it provide assistance? What is the patient’s clinical status in terms of immunosuppressive therapies, radiation, prior chemotherapy and conditioning chemotherapy, all of which increase the risk of secondary cancer?

Allen added that it is very easy to run a genetic test on cancer cells to see if CAR is present. There are two types of viral vectors used in CAR T therapy, lentiviral vectors and gamma-retroviral vectors, and genetic testing can indicate if one is more often seen in these rare secondary cancers, he said. Both analysts are hoping for an updated advisory from the FDA soon with more details.

The Risk-Benefit Calculation

Until it is clear what the risk of secondary cancer is, Banerjee said the expansion of CAR-T labeling will be slow. I see this warning putting a spook in the field for smoldering cancers, pre-cancers or autoimmune diseases, he said. But I for one am not calling for the field to stop using CAR-T in the cancer setting. For example, if you treat a cancer patient earlier, when they are healthier, you may have a lower risk of another cancer later.

In fact, Banerjee said, he, along with other oncologists, hopes the FDA will expand its approval for CAR-T in myeloma, which currently requires a patient who has received four prior treatment regimens. Those previous regimens could have been difficult and challenging for patients, he said. We hope that the FDA will allow us to switch to CAR-T in a strategic way [an] early stage of treatment.

There are hundreds of companies in the CAR-T space, Skorney said BioSpacebut the most painful after the announcement is [those] focus on autoimmune disease. On December 5, William Blair hosted a virtual panel on cell therapies as part of its Innovators Panel. In the next research note sent to BioSpace at the company, the consensus among physicians and public and private cell therapy companies is that the risk/benefit of CAR T cell therapies in autoimmune patients differs from that in patients with late-stage cancer because most autoimmune patients who are not terminal within the next 6 months. For these patients, the bar may be set higher for safety, with William Blair’s report suggesting that any adverse events higher than grade 2 (disturbing but not dangerous) may be of concern.

The announcement of the FDA’s investigation came days before the American Society of Hematology’s annual conference, which took place in San Diego from December 9-12. The advisory was a topic of discussion, Banerjee said, at nearly all of Friday’s scientific symposia that touched on CAR-T.

The FDA also recently delayed a decision on a label extension for Bristol Myers-Squibb and 2seventybios Abecma (ide-cel), with an initial review date of December 16. The drug in currently allowed as the fifth line of treatment, after four Other treatment regimens have been tested, and the partners hope that Abecma will be approved for early use. An advisory committee meeting on label expansion is likely to take place in the first quarter of 2024 and a large group of experts will be assembled then, Allen said, adding, he hopes CAR-T itself will be a topic. and we can all ask questions. .”

So far, Banerjee has not wavered in her enthusiasm for CAR-T. He recalls a recent patient who was hospitalized for a month and whose myeloma came back and physically grew into his kidney—a rare occurrence for blood cancer. This patient is like every other myeloma patient eligible for CAR T therapy after receiving four previous treatment regimens. One month after the CAR-T infusion, he was in remission.

CAR-T works very quickly and that’s what I love about it, he said. The benefits are very real. It’s a game changer, a life saver. That’s what our patients deserve.

Jill Neimark is a freelance science writer based in Macon, Georgia. Check her out at jillneimark.com.

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