CAR T-Cell Cancer Therapy Potentially Linked to Rare Blood Cancer, Experts Respond

CAR T therapies are currently used to treat blood cancers, including multiple myelomas, leukemias, and B-cell lymphomas.

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Some cancer patients on chimeric antigen receptor (CAR) T-cell therapy, a novel cancer treatment considered a breakthrough in the past decade, developed T lymphoma as an additional cancer—a very rare phenomenon.

As of Dec. 6, 11 cases of T-cell lymphomas have been reported to the U.S. Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS) Public Dashboard. The FDA is investigating the link.

CAR T therapies are currently used to treat blood cancers, including multiple myelomas, leukemias, and B-cell lymphomas.

“The potential risk of developing secondary malignancies is labeled as a class warning in the U.S. prescribing information (USPIs) for approved ... genetically modified autologous T cell immunotherapies,” the FDA wrote in a press statement published Nov. 28.

Secondary malignancies or cancers are additional cancers that develop in another location or tissue. They are usually derived from the original tumor or cancer but can also occur as a result of treatment and other cancer-causing agents.

All currently approved CAR T-cell therapies share the risk of T-cell cancers, the FDA wrote.

Oncologist and professor Dr. Michael Bishop from the University of Chicago told The Epoch Times that from the looks of current statistics, the risk of T-cell lymphoma seems to be very rare.

“There’s been a report of 10 cases of T-cell lymphoma among those 70,000 adverse events reported, and that’s an incidence of adverse only of 0.15 percent,” he said, adding that CAR T therapy can reduce the chance of dying among patients in general.

CAR T Therapy and Malignancy Risks

Normal T cells are immune cells that fight outside pathogens, infected cells, and cancer. CAR T cells are T cells that have been genetically edited in the laboratory using a virus, allowing them to make a more targeted and stronger immune reaction against cancer cells.

Theoretically, T-cell lymphoma can occur in these genetically modified cells, depending on which part of the T cell has a gene edit.

The virus may cause newly introduced DNA to be incorporated into sites that induce lymphoma, Dr. Bishop said.

“Now, that’s a theoretical concern. It’s not known that that is the exact problem.”

The first gene therapy trials in the 1990s used viruses to manipulate genes to fix enzyme deficiencies, Dr. Bishop said.

Participants observed a high incidence of acute leukemias due to edits in stem cells in the bone marrow.

“The difference in this situation is that they were using hematopoietic stem cells, which are very immature, and it was thought that the risk was significantly lower for CAR T cells because these are mature T lymphocytes.”

He also added that secondary cancers that arise after certain treatments are relatively common in cancer therapies.

However, since T lymphomas are rare both as a primary and as a secondary cancer, the adverse event reports are surprising.

Since it is so rare, it also makes the cancer a lot harder to treat.

In the literature, there have been several reports of T lymphoma related to multiple myeloma CAR T therapy.

Most recently, in the November issue of Blood, an abstract reported T lymphoma that occurred five months after CAR T therapy. It is unknown if this case was reported to FAERS.

The authors concluded that the rare malignancy was driven by mutations that may have existed before CAR T therapy, adding that the role the CAR gene manipulation plays in the development of T lymphoma is unclear and cannot be excluded.

Nevertheless, Dr. Bishop said he hoped the current investigation would not discourage patients from CAR T therapy due to its survival benefits.

Associate professor at Harvard University and oncologist Dr. Marcela Maus told The Epoch Times that “more data are needed to establish whether there is any link at all between the CAR T cell treatment and the risk of T cell lymphoma.”

According to a January 2023 report from Harvard University, over 20,000 people have been treated with this therapy since it was first approved in 2017.

How Do CAR T Cells Differ From Normal T Cells?

For T cells to be activated for a battle against cancer cells and other pathogens, they need two signals.

Antigen-presenting cells in the body first detect a cancer cell and present it to a T cell. Under normal circumstances, the two cells would bind their receptors together, resulting in two activating signals. From here, the T cell starts attacking the cancer cells by binding to cancer cell receptors.

Rather than being activated through signals from antigen-presenting cells, CAR T cells have been edited to have receptors that bind directly to cancer cells.

Newer-generation CAR T cells have more units to their receptors that create a more substantial activation effect, leading to a more robust immune response.

This is also the reason cytokine release syndrome, which manifests due to the strong immune response, often occurs after treatment for several weeks. Up to 90 percent of patients experience this systemic inflammatory syndrome due to the greater immune reaction.

Since currently approved CAR T therapies are intended to treat cancers in B cells, CAR T cells are designed with a particular receptor that binds to a B-cell protein. As long as the cell contains the protein the CAR T cell is made to bind to, CAR T cells will kill that cell.

This would kill normal B cells that carry the protein. Hence, patients who have undergone CAR T therapy are at an increased risk of infection, and some need intravenous antibody therapies to maintain some level of immunity.

Which CAR T Drugs Are Under Investigation?

So far, the FDA has approved six CAR T therapies for treating lymphoma, leukemia, or multiple myeloma. They are as follows:

• Abecma, owned by Bristol-Myers Squibb (BMS). It is approved for treating multiple myeloma and currently has no T-lymphoma adverse reactions reported on FAERS.
• Breyanzi, also owned by Bristol-Myers Squibb, is approved for treating B lymphomas. It currently has one case of unspecified peripheral T-cell lymphoma listed on FAERS.
• Carvkti, owned by Janssen Research & Development, is approved for treating multiple myeloma. It currently has one case of T-cell lymphoma listed on FAERS.
• Kymriah, owned by Novartis, is approved to treat B-cell leukemia. Six cases of T-cell lymphoma are listed on FAERS.
• Tecartus, owned by Gilead and approved to treat lymphoma or leukemia. It has no cases of T lymphoma reported on FAERS.
• Yescarta, also owned by Gilead and approved to treat two types of non-Hodgkin lymphoma. It has three cases of T lymphoma reported on FAERS.

It should be noted that FAERS reports do not indicate that the treatment causes the adverse reaction.

A spokesperson for Novartis wrote via email to The Epoch Times that since its approval in 2017, “there is no evidence to date that would change our confidence in Kymriah’s benefit/risk profile … Novartis has not identified a causal relationship between Kymriah and secondary malignancies.”

“The overall benefit-risk profile of CARVYKTI remains favorable,” a spokesperson for Janssen wrote to The Epoch Times.

“To date, BMS has not observed any CAR-positive T-cell malignancies cases,” a spokesperson for BMS stated.

All three companies said they are collaborating with the FDA as part of the ongoing investigation.

Gilead did not respond to emails for comments.

CAR T therapy has been successful in achieving blood cancer remission. Studies have shown that over 50 percent and up to 94 percent of patients who received CAR T therapy achieved remission in multiple myeloma, B-cell lymphoma, and leukemia.

Encephalopathy syndrome can also occur after CAR T treatment. Symptoms may include memory loss or confusion and, in rarer cases, may affect speech. Symptoms usually resolve after a few days.

The primary cause of death after CAR T therapy is a relapse of cancer. About half of the patients end up relapsing. Non-relapse mortality may also occur.

Other Secondary Cancers Linked to Blood Cancer Therapies

Depending on the therapy a patient receives, they can be at risk of developing different secondary cancers, Dr. Bishop said.

Patients who receive stem cell transplants to replace their cancerous immune cells, regardless of whether the cells are transplanted from themselves or donors, are at an increased risk of developing skin cancers and solid tumors.

Chemo and radiation therapy used to treat blood cancer can cause patients to develop a second cancer.

Patients with multiple myeloma who undergo a stem cell transplant using their own cells alongside an additional maintenance therapy using lenalidomide have a higher incidence of secondary leukemias.

“Did that stop the use of this drug as a maintenance therapy? No, because in that randomized trial, there was a significant survival benefit, which has been borne out by subsequent other studies, showing that, even though lenalidomide has this definite increased associated risk of secondary leukemias, the survival benefit exceeds it,” Dr. Bishop said.

Bruce Levine, a professor at the University of Pennsylvania Health System, said in a Nov. 29 X post that the FDA report leaves “many questions unanswered.”

Naveen Athrappully contributed to this report.