CAR-T therapy has been successfully used to treat hematologic cancers such as leukemia and lymphoma for more than a decade. However, some patients have developed secondary malignancies after treatment, casting a carcinogenic shadow on this emerging anti-cancer therapy.
Compile | Zhou Shuyi
Emerging therapies that were originally relied on to fight cancer are now caught in a vortex of carcinogenic suspicions.
On April 18, the FDA issued a notice formally requiring updates to the "black box warning" for chimeric antigen receptor T-cell (CAR-T) therapies, emphasizing the serious risk that they may lead to T-cell malignancies.
These risks ripple through all FDA-approved CAR-T therapies, and FDA requires revisions to the warnings and precautions, post-marketing adverse reactions, patient advisory information, and medication guidelines sections on the labels of these products. Mature T-cell tumours may "emerge a few weeks after the infusion of CAR-T immune cells" and "lead to fatal consequences," the notice reads. Patients receiving treatment should be monitored for secondary malignancy for life.
The announcement is the result of a five-month investigation. In November 2023, the FDA announced an investigation into the carcinogenic risk of the therapy in patients who developed T-cell malignancies after receiving autologous CAR-T cell immunotherapy targeting BCMA or CD19. In January 2024, the FDA required all approved CAR-T products to update their product labels to include carcinogenic warnings.
The "black box warning" incident dropped a bombshell on the industry. On the day the investigation was launched, Gilead, a leading CAR-T pharmaceutical company that owns Yescarta and Tecartus, issued a statement saying that the company was "confident" in the safety of the therapies. The next day, Gilead announced a net layoff of 5% of its cell therapy subsidiary, Kite Pharma, and about 300 employees were laid off.
Suspected cases of secondary cancer
CAR-T is a "personalized" cellular immunotherapy - the patient's own peripheral blood T cells are extracted, genetically engineered, and transferred into chimeric antigen receptor (CAR)-related genetic material, which is amplified in vitro and then infused back into the patient. T cells expressing specific CARs can specifically recognize surface antigen molecules and target the removal of tumor cells for precise cancer treatment.
The problem lies in the genetic engineering step. In order to transport the gene sequence encoding the CAR into the cell, it is usually necessary to γ a gamma retrovirus or lentivirus as a vector. All six of the FDA-approved therapies use retroviruses, which insert the CAR gene into the genome of a cell after entering T cells. However, there is currently no good way to precisely control the location of the insertion, once the gene is inserted near the "oncogene" to enhance its expression, or the tumor suppressor gene is inserted to "inactivate" it, it is possible to "blacken" the T cells and become cancer cells.
This phenomenon is known as "insertional mutagenesis" and is a risk for many gene therapies. In 2002, an international team of researchers tried gene therapy to treat 20 babies with severe combined immunodeficiency syndrome (SCID), and five babies developed leukemia and one of them died due to retroviral activation of the proto-oncogene.
Some patients develop secondary cancers after being treated with Carvykti, a type of CAR-T therapy, and not just T-cell cancers that the FDA warns about. Long-term follow-up of participants in Carvykti's early trial found that 10 out of 97 people developed myelodysplastic syndrome (a precursor to leukemia) or acute myeloid leukemia, and nine of them died. In December 2023, Legend Biotech added a warning message to the packaging of Carvykti products.
According to a case study published in the journal Blood, a 51-year-old man with multiple myeloma underwent a Carvykti clinical trial and the treatment was effective. But five months later, a lump quickly developed on his nose. A biopsy revealed that it was T-cell lymphoma. Sequencing revealed that the CAR gene was inserted into the regulatory region of the PBX2 gene.
However, to determine whether the culprit of cancer is CAR-T, it is not enough to detect the insertion of the CAR gene in cancer cells. The researchers found that the man's cancer cells also had a mutation in lymphoma, a common mutation in lymphoma, and that even without the insertion of the CAR gene, his risk of cancer was higher than normal. Piers Blombery, a hematologist at Australia's Peter McCallum Cancer Centre and head of the diagnostic laboratory responsible for evaluating tumor samples, said there was a high chance that precancerous T cells had been mixed in when the patient's cells were extracted.
"Do you have hard evidence?"
Bruce Levine, an immunologist at the University of Pennsylvania's Perelman School of Medicine, is a CAR-T pioneer who was involved in the development of Kymriah, the first approved CAR-T cell therapy. It wasn't until a reporter came to ask for advice that he learned of the FDA's warning. Levine has a lot of questions: How many patients develop cancer after treatment? What is the patient's condition? In addition to CAR-T, what other drugs have they used?
Now, despite warnings attached to the packaging of CAR-T drugs in the United States and an investigation by the European Medicines Agency, many of Levin's questions remain unanswered. In fact, many common cancer therapies, including chemotherapy and radiotherapy, have a carcinogenic risk, and the same patient often receives multiple treatments, and it is difficult to say to what extent the cancer is directly derived from CAR-T. As Crystal Mackall, head of the Cancer Immunotherapy Program at Stanford University, said, "Do you have hard evidence? ”
Data are limited because there are not enough samples available for analysis. In January, Nicole Verdun and Peter Marks of the FDA's Center for the Evaluation and Study of Biologics published at NEJM that they had received more than 27,000 reports of patients treated with CAR-T, including 22 cases of leukemia. Genetic sequencing showed that the cancerous T cells in 3 cases contained the CAR gene. "This suggests that CAR-T products are likely to be involved in T-cell cancer progression," the paper states. ”
As of March 25, 11 more reports of secondary cancers had been received, and genomic analysis of these cases had not been completed, but so far none have been confirmed as negative for the CAR gene, according to FDA spokesman Paul Richards. He stressed that the reports of positive CARS, in particular, "strongly suggested" that there was a risk of T-cell carcinoma from the therapy.
Scientists and regulators have made many efforts to reduce the risk. Researchers have made a series of modifications to the vector, and the FDA has recommended that CAR-T products be tested to ensure that the gene is inserted in the correct position and that the vector does not replicate on its own. Marco Ruella, a hematologist at the Perelman School of Medicine, said many researchers trust the viral vectors used in CAR-T therapy because it is difficult for T cells to induce malignancies. "In fact, the general perception is that lentiviruses and retroviruses for T cells are extremely safe."
Craig Tendler, vice president of clinical development and global medical affairs for oncology at Johnson & Johnson Innovative Medicine, said they did not find the CAR gene in cancer cells, but when comparing tissue samples from patients before and after treatment, the researchers found that some cells already had the same genetic makeup as cancer cells long before receiving CAR-T therapy. "So it's likely that in many of these cases, previous treatment for multiple myeloma has predisposed the patient to secondary malignancy," Tendler said. "Then, the long-term immunosuppression required for CAR-T therapy further fuels the carcinogenesis process.
Most cancer therapies can cause cancer
When Luela first saw the FDA warning, he immediately recalled a patient he had treated in 2020. It was a 64-year-old man with B-cell lymphoma. Three months after receiving CAR-T therapy, he developed T-cell lymphoma again. Lymph node biopsy shows the presence of the CAR gene. But the gene content is very low, and it doesn't look like it's integrated into the genome of cancer cells. Instead, Lueila thought at the time that the genes might have come from CAR-T cells that happened to pass through the lymph nodes at the time of biopsy. "We thought it was just an accident." Luela said.
And now, Luela has decided to revisit the case. He and his colleagues compared blood samples taken before and after treatment to assess whether the T cells had the same T cell receptors as the lymphoma cells before treatment, and the results were positive. This suggests that the "seed" of lymphoma existed long before CAR-T therapy. Luela believes that CAR-T therapy may create an inflammatory environment that allows these seeds to begin to germinate. So secondary cancer "isn't something that comes out of thin air like magic." ”
The good news is that whether the culprit is CAR-T or not, secondary cancers appear to be rare. Luella reviewed Penn Medicine's patient files. From January 2018 to November 2023, the institution treated 449 patients with leukemia, lymphoma, or multiple myeloma using commercial CAR-T products. Sixteen patients developed secondary cancers, but most of them were solid tumors that were unlikely to be directly caused by treatment. Only 5 developed blood cancer, 1 of which was T-cell cancer.
Mayo Clinic hematologist Rafael Fonseca and colleagues combed through a dataset of 330 million people's medical records, and in patients newly diagnosed with multiple myeloma or diffuse large B-cell lymphoma between 2018 and 2022, they found that the rate of secondary T-cell lymphoma (FDA report 22/27000) in patients treated with CAR-T therapy did not change much compared to other patients.
A study in the journal Blood analyzed data from the FDA's Adverse Event Reporting System (FAERS): of the 12,394 adverse reaction reports of CAR-T, 536 reported secondary primary malignancies, accounting for 4.3%; Among them, leukemia (333 cases, 2.7%), followed by skin cancer (54 cases, 0.4%); The most commonly used therapies for adverse events were axi-cel (Yescarta, 277 patients) and tisa-cel (Kymriah, 177 patients). According to the investigators, CAR-T therapy does lead to "an increased risk of certain secondary primary malignancies, but the rate is low and cannot be conclusive evidence that CAR-T causes cancer." This is also in line with the FDA's conclusion that carcinogenicity is very rare, and the overall benefits of the treatment still outweigh the potential risks.
Now, when faced with patients considering CAR-T therapy, Aric Hall, a hematologist at the University of Wisconsin-Madison, will tell them that there may be a risk of secondary cancer. He describes it as a definite, but very rare, risk, which is insignificant compared to the cancer at hand: "The main risk for my patients with advanced myeloma is that the CAR-T doesn't work and they die from myeloma. ”
McCaul and others agree, arguing that the FDA's warning will not change current medical practice in the slightest. "Most cancer therapies can cause cancer, and that's a paradox in our industry."
The six CAR-T therapies currently approved in the U.S. and Europe target only B-cell malignancies – leukemia, lymphoma and multiple myeloma. Compared to the hope of life, this risk is nothing at all. However, in recent years, the scope of application of CAR-T has been broadened, and several related therapies have been approved as relatively early second-line options. Several companies are also working on the use of CAR-T to fight autoimmune diseases, aging and AIDS. For these patients, there may be a trade-off between taking risks. "If patients have [other] better options, then even a small risk can become a big problem," Hall said. ”
Researchers have already experimented with CAR-T to treat lupus, with promising results, and more clinical trials for other autoimmune diseases are on the way. Clinical trials of CAR-T for the treatment of HIV were launched in 2022, and the therapy is also being used to suppress immune rejection and eliminate senescent cells in kidney transplants...... More and more possibilities are emerging for CAR-T.
Whether the benefits of CAR-T therapy outweigh the risks for these indications may only be answered by time.
Primary sources
https://www.nature.com/articles/d41586-024-01215-0#ref-CR2
Producer: Popular Science China
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