CAR-T Therapy Under Scrutiny: The Emerging Risk of Secondary Malignant Tumors

By Medicine.net Updated on 2024-05-29 15:01:40 0 0

By Medicine.net

Updated on 2024-05-29 15:01:40 0 0

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CAR-T therapy has long been an effective treatment for hematological cancers such as leukemia and lymphoma. However, some patients have developed secondary malignant tumors after undergoing CAR-T therapy, casting a shadow over this emerging anti-cancer treatment.

What is CAR-T Therapy?

CAR-T therapy is a personalized cell immunotherapy. It involves extracting peripheral blood T cells from the patient, genetically engineering them to introduce the gene for a Chimeric Antigen Receptor (CAR), expanding these cells in vitro, and then reinfusing them into the patient. The T cells expressing the specific CAR can specifically recognize surface antigen molecules and target tumor cells for precise cancer treatment. Currently, the six CAR-T cell therapies approved in the United States and Europe target antigens on the immune system's B cells. Consequently, they are only effective against B-cell malignancies, such as leukemia, lymphoma, and multiple myeloma. Some companies believe that CAR-T therapy could also be effective for autoimmune diseases, solid tumors, HIV, and other conditions.

Suspected Cases of Secondary Cancers

In 2002, an international research team attempted a gene therapy similar to CAR-T therapy on 20 infants with Severe Combined Immunodeficiency (SCID). Due to the activation of proto-oncogenes by the retrovirus, five infants developed leukemia, and one died. This incident has led many countries to remain skeptical about CAR-T and similar gene therapies, imposing strict ethical review requirements.

In the US and Europe, Legend Biotech conducted long-term follow-up studies on early trial participants of a CAR-T therapy called Carvykti. Among 97 patients, 10 developed Myelodysplastic Syndrome (a precursor to leukemia) or Acute Myeloid Leukemia, with nine fatalities. Consequently, Legend Biotech added relevant warnings to Carvykti’s packaging.

Additionally, a case study published in the journal Blood reported that a man developed T-cell lymphoma five months after participating in a Carvykti trial. Tests revealed that the CAR gene had inserted into the regulatory region of the PBX2 gene. Although it was not conclusively proven that the patient's T-cell lymphoma was caused by the CAR insertion into the PBX2 regulatory region, such cases have increased concerns among clinicians and patients.

Why Might CAR-T Therapy Cause Cancer?

CAR-T is an emerging cancer treatment, and many of its technologies are not yet fully mature. CAR-T therapy is based on genetic engineering, requiring the transportation of the gene encoding CAR into cells using gamma-retroviruses or lentiviruses. Currently, retroviruses are used as vectors in CAR-T therapy. These retroviral vectors randomly insert the CAR gene into the cell genome. No researcher can yet predict where in the human genome the gene will be inserted without affecting normal function. Therefore, if the CAR gene inserts near an oncogene and enhances its expression, or inserts into a tumor suppressor gene and disrupts its expression, it could potentially transform T cells into cancer cells, posing a significant health risk.

Follow-Up to cancer-causing findings of CAR-T Therapy

Due to the occurrence of secondary malignant tumors post-CAR-T therapy, the FDA conducted a safety investigation of CAR-T products available in the US in November 2023. On April 18, 2024, the FDA issued a notice requiring CAR-T products to update their “black box warnings” to emphasize the serious risk of T-cell malignancies.

While CAR-T therapy remains a treatment option for leukemia, lymphoma, and other cancers, the ongoing follow-up studies suggest that the risk is relatively rare. Conventional cancer treatments such as radiotherapy and chemotherapy also carry certain risks of inducing cancer. However, both doctors and patients should consider the potential risk of T-cell malignancies when choosing CAR-T therapy. This investigation is likely to increase awareness and vigilance among companies producing CAR-T products regarding these risks.

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