July 23, 2024

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FDA Investigates T-Cell Malignancy Risk in CAR-T Cell Therapy

FDA Investigates T-Cell Malignancy Risk in CAR-T Cell Therapy

Breaking News: FDA Investigates T-Cell Malignancy Risk in CAR-T Cell Therapy

FDA Investigates Serious Risk of T-Cell Malignancy in Patients Following CAR-T Cell Therapy, Involving All 6 Approved Products.

Over the past decade, CAR-T cell therapy has revolutionized the field of oncology, offering a cure for previously incurable blood cancers.

In 2010, Professor Carl June pioneered CAR-T cell therapy in human clinical trials, successfully “curing” several leukemia patients.

In 2017, the FDA approved CAR-T therapy for commercial use, and since then, six CAR-T therapies have received FDA approval for treating blood cancers like leukemia and lymphoma.

The success of CAR-T therapy has rekindled hope for cancer patients awaiting bone marrow transplants and symbolized the arrival of the era of cell therapy.

CAR-T cell therapy, or chimeric antigen receptor T-cell immunotherapy, involves engineering a patient’s immune T-cells outside the body to recognize antigens on the surface of tumor cells.

These modified cells are then reintroduced into the patient’s body to identify and eliminate cancer cells.

Scientists have been exploring the application of CAR-T therapy beyond blood cancers, including solid tumors, autoimmune diseases, chronic infections, heart diseases, and age-related conditions.

Recently, the U.S. FDA announced an investigation into the serious risk of T-cell malignancy in patients who underwent autologous CAR-T cell immunotherapy targeting BCMA or CD19.

FDA Investigates T-Cell Malignancy Risk in CAR-T Cell Therapy


Tumor immunotherapy: What is the difference between CAR-T and TCR-T?

The FDA has received reports of T-cell malignancies in patients treated with autologous CAR-T cell immunotherapy targeting BCMA or CD19, both from clinical trials and adverse event data of marketed CAR-T cell therapies.

The FDA has determined that the risk of T-cell malignancy applies to all currently approved autologous CAR-T cell immunotherapies targeting BCMA or CD19. Incidences of T-cell malignancies have been observed in patients treated with these products. The FDA-approved CAR-T therapies include:

  1. Yescarta and Tecartus developed by Gilead Sciences’ Kite Pharma,
  2. Kymriah developed by Novartis,
  3. Breyanzi developed by Bristol Myers Squibb,
  4. Carvykti developed by Legend Biotech and Johnson & Johnson,
  5. Abecma developed by Bristol Myers Squibb.

Despite the overall benefits of these CAR-T cell therapies outweighing potential risks, the FDA is investigating the severe consequences of confirmed T-cell malignancy, including hospitalization and death, and evaluating the need for regulatory action.

FDA Investigates T-Cell Malignancy Risk in CAR-T Cell Therapy

Similar to all gene therapy products using integrated vectors (such as retroviral or lentiviral vectors integrating into the host cell’s genome), potential risks of secondary malignancies are flagged as a class warning in prescriptions for FDA-approved autologous CAR-T cell immunotherapies targeting BCMA and CD19. Approval for these products includes a requirement for 15 years of long-term follow-up observational safety studies post-treatment to assess long-term safety and the risk of secondary malignancies.

The FDA advises patients receiving CAR-T cell therapy and participants in clinical trials to undergo lifelong monitoring for new malignancies. In case of new malignancies post-treatment, patients are urged to report adverse events to the developing company and provide patient samples for detecting chimeric antigen receptor (CAR) transgenes.

In response to the FDA investigation, Gilead Sciences expressed confidence in the overall safety of Tecartus and Yescarta. The company stated that, to date, these therapies have treated 17,700 cancer patients with no evidence suggesting a causal relationship with the development of new malignancies. Gilead emphasizes its rigorous monitoring procedures and commitment to full cooperation with the FDA’s data analysis related to this investigation.

Novartis also expressed confidence in the risk-benefit profile of its CD19-CAR-T product, Kymriah, stating no evidence of a causal relationship between treatment and secondary malignancies among over 10,000 patients treated with Kymriah.

Bristol Myers Squibb, the developer of Abecma and Breyanzi, reported no cases of CAR-positive T-cell malignancies among the 4,700 patients treated with these therapies. The company is responding to FDA requests and maintains confidence in the safety and clinical value of its cell therapies.

Legend Biotech noted that T-cell malignancies might occur in multiple myeloma patients even without CAR-T cell therapy. The company highlighted that other treatments related to multiple myeloma, such as alkylating agents, immunomodulatory drugs, and autologous stem cell transplants, are associated with an increased risk of secondary cancers. Johnson & Johnson shared monitoring data with the FDA for Carvykti, which has been used in 2,000 patients with a favorable benefit-risk ratio.

Yescarta, the first FDA-approved CAR-T cell therapy in 2017, generated $1.13 billion in revenue in the first nine months of 2023, making it the world’s top-selling CAR-T therapy.

Overall, the FDA believes that the benefits of these CAR-T cell therapies still outweigh the potential risks. While investigating the risk of T-cell malignancy associated with treatment, the FDA currently has no plans to withdraw approval for these six CAR-T cell therapies.

The cancer risk associated with CAR-T cell therapy is believed to stem from the use of gene delivery vectors, particularly retroviral or lentiviral vectors. These viral vectors integrate into the host cell’s genome, providing stability to the therapeutic effect. However, if the insertion site is near DNA sequences associated with cancer, there is a potential risk of causing malignancies.

It’s worth noting that on November 8, 2023, researchers from Stanford University published a study in Nature titled “Latent human herpesvirus 6 is reactivated in CAR T cells.”

Using comprehensive genomic analysis, the study linked specific human cell states to the reactivation of latent viruses. Through reanalysis of existing sequencing datasets, the research team discovered the reactivation of human herpesvirus 6 (HHV-6), a betaherpesvirus, in standard CD4+ T cell cultures. Using single-cell genomics, the team described a rare CAR-T cell state with high HHV-6 expression in both in vitro cell cultures and patients.

Based on these findings, the research team suggests that the possibility of latent virus reactivation should be widely considered in current and future cell therapy products.

FDA Investigates T-Cell Malignancy Risk in CAR-T Cell Therapy

Information about CAR-T therapy


CAR-T (Chimeric Antigen Receptor T-cell) therapy is a groundbreaking form of immunotherapy designed to treat certain types of cancer.

Unlike traditional cancer treatments like chemotherapy and radiation, which target both cancerous and healthy cells, CAR-T therapy is a form of targeted immunotherapy that harnesses the power of the patient’s own immune system to combat cancer.

Detailed overview of CAR-T therapy:

  1. Collection of T-cells: The process begins by extracting T-cells, a type of immune cell, from the patient’s blood. T-cells play a crucial role in the immune system, recognizing and attacking abnormal cells, including cancer cells.

  2. Genetic Modification: In the laboratory, scientists genetically modify the extracted T-cells to express a chimeric antigen receptor (CAR) on their surface. This modification allows the T-cells to recognize specific proteins on the surface of cancer cells.

  3. Expansion of Modified T-cells: The genetically modified T-cells, now equipped with the CAR, undergo a process of rapid multiplication in the laboratory. This step is crucial for generating a sufficient quantity of modified T-cells for therapeutic use.

  4. Infusion into the Patient: Once an ample number of CAR-T cells have been produced, they are infused back into the patient’s bloodstream. The modified T-cells are now primed to seek out and destroy cancer cells bearing the specific antigen targeted by the CAR.

  5. Targeting Cancer Cells: The CAR on the surface of the T-cells enables them to recognize and bind to the specific antigen present on the cancer cells. This recognition triggers the T-cells to attack and destroy the cancer cells.

  6. Proliferation of CAR-T cells: The CAR-T cells continue to multiply and persist in the patient’s body, providing a sustained immune response against the cancer cells. This prolonged activity enhances the therapy’s effectiveness.

CAR-T therapy has shown remarkable success, particularly in treating certain types of blood cancers, such as leukemia and lymphoma.

The therapy’s ability to precisely target cancer cells makes it a promising treatment option, especially for patients who have not responded well to traditional treatments.

However, as highlighted in the recent news, there are also potential risks associated with CAR-T therapy, such as the development of T-cell malignancies.

Ongoing research and clinical trials aim to refine and improve the safety and efficacy of CAR-T therapy, and regulatory agencies closely monitor these developments to ensure patient safety.

FDA Investigates T-Cell Malignancy Risk in CAR-T Cell Therapy



2. fiercepharma.com/pharma/fda-investigates-serious-risk-secondary-cancer-following-car-t-therapy-treatment

3. nature.com/articles/s41586-023-06704-2

(source:internet, reference only)

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