March 2, 2024

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Potential Secondary Tumors Linked to CAR-T Cancer Therapy?

Potential Secondary Tumors Linked to CAR-T Cancer Therapy?


Potential Secondary Tumors Linked to CAR-T Cancer Therapy?

CAR-T therapy, a groundbreaking advancement in cancer treatment over the past decade, has significantly changed the landscape of cancer therapy, particularly in addressing various blood cancers.

Many researchers and pharmaceutical companies are actively improving CAR-T, aiming not only for enhanced effectiveness and safety in blood cancers but also breakthroughs in solid tumors.

However, on November 28, 2023, the FDA announced an investigation into the risk of secondary tumors associated with CAR-T therapy.

Subsequently, on January 23, the FDA mandated the inclusion of warning language regarding the risk of secondary tumors in the labeling of six CAR-T therapies approved for market use in the United States.

Despite the FDA emphasizing the benefits outweighing the risks in its November investigation announcement, concerns and speculations persisted.

On January 24, the leader of the FDA’s Center for Biologics Evaluation and Research (CBER) published an article in the New England Journal of Medicine titled “Secondary Cancers after Chimeric Antigen Receptor T-Cell Therapy.” This article presented preliminary data on CAR-T therapy-induced secondary tumors, based on information collected by the FDA.

Potential Secondary Tumors Linked to CAR-T Cancer Therapy?

Since the approval of the first CAR-T therapy in 2017, six different CAR-T therapies have gained FDA approval and are available in the U.S.

These include Kymriah, Yescarta, Tecartus, and Breyanzi, targeting CD19 for B-cell acute lymphoblastic leukemia (B-ALL) and various lymphomas, as well as Abecma and Carvytki, targeting BCMA for multiple myeloma.

All these CAR-T therapies share a commonality in using viral vectors to introduce the CAR gene, modifying the patient’s own T cells into specialized cancer-targeting killer cells. Similar to other gene therapies utilizing viral vectors, this production method implies a risk of secondary tumors associated with CAR-T.

Although the risk of tumors induced by current viral vectors has significantly decreased compared to early gene therapies, certain risks remain, especially with commonly used retroviral vectors showing a preference for active gene expression regions during gene insertion, potentially leading to cancer. Considering these factors, the FDA has previously mandated longer-term tracking post-market approval for CAR-T therapies to monitor adverse events, including tumors.

According to data revealed in the New England Journal of Medicine article, as of December 31, 2023, the FDA was aware of 22 cases of T-cell cancers occurring after CAR-T therapy, including T-cell lymphomas and T-large granular lymphocyte leukemia. Fourteen of these cases had sufficient data, with occurrences within two years of CAR-T treatment, ranging from 1 to 19 months post-treatment. Approximately half of these cases emerged within the first year of treatment, and five out of the six marketed CAR-T therapies reported cases of T-cell cancers.

Based on specific modifications requested by the FDA for the labeling of the six CAR-T therapies, Tecartus appears to be the only drug without recorded cases of T-cell cancers, as it was not required to include language about observing T-cell cancers after its use. However, the article in the New England Journal of Medicine highlights that differences in the patient populations using different CAR-T therapies make it challenging to assess the specific risk correlation of each product with secondary cancers. Additionally, ongoing investigations are underway for some cases.

In three cases with sequencing data, the CAR gene was detected in the clones of T cells undergoing carcinogenesis, indicating a likely association between CAR-T and the development of T-cell cancers. Despite the FDA’s efforts to gather as much data as possible for each case, the lack of adequate tumor samples for sequencing in many instances makes it impractical to determine the cause of T-cell cancers in each case.

It’s crucial to note that even if every known case of T-cell cancers is assumed to be caused by CAR-T, and considering the possibility of underestimation in adverse event tracking, T-cell cancers induced by CAR-T remain extremely rare. As emphasized by the FDA during the investigation announcement, the benefits patients derive from these drugs far outweigh the risks, given that over 27,000 doses of CAR-T therapy have been administered in the United States.

However, as the duration of the risk of secondary tumors post-CAR-T therapy is unknown, the FDA recommends long-term, potentially lifelong monitoring of patients. Effective communication between healthcare teams and patients is also crucial in addressing these risks.

Looking ahead, with attempts to expand the indications of CAR-T from blood cancers to other diseases, the safety thresholds differ, particularly for indications outside late-stage cancers. Strategies to minimize the risk of CAR gene insertion into specific locations triggering cancers may be necessary.

Conducting more comprehensive monitoring of T-cell cancers, in-depth studies on cases experiencing such secondary tumors, can provide more comprehensive information on this risk. This approach may also shed light on the specific mechanisms and avoidance strategies leading to these secondary tumors.

In conclusion, CAR-T remains an indispensable treatment option for many blood cancers, and if extended to solid tumors, it could offer significant assistance to late-stage cancer patients. However, similar to other gene therapies, the use of viral vectors introduces an unavoidable risk of secondary tumors.

On January 24, an article was also published in Nature Medicine regarding the risk of secondary T-cell cancers associated with CAR-T therapy from the University of Pennsylvania, including one of the pioneers of CAR-T therapy, Carl June. The article, based on data tracking patients treated at the University of Pennsylvania, concludes that the risk of CAR-T-induced secondary T-cell cancers is low.

It’s important to note that the incidence of various secondary tumors, including T-cell cancers, is inherently higher in patients with blood cancers. Common cancer treatment methods such as chemotherapy and radiation also increase the risk of secondary tumors. For example, the observed rate of secondary tumors after CAR-T therapy is around 15%, but this does not imply that all these cases are due to CAR-T cell carcinogenesis. Distinguishing overall secondary tumor risk from CAR-T-specific secondary tumor risk may help us better understand the risk-benefit balance of this therapy.

Potential Secondary Tumors Linked to CAR-T Cancer Therapy?


References:

1.https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-investigating-serious-risk-t-cell-malignancy-following-bcma-directed-or-cd19-directed-autologous

2.https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/2024-safety-and-availability-communications

3.DOI: 10.1056/NEJMp2400209

4.https://www.fiercepharma.com/pharma/fda-tweaks-tecartus-secondary-cancer-labeling-change-demand-classwide-boxed-warning

5.https://www.nature.com/articles/s41591-024-02826-w

(source:internet, reference only)

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