July 15, 2024

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Low Probability of Secondary T-Cell Malignancies After CAR-T Therapy

Low Probability of Secondary T-Cell Malignancies After CAR-T Therapy

Low Probability of Secondary T-Cell Malignancies After CAR-T Therapy, Recent Study Finds

In recent times, CAR-T therapy has faced challenges, particularly with the emergence of secondary T-cell malignancies after treatment.

Many readers may be aware that in late November of last year, the US FDA officially announced an investigation into cases of secondary T-cell malignancies following CAR-T therapy.

Just a few days ago, the FDA added a “black box warning” to the labeling of all approved CAR-T therapies, highlighting the significant risk of secondary T-cell malignancies.

This undoubtedly marks a major event affecting CAR-T therapy, raising questions about the future prospects of what was once considered a flagship treatment.

However, on January 25th, a research team from the University of Pennsylvania published a recent case report and analysis in the journal “Nature Medicine,” indicating that the occurrence of secondary T-cell lymphomas (TCL) and other T-cell malignancies after CAR-T therapy is a very rare event.

The industry and patients, therefore, need not be overly alarmed. Still, there is a call to swiftly find ways to reduce the nearly 20% incidence rate of secondary primary tumors (SPMs) after CAR-T treatment and to determine the association between secondary TCL and CAR-T therapy, seeking appropriate strategies.

Low Probability of Secondary T-Cell Malignancies After CAR-T Therapy

As one of the hottest tracks in cancer treatment, any development related to CAR-T therapy garners significant attention. The recent “black box warning” from the FDA, the highest level of adverse reaction designation, further emphasizes the need for scrutiny. The FDA’s Center for Biologics Evaluation and Research (CBER) head recently published an article in the “New England Journal of Medicine,” explaining the decision behind the “black box warning” and the current state of investigations.

As of the end of December 2023, the FDA had received reports of 22 cases of secondary T-cell malignancies following CAR-T therapy, involving five of the six CAR-T therapies commercially available in the United States. While the correlation between CAR-T therapy and secondary T-cell malignancies is not yet clear due to the limited number of cases and ongoing investigations, in three cases where genetic sequencing was completed, CAR transgenes were detected in malignant T-cell clones, suggesting a potential causal relationship.

To be fair, considering that CAR-T therapy has been administered over 27,000 times in the United States alone, even if all 22 reported cases were directly related to CAR-T therapy, the benefits still outweigh the risks. This remains a key reason for the FDA’s continued support for CAR-T therapy, albeit with the added “black box warning.” The FDA explicitly calls for clinical practitioners to actively report relevant cases to avoid underestimating risks due to insufficient adverse reaction reports post-approval.

The University of Pennsylvania team’s report on a case of secondary T-cell lymphoma after CAR-T therapy, occurring three months after receiving Axi-cel as third-line treatment for gray zone lymphoma, revealed complexities. Despite the patient’s gray zone lymphoma being in complete metabolic remission at the time, a PET/CT scan suggested a nodule in the lower lobe of the right lung. Subsequent surgery confirmed the nodule as poorly differentiated lung squamous cell carcinoma, leading to the patient’s eventual demise after non-small cell lung cancer relapse five months post-surgery.

Unexpectedly, one of the three excised lymph nodes showed no infiltration of lung cancer cells but rather T-cell lymphoma cells identified as CD8+ peripheral non-specified T-cell lymphoma (PTCL-NOS) after immunohistochemical staining. Real-time fluorescence quantitative PCR (qPCR) detected only 0.005% CAR transgene cells in the tumor sample, suggesting potential CAR-T cell infiltration into the tumor. Researchers conclude that this secondary TCL is likely CAR transgene-negative.

Further analysis by researchers suggests that the malignant T-cell clone causing TCL may have existed in the patient’s body at the time of CAR-T infusion, making it challenging to identify the exact trigger among CAR-T preparation, infusion, and the simultaneous occurrence of non-small cell lung cancer and related inflammation. The patient’s relatively advanced age (64 years) and previous exposure to chemotherapy and PD-1 inhibitors add complexity to the case. However, researchers also identified JAK3 gene mutations in the TCL, previously reported in secondary TCL after CAR-T therapy, requiring further clarification on its involvement in TCL occurrence.

Finally, the researchers conducted a retrospective analysis of 449 cases of hematological malignancies treated with CAR-T therapy at the University of Pennsylvania medical system since 2018. At a median follow-up time of 10.3 months, 16 patients (3.6%) developed SPMs, with an estimated 5-year cumulative incidence rate of 17.0%. Of these, 15.2% were solid tumors, and the remaining were hematologic cancers. The median time from treatment to SPMs was 26.4 months for solid tumors and 9.7 months for hematologic cancers.

While the 17.0% figure may seem high, it aligns with similar research reports, indicating that SPMs after CAR-T therapy are not uncommon. However, for the majority of patients currently undergoing CAR-T treatment, this risk may seem distant compared to the immediate threat of recurrent or refractory hematological malignancies. The University of Pennsylvania team suggests future considerations to reduce myeloablative chemotherapy intensity, enhance clinical monitoring for SPMs, and employ specifically designed therapies to eliminate malignancies expressing aberrant CARs.

Low Probability of Secondary T-Cell Malignancies After CAR-T Therapy


[1]Verdun N, Marks P. Secondary Cancers after Chimeric Antigen Receptor T-Cell Therapy[J]. New England Journal of Medicine, 2024.

[2]Ghilardi G, Fraietta J A, Gerson J N, et al. T-cell Lymphoma and Secondary Primary Malignancy Risk After Commercial CAR T-cell Therapy[J]. Nature Medicine, 2024.

[3]Cappell K M, Kochenderfer J N. Long-term outcomes following CAR T cell therapy: what we know so far[J]. Nature Reviews Clinical Oncology, 2023, 20(6): 359-371.

[4]Ruella M, Barrett D M, Shestova O, et al. A cellular antidote to specifically deplete anti-CD19 chimeric antigen receptor–positive cells[J]. Blood, 2020, 135(7): 505-509.

(source:internet, reference only)

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