CAR-T for aml: A Promising Therapeutic Option
CAR-T for aml: A Promising Therapeutic Option
Acute myeloid leukemia (AML) is a serious and challenging hematological malignancy that demands effective treatment strategies. In this article, we will explore the exciting potential of CAR-T cell therapy in the management of AML.
What is Acute Myeloid Leukemia (AML)
AML is a type of blood cancer that originates from the abnormal growth and proliferation of myeloid stem or progenitor cells. It is a common form of leukemia in adults, with a relatively high incidence in the elderly. The symptoms of AML can include anemia, manifested as fatigue, weakness, and pale complexion; bleeding tendencies such as easy bruising, gum bleeding, or more severe internal bleeding; and fever due to a compromised immune system.
The Challenges of AML Treatment
Despite the continuous advancement of treatment methods, the long-term prognosis for relapsed or refractory AML patients remains poor. Traditional chemotherapy and hematopoietic stem cell transplantation (SCT) offer treatment options for some patients, but not all are suitable or can benefit from these approaches.
The Emergence of CAR-T Cell Therapy
Chimeric antigen receptor (CAR) T cell therapy has emerged as a revolutionary treatment modality. It involves modifying a patient’s own T cells to express a receptor that can recognize and attack cancer cells.
Research on C-JUN Overexpressing CAR-T Cells
A recent study published in Nat Commun in July 2024 investigated the use of C-JUN overexpressing CAR-T cells in AML. In this open-label, non-randomized, phase I clinical trial, four patients who had received chemotherapy and experienced lymphopenia were included. They received a dose of 0.5 × 10^6 (±20%) CAR-T cells/kg.
Findings of the Study
It was found that compared to B-cell leukemia, the activity of CAR-T cells was impaired in AML patients. Specifically, the expression levels of activation markers CD25 and CD69, as well as effector molecules such as interferon-γ (IFN-γ), granzyme B, and interleukin-2 (IL-2) were lower in U937CD33 co-cultured CAR-T cells than in Nalm6CD33 co-cultured CAR-T cells.
However, the key discovery was that overexpression of C-JUN could maximize the anti-tumor function of CAR-T cells. Through animal experiments, it was confirmed that C-JUN overexpression increased the expression of costimulatory molecules and cytokines by reactivating intracellular mitogen-activated protein kinase (ERK) or transcriptional activation, independent of the anti-exhaustion effect. Concrete data showed that C-JUN overexpressing CAR-T cells exhibited higher cytotoxicity, more cell counts, and a higher proliferation rate in vivo.
In the clinical trial, among the four AML patients treated with C-JUN overexpressing CAR-T cells, one patient experienced grade 4 (DLT) cytokine release syndrome (CRS), while the other three patients had grade 1 to 2 CRS. Regarding treatment responses, two patients achieved complete remission without minimal residual disease (CRi) after treatment, which persisted until day 30. Additionally, one patient reached partial remission (PR) on day 15 but had a disease relapse on day 30, and then achieved CRi after a second infusion.
Although the C-JUN overexpressing CAR-T cells showed certain efficacy in the clinical trial, the study was suspended due to safety concerns. Notably, one patient developed severe CRS, although the symptoms were relieved after treatment with anti-tumor necrosis factor (TNF). Moreover, all patients experienced grade 2 to 4 neutropenia, monocytopenia, and thrombocytopenia after treatment.
Other CAR-T Cell Therapies and Research
Beyond the study mentioned above, there are various ongoing efforts in the field of CAR-T cell therapy for AML. For example, some studies focus on targeting antigens such as CD123, CLL-1, or CD33. CD7, which is not expressed in the normal hematopoietic system, has also shown promise in certain studies. However, challenges remain, such as antigen escape and the need for more effective and safe treatment strategies.
One approach is Adapter CAR-T (AdCAR-T) cell technology, which offers advantages in terms of safety. The adapter molecules are small, with a controlled molecular weight, and can be given as a continuous infusion. In case of higher-grade toxicity, stopping the infusion of the adapter molecule can potentially reverse and stop the side effects.
Another area of research is the use of CYAD-01, a targeted NKG2D CAR-T cell product. Initial clinical evaluations have shown its feasibility and anti-leukemia activity, especially in patients with a low disease burden. However, its clinical activity is limited, and issues such as limited CAR-T cell expansion and persistence need to be addressed. Studies are ongoing to optimize production methods and explore combination therapies.
Current Status and Future Directions
The field of CAR-T cell therapy for AML is evolving rapidly. While challenges exist, the progress made so far provides valuable insights and research directions for the future. The overexpression of C-JUN, as demonstrated in the study, may offer a new strategy to enhance the therapeutic effect of CAR-T cells. Additionally, combination therapies, multi-target approaches, and the development of universal CAR-T cells are areas of active investigation.
In conclusion, CAR-T cell therapy holds great potential for AML treatment. However, further research and clinical trials are needed to optimize its efficacy, safety, and broader application. Patients and their families should stay informed about the latest developments and consult with medical experts to explore the most suitable treatment options. Our goal is to provide hope and relief to those affected by AML, improving their prognosis and quality of life. If you or someone you know is diagnosed with AML, it is essential to seek medical advice promptly and explore the potential benefits of CAR-T cell therapy in individual cases. Together, we can strive towards better treatment outcomes for AML patients.