April 20, 2024

CAR T Therapy For Aggressive Youth T Cell Leukemia

In recent years, CAR T therapy has become an established treatment for patients suffering from blood cancers derived from B cells; this includes B-cell lymphoma, leukemia and multiple myeloma. However, the therapy has been less successful in T-derived cancers. A a small published study in the New England Journal of Medicine (NEJM) suggested that highly precise gene editing could be used to address this therapeutic gap. Their method represents proof of concept and opens doors for CAR T therapy to treat children with aggressive T-cell leukemia.

T Cell Acute Lymphoblastic Leukemia

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood cancer that forms rapidly from white blood cells called T cells. Healthy T cells normally target abnormal or infected cells and help other immune cells; With this type of cancer, the immature T cells are crowded and weaken the immune system.

People with T-cell leukemia often have persistent infections, bruising and symptoms such as anemia and bone pain. Treatment usually includes chemotherapy and, if that fails, a stem cell transplant. these measures to successfully extend survival, but unfortunately relapse can still happen afterwards. When this happens, previous lines of treatment lose their effectiveness.

cchimeric Ababy Receptor T Cell therapy (CAR T), a recent medical innovation, can achieve permanent remission for patients with relapsed B cell-derived cancers. With modification, it may be possible to use CAR T therapy to treat T cell cancer patients as well.

Challenges of CAR T Therapy for T Cell Leukemia

The current standard for CAR T therapy involves removing the patient’s T cells, genetically modifying them to improve their cancer detection, and then returning the strengthened cells to the patient to destroy cancer. The cells identify a specific biological tag, or antigen, found on the surface of a lining of white blood cells; This destroys cancerous and healthy cells in the process. Although effective for patients with B-cell-derived cancers, this relentless killing poses challenges for patients with T-cell leukemia.

CAR T therapy relies on T cells. Therefore, a CAR T cell designed to attack T cell antigens would cause CAR T cell fratricide, a phenomenon in which CAR T cells attack each other. This would reduce the effectiveness of the treatment. In addition, CAR T cells can attack too many healthy T cells and lead to T cell deficiency. This deficiency is difficult to supplement and affects the patient’s ability to fight back viral and fungal infections.

Adapting CAR T therapy for T Cell leukemia

Researchers from University College London and the National Health Services Trust have collaborated to address these unique challenges of CAR T therapy. They used healthy donor T cells and bioengineered them to express chimeric receptors against a T cell antigen called CD7. Unlike traditional CAR T therapy, this procedure does not alter the patient’s own immune cells.

Most interestingly, the team used CRISPR-Cas9 gene editing to simultaneously and precisely target three genes in the donor T cells. The genes underwent base editing, a process that converts one base of DNA code into another (ie C to T, cytosine changed to thymine). This change is read as a stop codon and turns the gene off.

The first gene change involved deactivating T cell receptor genes, for example TRBC1 and TRBC2. Disrupting T cell receptor expression means that host T cells will be unable to find and destroy the CAR T cells. This should prevent donor CAR T cells from being rejected upon infusion as a tissue transplant would, a phenomenon known as graft-versus-host disease (GVHD).

The second gene change eliminated the expression of CD7 antigen on the T cells. Without CD7 on their cell surface, the CAR T cells should be able to ignore each other.

Finally, a gene called CD52 was silenced to prevent T cell exhaustion. Potential CAR T therapy candidates typically undergo preparatory chemotherapy to kill some immune cells and make room for the CAR T cell infusion to proliferate. This gene change helps CAR T cells evade alemtuzumab, a chemotherapy drug that targets CD52.

Results Show Proof of Concept

The researchers enrolled three children with relapsed leukemia in their study. All children underwent a chemotherapy regimen of alemtuzumab, fludarabine, and cyclophosphamide before receiving a single infusion of preformed CAR T cells. A follow-up was performed 28 days after the initial infusion to determine the safety of the therapy and measure its ability to achieve remission.

CAR T therapy put two patients into remission—a result consistent with CAR T therapy for B cell-derived cancers. The third patient responded to the therapy, but also suffered fatal adverse effects.

The first patient, a 14-year-old girl, had complete remission of cancer symptoms at Day 28. She subsequently received a stem cell transplant from her original donor and continued to maintain cancer remission. Similarly, one 15-year-old boy managed to go into remission and went on to receive a stem cell transplant. The last patient, a 13-year-old boy, had a very different experience. This patient responded to therapy, but later developed fatal pulmonary disease in addition to pre-existing complications.

Significant Adverse Events

CAR T therapy has had significant side effects – some are consistent with other CAR T therapies and may contribute to other T cell leukemia challenges.

All patients had symptoms of cytokine release syndrome (CRS) within a week after the infusion. This is a common but potentially fatal side effect of CAR T therapy. Neurotoxicity, another known side effect of CAR T, has also been observed.

Patients with T-cell leukemia may be at higher risk of infections due to T-cell deficiency. All three children had low white blood cell counts; this is likely to leave them vulnerable to viral reactions (cytomalarial virus) and fungal infections. Overlapping infections can put a heavy burden on the body, as seen in the third patient. Previous studies suggest that this deficiency could be attributed to the anti-CD7 activity of CAR T cells.

It would be useful to control the CAR T cells before they trigger adverse events. The authors mention a possible solution: integrating suicide genes into CAR T cells. These genes could be stimulated externally, allowing the engineered cells to destroy themselves before they become too dangerous. Toxic genes could also be used to eliminate CAR T cells that help and reverse cancer. Otherwise these cells would grow unchecked by the immune system due to reduced T cell receptor expression.

Implications for the Future

There may still be hope for patients with difficult-to-treat T-cell leukemia. CAR T therapy, an established treatment for certain B-cell-derived cancers, could achieve remission — but not without significant changes. The universal CAR T cells in this study are designed to prevent host rejection, T cell deficiency and CAR T cell fratricide. The infusion achieved remission for two out of three patients, but there were no significant risks. It will be interesting to see how this neat concept performs with further investigation and a larger study cohort.

For more information on developing therapies for T cell leukemia, please read the article CAR T-cell-like therapy to treat T-cell leukemia (T-ALL).

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