CAR-T cells can persist in the human body for at least 10 years and achieve sustained remission of leukemia

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CAR-T cells can persist in the human body for at least 10 years and achieve sustained remission of leukemia

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Nature: Revealing that CAR-T cells can persist in the human body for at least 10 years and achieve sustained remission of leukemia.

In the summer of 2010, Bill Ludwig and Doug Olson were battling a vicious blood cancer called chronic lymphocytic leukemia (CLL).

They both received many treatments, and with fewer treatment options left, they volunteered to be the first batch of participants in an ongoing clinical trial of an experimental therapy at the Abramson Cancer Center at the University of Pennsylvania and the Perelman School of Medicine. 

The therapy will eradicate their advanced leukemia, make global headlines, and usher in a new era of highly personalized medicine.

In this experimental therapy, called chimeric antigen receptor (CAR) T-cell (CAR-T) therapy, genetically engineered T cells that target tumor cells are made for each patient using their own T cells of living medicines.

Now, in a new study, researchers from the University of Pennsylvania and Children’s Hospital of Philadelphia have published an analysis of these two patients, explaining that CAR-T cell therapy has recorded the longest duration of CLL to date, and The CAR-T cells were shown to remain detectable for at least a decade after infusion into the patients, and both patients continued to experience remission .

The related research results were published online in the journal Nature on February 2, 2022, with the title of “Decade-long leukaemia remissions with persistence of CD4+ CAR T cells” .

“This long-term remission is remarkable, and witnessing patients living cancer-free is a testament to this,” said J. The tremendous potency of ‘living drugs’ that are effective against cancer cells. Seeing our patients respond well to this innovative cell therapy has been worth all our efforts. Allowing them to spend more time with their loved ones spend together.”

CLL is the first cancer at Penn to study and use CAR-T cells and is the most common type of leukemia in adults.

While treatment for the disease has improved, it remains incurable with standard methods. Eventually, patients become resistant to most treatments, and many still die from the disease.

Based on T cell receptor sequencing data, the clonal evolution of CAR-T cells in patients 1 and 2 was analyzed. Image via Nature, 2022, doi:10.1038/s41586-021-04390-6.

Olson was diagnosed with CLL in 1996 and Ludwig was diagnosed with CLL in 2000. By 2010, their cancers had mutated and no longer responded to standard treatments.

But as pioneers of patients receiving CD19 CAR-T cell therapy, both achieved complete remission that year. A former scientist, Olson has started long-distance running and has completed six half-marathons.

He also raises money for the Leukemia and Lymphoma Society and helps newly diagnosed patients. Ludwig, a retired corrections officer, drove his RV around the country with his wife after treatment, celebrating major events with his family, from vacations to the birth of their grandchildren.

In early 2021, he died from complications from COVID-19.

Although durable remissions have been achieved with CD19-specific CAR-T cells in relapsed, refractory B-cell malignancies, until now little was known about the long-term potential and stability of infused CAR-T cells. In their latest analysis, the authors observed that CAR-T cells evolved over time, with a population of highly activated CD4+ cells emerging and predominant in both patients.

These data suggest two distinct phases of CAR-T cell response in these two patients: an initial phase dominated by killer T cells, and a long-term remission phase dominated by CD4+ T cells.

In the years that followed, these CD4+ T cells continued to exhibit tumor -killing properties and continued proliferation, a hallmark of CAR-T cell anticancer efficacy: its robust ability to survive and thrive in vivo.

The CD4 protein is encoded by the CD4 gene. CD4+ helper T cells are white blood cells that are an important part of the immune system.

In one of these patients, CD4+ T cells accounted for 97.5% of CAR-T cells at year 1.4, and then more than 99.6% from year 3.4 to the most recent time point after infusion (9.3 years).

In the second patient, CD4+ T cells accounted for 97.6% of CAR-T cells 7.2 years after infusion.

This surprising finding of CD4+ T cell predominance has led to rethinking the possibility that CD4+ T cells may be primarily responsible for distinguishing between helper and cytotoxic T cells.

“CAR-T cell therapy is extremely effective against certain leukemias and lymphomas, and we look forward to continuing our efforts in these cancers, while also focusing on their effect on solid tumors,” said co-author David L.

The impact of research in the solid tumor field will see more progress in the coming years. We often say that we have learned something from every patient treated with this therapy, especially Ludwig and Olson, who gave We have so many leads that allow us to focus on the next generation of personalized therapy.”

“The University of Pennsylvania has begun testing the next generation of T cells in more blood cancers,” said co-corresponding author Carl H. , including lymphoma, and targeting challenging solid tumors.

Substantial deep learning research will fine-tune the way cancer patients are treated with CAR-T cells, and we look forward to the next phase of research and improvements, including how best to use this approaches to target other cancers and diseases.”

Reference:
J. Joseph Melenhorst et al. Decade-long leukemia remissions with persistence of CD4+ CAR T-cells . Nature, 2022, doi:10.1038/s41586-021-04390-6.

CAR-T cells can persist in the human body for at least 10 years and achieve sustained remission of leukemia

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