May 30, 2024

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The clinical results of the first base-edited universal CAR-T therapy

The clinical results of the first base-edited universal CAR-T therapy saved two children with leukemia


The clinical results of the first base-edited universal CAR-T therapy were released, saving the lives of two children with leukemia.

On June 14, 2023, researchers at University College London (UCL) and Great Ormond Street Hospital for Children (GOSH) published a study in the New England Journal of Medicine ( NEJM) entitled: Base-Edited CAR7 T Cells for Relapsed T – Research paper on Cell Acute Lymphoblastic Leukemia .

The study developed a universal off-the-shelf CAR-T cell based on base editing .

Base editing was used to knock out three genes on T cells from healthy volunteers – CD52 , CD7 and TCRαβ , and then a CAR (CAR7) that specifically recognized CD7 was introduced into the above triple gene knockout T cells using a lentiviral vector .


The research team then administered this base-editing-based CAR7-T cell therapy to three children with T-cell leukemia who had relapsed after multiple treatments.

This is also the world’s first human clinical trial of a general-purpose cell therapy based on base editing. Interim results of this phase 1 clinical trial support further investigation of base-edited T cells for the treatment of patients with relapsed leukemia.


Among the three patients, the first patient, a 13-year-old girl Alyssa (Alyssa), had no cancer cells detected within four weeks after CAR7-T cell therapy, and then she successfully underwent allogeneic stem cell transplantation, And rebuilt the immune system, now a year later, she is still very healthy.

The second patient was treated to clear the cancer in the same amount of time and has now undergone an allogeneic stem cell transplant and is recovering at home. Unfortunately, although the third patient responded to CAR7-T cell therapy, he subsequently died of a fungal infection.

The clinical results of the first base-edited universal CAR-T therapy were released, saving the lives of two children with leukemia



In May 2021, a 12-year-old girl, Alyssa , was diagnosed with acute T-lymphoblastic leukemia (T-ALL) .

We all know that T cells are supposed to be the guardians of our body, responsible for finding and destroying threats, but for Alyssa, the T cells in her body had become dangerous and were growing out of control.

With this aggressive cancer, neither chemotherapy nor a bone marrow transplant can remove the cancer cells from the body. Various treatments for Alyssa also failed.


In order to save Alyssa’s life, doctors from Great Ormond Street Children’s Hospital in the UK (one of the world’s four authoritative children’s hospitals) customized a base editing- based CAR-T cell therapy for her.

The base-edited CAR-T cells used in this treatment were prepared by a team led by Professor Waseem Qasim of University College London. He said that this is the most complex cell engineering therapy to date, paving the way for other new treatments and will also Create a better future for sick children.


Base editing is a new gene editing technology developed and gradually expanded and perfected by David Liu in 2016.

Base editing can edit a single base pair at a specific point with high precision and high efficiency . And it does not rely on DNA double-strand breaks (DSB) , so it is considered to be safer than CRISPR-Cas9. Therefore, it is also called CRISPR2.0.



Specifically, our genes are composed of 4 bases – adenine (A) , cytosine (C) , guanine (G) and thymine (T) , these 4 bases are like spelling letters Composing a single sentence and connecting it into an article constitutes the instruction manual for our body, and even if a single base is wrong, it may lead to serious consequences. The base editing technology can accurately and efficiently convert one of the bases into another base, thereby realizing the repair of a single base amino group.


In Alyssa ‘s treatment, a large team of doctors and scientists used base editing technology to engineer and modify T cells from healthy donors to be able to track down and kill cancerous T cells in the body.


The principle of gene knockout using base editing technology is to change a specific codon in a gene to a stop codon by modifying a single base, which will cause the gene to stop expressing and achieve the purpose of gene knockout.


This study chose CD7 as the therapeutic target, CD7 is highly expressed in the vast majority of T-ALL cells (95%) , however, healthy T cells also express CD7, which will lead to CAR-T cells killing T-ALL At the same time, they will kill each other.


When T cells from donors are used for treatment, there are several major problems, such as avoiding rejection of patients , preventing graft-versus-host disease (GvHD) , and preventing cannibalism of modified T cells .


The research team carried out a four-step genetic modification of the donor’s T cells:

1. Use base editing to knock out T cell receptors on T cells , so that these T cells become a “universal” cell that can be stored for use by different patients;

2. Use base editing to knock out CD7 on T cells to prevent CAR-T cells from cannibalism;
3. Use base editing to knock out CD52 on T cells , which makes other drugs used in the treatment process not kill CAR-T cells;
4. Adding CAR to the above-mentioned triple base-edited T cells , that is, adding CD7 receptors, so that CAR-T cells can specifically recognize cancerous T cells expressing CD7 in patients.

These genetically engineered CD7-CAR-T cells can recognize cancerous T cells (highly expressing CD7) in patients and further eliminate these cancerous T cells.


The clinical results of the first base-edited universal CAR-T therapy were released, saving the lives of two children with leukemia


Dr Robert Chiesa , from Great Ormond Street Hospital’s Bone Marrow Transplant Unit, who led the treatment, said: ‘It’s very exciting, it’s a new area of ​​medicine and it shows that we can redirect the immune system to fight cancer, which is very exciting. People are fascinated.


Liu Ruqian, the inventor of the base editing technology , said that it is a bit surreal that the human body has been treated only 6 years after the invention of the base editing technology.


At present, base editing technology has started clinical trials in sickle cell disease, β-thalassemia, and familial genetic hypercholesterolemia. Liu Ruqian said that the therapeutic application of base editing has just begun, and it is a great honor to be part of the era of therapeutic human gene editing, and science is taking key steps towards controlling our genome.


It is worth mentioning that on December 2, 2022, the FDA approved the clinical trial application for the base editing-based CAR-T cell therapy BEAM-201 of Beam Therapeutics founded by Liu Ruqian for the treatment of relapsed/refractory acute T Lymphoblastic leukemia (T-ALL) and T-lymphoblastic lymphoma (T-LL) .


BEAM-201 therapy knocked out four genes through base editing: CD7, TRAC, CD52, and PD-1. Compared with the base-editing CAR-T therapy published in NEJM, BEAM-201 additionally knocked out PD- 1. It aims to improve the persistence of CAR-T cell anti-tumor activity.


These genetically engineered CAR-T cells can be used as a “universal” cell therapy, which means that this therapy can become an “off-the-shelf drug” that can be provided to many patients, compared with current time-consuming and expensive treatments. In stark contrast to personalized T cell therapy .


Base editing can stop the expression of specific genes by changing a single base without causing DNA double-strand breaks, which is very effective for engineering T cells.

The interim results of this phase 1 clinical trial support further research on base-edited T cells for the treatment of patients with relapsed leukemia .






References :

The clinical results of the first base-edited universal CAR-T therapy

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