STM: CRISPR gene-edited universal CAR-T, clinical trial results for the treatment of childhood leukemia released

In October 2017, the FDA approved the first CAR-T cell therapy on the market, and humans entered the era of cell therapy, and CAR-T cell therapy has achieved good clinical results
in blood cancers.
Because CAR-T cells are engineered from the patient's autologous T cells, they can function in the patient for a long time without rejection
.

Today, CAR-T cell therapy has become the standard of
care for childhood B-cell acute lymphoblastic leukemia (B-ALL).
However, genetically engineering a patient's own T cells, a personalized procedure, takes a long time, and some patients with acute leukemia do not have enough time to wait
.
In addition, many severe patients no longer have enough T cells for engineering modification
.

Therefore, CAR-T built from healthy donor-derived T cells can avoid these problems and potentially develop "off-the-shelf" CAR-T products
.
But this requires additional genetic modification of CAR-T cells to prevent graft-versus-host disease (GvHD) and the body's rejection
of CAR-T cells.

At present, many studies and some clinical trials have used CRISPR-Cas9 gene programming technology to build allogeneic "off-the-shelf" CAR-T cells, knock out the TRAC gene (expressing the α chain of T cell receptors) of T cells, and avoid the graft-versus-host response (GvHD), which is the most important complication after transplantation and the main cause of
post-transplant death.
Knocking out CD52 of T cells improves the persistence
of generic CAR-T cells in the presence of alemtuzumab.

On October 26, 2022, researchers at Great Ormond Street Hospital for Children in the United Kingdom published a paper in Science Translational Medicine titled: Phase 1 clinical trial of CRISPR-engineered CAR19 universal T cells for treatment of children with refractory Phase 1 clinical trial paper
for B cell leukemia.

The research team used next-generation CRISPR-Cas9 gene editing technology to knock out TRAC and CD52 of CAR19 T cells, construct a universal CAR-T cell, TT52CAR19 T cells, and conducted a phase 1 clinical trial
for the treatment of childhood B-cell acute lymphoblastic leukemia (B-ALL).

Four of the six children received CRISPR gene-edit-based CAR-T cell therapy, which allowed them to undergo bone marrow stem cell transplants and rebuild healthy immune systems
.
Of the 4, 2 were in sustained remission 9 and 18 months after treatment, respectively, but unfortunately the other 2 relapsed
after stem cell transplantation.

In this study, the overall side effects were within expected ranges, in line with the main safety goals, which provided evidence
for the therapeutic potential of CRISPR gene-edit-based CAR-T cell therapies.

This study combines lentiviral vector-based CAR-T technology with cutting-edge mRNA technology, using lentiviral vectors to add CAR to T cells and deliver gRNA from the CRISPR system, and mRNA technology to deliver and express Cas9 protein
to cells.

The study used lentiviral vectors to deliver CAR19, CD52 sgRNA, and TRAC sgRNA, and Cas9 mRNA using electrotransfection to construct TT52CAR19 T cells
.

Patients with lymphocyte clearance by fludarabine, cyclophosphamide, and alemtuzumab were given a single infusion of 0.
8×10E6 cells-2.
0×10E6 cells/kg body weight, and no immediate toxicity occurred
.

After 6 patients were infusion of TT52CAR19 T cells, 4 developed cell expansion and continued infusion
after remission.
Two patients developed grade 2 cytokine release syndrome, one developed transient grade 4 neurotoxicity, and one patient developed skin graft-versus-host disease (GvHD), which later went into remission
.
Other complications are within expected range and consistent with major safety objectives
.

This study proves that CAR-T cell therapy based on CRISPR gene editing is safe and feasible and has therapeutic potential
.

Professor Waseem Qasim, a cell and gene therapy expert and lead leader in the clinical trial, said the unresponsive leukaemia treated in this study was very rare, but was excited to offer new therapies for these most difficult-to-treat childhood leukemias, especially if
other options have been exhausted.
While there are challenges to overcome, this study is a promising demonstration of how emerging genome editing technologies can be used to address some of the sickest and unmet health needs
.

Professor Ajay Vora, a leukemia specialist who participated in the clinical trial, said the treated children were already facing the worst possible prognosis
.
Only through clinical trials will it be possible to save more young lives, and forever thanks to all the families who participated in this study, whose participation will help more children
in the future.

Dr.
Kanchan Rao, a bone marrow transplant expert who participated in the clinical trial, said the study adds to a growing body of evidence that genome-edited T cells could be a viable alternative
to currently available treatments.
While this will not be successful in all cases, it has been a life-saving approach
for some of the children involved in this study.

Links to papers: