Further development of using CRISPR to edit T cells to treat drug-resistant leukemia

Researchers at Great Ormond Street Hospital for Children (GOSH) and University College London's Great Ormond Street Institute for Child Health (UCL GOS ICH) used CRISPR/Cas9 technology to engineer donor T cells in an attempt to treat critically ill children with drug-resistant leukaemia who would otherwise have exhausted all available treatments
.

The first phase trial, published in Science Translational Medicine, is the first use of "universal" CRISPR-edited cells in humans and represents an important step
forward in using gene-edited cells to treat cancer.
As part of the trial, the team constructed and applied a new generation of "universal" genome-edited T cells, building on older
, less precise techniques previously used.

T cells are modified by CRISPR, which makes an incision in the cell's DNA and inserts a genetic code
.
In this case, this genetic code allows T cells to express a receptor — called a chimeric antigen receptor (CAR) — that recognizes markers on the surface of cancerous B cells and then destroys them
.
These T cells were then gene-edited using CRISPR so they could be used
directly without any donor matching.

Although the NHS is currently offering some CAR-T cell therapies, they rely on collecting and modifying patients' own cells
.
It's expensive and not always feasible or feasible
in a short period of time.
Genome editing is being studied to prefabricate donated cells for use in multiple patients, with the goal of reducing costs and making treatments more accessible
.

In a specialist cleanroom at London's Tiansheng Hospital, researchers fabricate a donor CAR-T cell bank from a single inactivated virus, transfer CAR-T cells and the CRISPR guidance system simultaneously, and then apply cutting-edge mRNA technology to activate the gene editing step
.
The donors are healthy volunteers
from the UK.

As of February 2022, six relapsed and drug-resistant B-ALL children aged 14 months to 11 years have been treated
.
All of the children had previously received British standard B-ALL treatment, but unfortunately their disease recurred
multiple times.
The patient is injected with edited cells, which are expected to be active for about
four weeks.
This time is sufficient to achieve deep remission, which is a state in which
cancer is significantly reduced or undetectable.
Upon success, patients are eligible for a bone marrow stem cell transplant to help rebuild a healthy immune system
.
Of the six children initially treated, four went into remission within 28 days, which allowed them to receive a stem cell transplant
.
Of these 4 children, 2 were still in persistent remission at 9 and 18 months after treatment, while unfortunately, 2 had relapse
after stem cell transplantation.
In this study, the overall side effects were within expectations and managed in a hospital, where one patient required short-term intensive care
.

Professor Waseem Qasim, consultant immunology at University Hospital London and professor of GOS cell and gene therapy at University College London, said:

"Thankfully, this unresponsive form of leukemia is very rare, but we are excited to offer new treatments for some of the most difficult childhood leukemias, especially when
all 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 leveraged to address the unmet health needs
of some of the most ill children we see.
”

What other scientists say:

"The children treated in this study face the worst possible prognosis
for their disease.
Only through clinical trials will it be possible to save more young lives, and we are forever grateful to all the families involved in this study who will help more children
in the future.
" ”

"This study adds to a growing body of evidence that genome-edited T cells may be a viable alternative
to currently available treatments.
" While this wasn't successful in all cases, it was a life-saving approach
for some of the children in this study.
”

Next, the researchers will offer treatment to more children in the early stages
of their cancers before they have developed the treatment pathways so far.

CAR-coupled CRISPR-Cas9 engineered universal donor T cells: Phase 1 trial of TT52CAR19 in paediatric refractory B-cell acute lymphoblastic leukaemia is published in Science Translational Medicine