A leap forward in personalized cancer therapy! CRISPR-engineered T cells for clinical trials

Recently, 16 cancer patients with solid tumors received personalized treatment
.
It is worth mentioning that the scientists used CRISPR technology to edit their T cells in order to better attack tumors
.

Researchers at UCLA and PACT Pharma conducted a phase I cell dose-escalation clinical trial
.
They isolated T cells from 16 patients, most of whom had colorectal cancer, and used CRISPR to convert their endogenous T cell receptor (TCR) genes into genes that were more specific for cancer, allowing immune cells to better target tumors
.

This approach combines CRISPR's ability to insert or delete specific genes with the ability of immunotherapy to boost the immune system's ability to
fight cancer cells.
The researchers published their findings in the journal Nature last Thursday, confirming the feasibility
of this approach.

Antoni Ribas, a professor of medicine and surgery at UCLA, said in a statement: "This is a leap forward in developing personalized therapies for cancer that treat cancer by isolating immune receptors that specifically recognize a patient's cancer
mutation.
”

The research team first collected tumor biopsy samples and peripheral blood mononuclear cells, and isolated TCRs
that can identify the patient's own tumor neoantigens.
In total, they identified 175 cancer-specific TCRs from 16 patients, with up to 3 TCRs selected for treatment per patient
.
They then used CRISPR technology to knock out endogenous TCR in the patient's T cells and knocked in tumor-specific TCR
.

All 16 patients received these cancer-specific neoTCR T cells
.
They have a range of solid tumors, including colorectal, breast, ovarian, lung, and melanoma
.
After a course of pretreatment chemotherapy, patients were infused with up to three gene-edited TCR transgenic cell products—a total of 37 immune receptors infused into 16 patients
.

The researchers found that all patients experienced pancytopenia (that is, a decrease in red blood cells, white blood cells, and platelets), which they attributed to patients receiving a lymphocyte-wasting pretreatment regimen
prior to the infusion.
In addition, two additional toxicity reports could be attributed to neoTCR transgenic T cell therapy: one patient experienced cytokine release syndrome, while the other developed encephalitis
.
Both patients recovered, suggesting that the treatment may be relatively well tolerated
.

When the researchers analyzed tumor biopsies of patients after treatment, they found that gene-edited immune cells accounted for at least 2 to 20 percent of immune cells, suggesting that gene-edited immune cells arrived where the tumor was
.

Overall, after 28 days of treatment, 11 patients progressed their disease, while 5 patients remained stable, and two of them had a reduced
area of lesions.

Stefanie Mandl, co-corresponding author and Chief Scientific Officer of PACT Pharma, said: "We are pleased to share the results of this first-in-human clinical trial, which met its primary endpoint, demonstrating the tolerability and feasibility of producing multiple TCR products using non-viral gene editing and the safety of infusion of
three TCR products.
”

Astero Klampatsa, of the Institute of Cancer Research, London, said: "This study shows that T-cell therapy has the potential to be used in the treatment of solid cancer, and its safety is undoubtedly encouraging
.
She herself was not involved in the study
.

However, Klampatsa points out that there are limitations to treatment, including time, labor and cost
.
"We would love to see if this therapy can be used in larger clinical trials, where its efficacy and protocol can be further tested," she added
.

Original search

Foy, S.
P.
, Jacoby, K.
, Bota, D.
A.
et al.
Non-viral precision T cell receptor replacement for personalized cell therapy.
Nature (2022).
https://doi.
org/10.
1038/s41586-022-05531-1