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Take a look at a selection of our recent media coverage:
19th June 2023
The use of base-edited chimeric antigen receptor (CAR) T cells with a specificity for CD7 could become a therapeutic option for children with relapsed T-cell leukaemia, according to the interim findings of a recent phase 1 trial.
A potential problem with CAR T cell therapy is that since both the CAR T cells and the malignant T cells share the same antigen target, there is a risk of fratricide or self-killing of the CAR T cells. One solution is to use base-edited universal and hence ‘off-the-shelf’ CAR T cells. The base-editing process involves making changes to single letters of DNA code, which stop genes being expressed without having to make a cut to the chromosomes.
In the current study, published in the New England Journal of Medicine, researchers investigated the safety of these edited cells. They used base editing to inactivate three genes encoding for CD52 and CD7 receptors, as well as the β chain of the αβ T-cell receptor. Next, they added a CAR, which recognised the CD7 T-cell receptor on leukaemic T cells. The final base-edited CD7-targeted CAR (BE-CAR7) T cells were then given to three children as an infusion.
The first patient receiving the BE-CAR7 T cells was a 13-year-old girl with relapsed T-cell acute lymphoblastic leukaemia. After 28 days, it was found that BE-CAR7 T cells were the major circulating mononuclear cells. She then received a reduced-intensity (non-myeloablative) allogeneic stem cell transplant from her original donor, with successful immunologic reconstitution and ongoing leukaemic remission.
The other two patients receiving BE-CAR7 T cells had less successful results. One died of a fatal fungal infection-related complication, whereas the other patient underwent allogeneic stem cell transplantation while in remission.
The researchers suggested that these interim results support further investigation of base-edited T cells for patients with relapsed T cell leukaemia and are aiming to recruit 10 children for the initial cohort.
18th April 2023
GD2-CART01 has been found in a phase 1-2 clinical trial to be both safe and effective for children with heavily pretreated neuroblastoma.
GD2-CART01 is a safe and feasible therapy for children with relapsed or refractory (R/R) high-risk neuroblastoma according to a phase 1 – 2 trial by Italian researchers.
Neuroblastoma is responsible for 11% of paediatric cancer deaths and these cancer cells express high levels of disialoganglioside GD2.
Moreover, targeting this protein, while a valid and safe strategy, requires further modification to promote CAR-T cell longevity.
In the current trial, researchers used a third-generation CAR-T cell therapy in patients with R/R high-risk neuroblastoma. The therapy included the inducible caspase 9 suicide gene, designed to kill cells in the presence of dangerous toxic effects.
The trial enrolled 27 children with heavily pretreated neuroblastoma.
The overall response rate was 63%; 9 children had a complete response and 8 a partial response. The three-year overall survival and event-free survival were 60% and 36%, respectively.
Overall, after infusion 33% of patients (eight patients) had a complete response or maintained a complete response (one patient).
Cytokine release syndrome occurred in 74% of patients but was of mild severity in the majority (95%). The suicide gene activation occurred in only one patient. GD2-targeted CAR T cells were detectable in peripheral blood in 26 of 27 patients up to 30 months after infusion.
The authors concluded that GD2-CART01 may induce sustained eradication of disease in a proportion of patients with R/R neuroblastoma.
Del Bufalo F et al. GD2-CART01 for Relapsed or Refractory High-Risk Neuroblastoma. N Eng J Med 2023.
17th February 2023
In a randomised controlled trial, an international group of researchers showed that the CAR T-cell therapy, Ide-cel (idecabtagene vicleucel) gave rise to greater progression-free survival than any of five other standard regimens in heavily pre-treated patients with relapsed or refractory multiple myeloma.
Although treatments for multiple myeloma have improved in recent years, evidence suggests that around 16% of patients relapse after 8 months of treatment. Nevertheless, while CD38-targeting monoclonal antibodies have made a significant impact to the treatment of patients with multiple myeloma (MM), those who a refractory to this regime have a poor prognosis. The use of CAR T-cell therapies directed against the B-cell maturation antigen (BCMA) expressed on myeloma cells, have proven to be effective in MM. In fact, one Phase II trial in which Ide-cel was given to relapsed or refractory MM patients, generated a response in over 70% of patients, with 33% experiencing a complete response. While CAR T-cell therapy clearly works in relapsed/refractory MM, there is an absence of comparative studies of the treatment compared to other regimes.
In the current study, researchers recruited MM patients who were refractory to between two and four prior regimes. Eligible participants were then randomised 2:1 to Ide-cel or one of five standard regimens and which included immunomodulatory agents, proteasome inhibitors and daratumumab. The primary endpoint was set as progression-free survival whereas secondary endpoints included the overall response and survival.
Ide-cel and progression-free survival
A total of 386 patients with a median age of 63 years (60.5% male) received either Ide-cel (254) or one of the standard regimes. Among the entire cohort, 66% had triple-class refractory disease and 95% daratumumab-refractory disease.
After a median of 18.6 months follow-up, the median progression-free survival in the Ide-cel group was 13.3 months compared to 4.4 months in the standard regime groups (hazard ratio for disease progression or death, HR = 0.49, 95% CI 0.38 – 0.65, p < 0.001). In fact, 12-month progression-free survival was 55% for Ide-cel but only 30% in the standard regimen. Furthermore, a complete response occurred in 39% of the intervention group and on 5% in the standard therapy group. Data on overall survival were immature. In addition, adverse effects of either grade 3 or 4 were more frequent in the Ide-cel group (93% vs 75).
Based on these results, the authors concluded that Ide-cel gave rise to an improved response compared to standard therapy in patients who failed to respond to two to four prior regimens.
Rodriguez-Otero P et al. Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma. N Engl J Med 2023
27th January 2023
A T cell biomarker, represented by low levels of differentiated CD3+CD27–CD28– T cells before leukapheresis could serve as a novel marker to predict an individual’s response to CAR T cell therapy in those with relapsed/refractory diffuse large B cell lymphoma (DLBCL), according to a study by researchers from the Medical University of Vienna, Austria.
Chimeric antigen receptor (CAR) T cell therapy produces a durable response in patients with either relapsed or refractory DLBCL. However, trying to identify which groups of patients are likely to respond to therapy is difficult and currently based on lactate dehydrogenase after lymphodepletion, tumour volume and Eastern Cooperative Oncology Group performance status. Nevertheless, each of these three measures does not relate to the immune system. In the current study, the Austrian team looked at a particular T cell biomarker and made use of a matched group of healthy control patients for comparative purposes.
T cell biomarker and CAR T treatment response
A total of 33 patients (mean age = 61.8 years, 42.4% female) with either relapsed or refractory DLBCL were matched with a health control group of 24 patients (median age = 60, 41.7% female).
When compared to healthy controls, DLBCL patients had significant lymphopenia and a higher frequency of differentiated CD3+CD27–CD28– T cells (28.7% vs 6.6%, p < 0.001). There were 26 patients infused with CAR T cell therapy and the overall response (OR) 3 months after the infusion was 57.7%, with a complete response (CR) seen in 42.3% of patients.
In regression analysis, the Austrian team found that low levels of differentiated CD3+CD27–CD28– T cells (23.3% vs 35.1%) were independently associated with an overall response. In fact, the association was even more evident when patients were stratified by either complete remission or non-complete remission (13.7% vs 37.7%, p = 0.001). Using a cut-off value of below 18% of CD3+CD27–CD28– T cells was highly predictive of a complete response at 12 months (67% vs 13%, p = 0.009).
The authors concluded that a low number of CD3+CD27–CD28– T cells at leukapheresis represented a novel, pre-infusion T cell biomarker that enabled prediction of a CAR T cell response in patients with relapsed or refractory DLBCL.
Worel N et al. The frequency of differentiated CD3+CD27–CD28– T cells predicts response to CART cell therapy in diffuse large B-cell lymphoma. Front Immunol 2023
25th May 2021
Researchers say ‘stem cell memory T-cells’ appear critical in both destroying the cancer at the outset and for long term immune surveillance and exploiting this quality could improve the design and performance of CAR T therapies.
Researchers assessed the cells of patients involved in the CARPALL Phase I Study, which used a new CAR molecule known as CAT-19 developed between UCL Cancer Institute and UCL Great Ormond Street Institute of Child Health, for treatment in children with acute lymphoblastic leukaemia.
The team compared T-cells from patients who still had CAR T-cells detectable in the blood more than two years after their treatment, with individuals who had lost their cells in the one to two months post treatment.
Using a technique called ‘insertion site barcoding’, researchers were able to study the fate of different types of CAR T-cells in patients after they were given.
Corresponding author Professor Persis Amrolia, based at UCL Great Ormond Street Institute of Child Health and Consultant in Bone Marrow Transplant at GOSH, said: “Using this barcoding technique, we were able to see ‘stem cell memory T-cells’ play a central role both during the early anti-leukaemic response and in later immune surveillance, where the body recognises and destroys cancer cells.
“This suggests that this small sub-group of T-cells are critical to the long-term success of the therapy.”
Researchers say, this work indicates that the teams caring for patients could measure the types of CAR T-cells present after some someone has had their anti-leukaemia therapy, to gain an indication of whether they will be able to preserve their CAR T-cells into the future, avoiding relapse.
Professor Amrolia added: “This new insight may help us to improve our CAR T-cell therapy and work out which patients are at a higher risk of relapse and may benefit from a stem cell transplant after CAR T-cell therapy.”
Dr Biasco added: “It was extremely rewarding to see how the application of our new barcoding technology to study CAR T-cells is unveiling such important information about what happens to these cells after they are given to patients. We now plan to expand the technology we established at UCL and validate these findings in larger groups of patients.”
Co-author Dr Martin Pule said: “This research opens up new avenues to improve CAR design and manufacture, improving the performance of CAR T-cell therapy, to achieve a combination of early tumour clearance and long-term protection from relapses in patients with B cell leukaemia.”