Next day CAR T cells effective and have acceptable safety in acute lymphoblastic leukaemia

7th July 2022

CAR T cells made in 24 hours are both effective and have an acceptable safety profile in patients with acute lymphoblastic leukaemia according to a first-in-human study

CAR T cells (CTC) which can be manufactured in a single day have been shown to be effective and with an acceptable safety profile, for the treatment of patients with relapsed or refractory B cell acute lymphoblastic leukaemia according to a first-in-human clinical study by a group of Chinese researchers.

Chimeric antigen receptor-engineered T cells (CAR T cells) represents a novel yet safe and effective therapy for B-cell acute lymphoblastic leukaemia patients relapsing after an allotransplant.

In CTC therapy, the patient’s own T cells are genetically engineered and then re-infused in an effort to eliminate their tumour cells. The T cells contain an extracellular ligand binding domain which is able to recognise antigens displayed on the surface of tumour cells (normally CD19).

Moreover, it appears to be an effective form of therapy with one study from 2018 demonstrating complete remission in 83% of patients with relapsed B-cell acute lymphoblastic leukaemia.

Nevertheless, as more clinical trials have been undertaken, it has become evident that 30-60% patients relapse after treatment, probably due to persistence of CAR T-cells and escape or down-regulation of CD19 antigen. A further problem is that the T-cell engineering process can take 9 to 14 days and up to four weeks before infusion back into the patient.

For the present study, the Chinese team developed a type of CAR T cells that were manufactured using a novel process completed in 24 hours. The final product CTC product, GC007F, was tested in patients with relapsed or refractory B cell acute lymphoblastic leukaemia and for comparative purposes, the researchers also manufactured CTCs by conventional methods.

CAR T cells and patient outcomes

A total of 21 patients with CD19+ relapsed or refractory B cell acute lymphoblastic leukaemia were enrolled and given a single infusion of GC007F cells although only 18 were included in the final analysis after the others withdrew due to adverse effects. The median peak of CAR T cells was on day 10 and the median persistence was 56 days. The GC007F cells also showed better proliferation and tumour killing than conventional CTCs.

After 28 days, all patients had achieved complete remission (CR), with 17 achieving CR and maintaining minimal residual disease negative, MRD (i.e., no disease was detected after treatment) after 3 months. Additionally, at 6 months, 16 patients maintained CR with 14 maintaining MRD negative and the longest duration at the time of writing was 29 months without the need for transplant.

In terms of safety, 95.2% (n = 20) of patients experienced cytokine release syndrome (a recognised adverse effect) and which was greater than grade 3 (i.e., severe) in 52.4% (11) of patients. Neurotoxicity developed in 6 patients and was greater than grade 3 severity in 3 patients.

Overall, eight patients underwent allogeneic haematopoietic stem cell transplantation after GC007F treatment.

The authors concluded that these preliminary data suggested that their next day GC007F cells appeared to be effective and with a manageable toxicity profile.

Citation
Zhang C et al. Novel CD19 chimeric antigen receptor T cells manufactured next-day for acute lymphoblastic leukemia Blood Cancer J 2022

Total bile acid concentration a possible biomarker for coronary artery disease

29th November 2021

The total bile acid concentration is lower in patients with visible coronary artery disease and could be an important disease biomarker

The total bile acid concentration among those with visible coronary artery disease (CAD) as seen with coronary angiography was approximately 50% lower than in patients without CAD, indicating that this might serve as an important biomarker for the disease. This was the finding of a study by researchers from the department of Cardiology, Cochin Hospital, Paris, France.

Cardiovascular disease is the leading cause of death globally, accounting for an estimated 17.9 million deaths every year. Moreover, other evidence shows that in patients with non-alcoholic fatty liver disease (NAFLD), who have an excessive fat deposition in the liver, there is a dysregulation of bile acid (BA) metabolism. Finally, one systematic review in 2013, revealed how NAFLD is a strong independent predictor of cardiovascular disease. Taken together, these findings might suggest that dysfunctional BA metabolism could be indicative of CAD.

For the present study, the French team sought to explore the relationship between total bile acid concentration and CAD by measuring the level of acids in patients referred for coronary angiography and who could well have CAD. In addition, the team also measured the concentration of 7-alpha C4, which serves as a marker for the production of bile acids by the liver to determine whether there was any correlation with CAD.

Findings

A total of 80 patients with a mean age of 61.5 years (61% male) were recruited, 45 who presented with significant CAD on angiography and the remainder who were normal. Both groups were comparable apart from the CAD group being significantly older (66 vs 57 years, p = 0.004), including more men (73% vs 49%, p = 0.02) and with a significantly higher diastolic pressure (77 vs 72 mmHg, p = 0.04).

After adjustment for age and gender, the total bile acid concentration was highly predictive of CAD, with an area under the curve of 83.6% (95% CI 74.5% – 92.8%) and an odds ratio, OR of 0.51 (95% CI 0.31 – 0.85, p = 0.01). In other words, bile acid levels were approximately 50% lower in patients with CAD. From a total of 28 different bile acids, the researchers identified that one particular BA, GCDCA acid, was also predictive of CAD (AUC = 83.6%) and with a similar odds ratio (OR = 0.60, 95% CI 0.01 – 0.51, p = 0.01). A further observation was how the levels of 7-alpha C4 was similar in both groups (0.13 vs 0.12 micromol/L). One interesting finding was how among 17 patients who had been prescribed statins, the mean concentration of total bile acid, doubled (0.68 to 1.37 micromol/L, p = 0.01) after one month of treatment.

In discussing these results, the authors suggested that the total bile acid concentration might serve as a natural braking mechanism and which protected against the development of atheromatous plaques. They concluded by proposing that GCDCA could serve as a biomarker and predictor of visible atheroma in patients with CAD.

Citation

Nguyen CC et al. Circulating bile acids concentration is predictive of coronary artery disease in human Sci Rep 2021