Some ALL patients have genomic signature for poor response to CAR T therapy

Acute lymphoblastic leukaemia (ALL) cells from patients whose cancers do not respond to CD19-targeted CAR T therapy have gene regulation signatures that could potentially facilitate treatment resistance, according to results presented at the AACR Annual Meeting 2022.

Researchers in the Genetics Branch at the National Cancer Institute acquired pretreatment bone marrow samples from seven patients who experienced a complete remission following CD19-targeted CAR T therapy and seven patients who did not have a response.

Using cell profiling methods such as whole-exome sequencing they identified three notable features that differentiated the gene regulatory mechanisms of CAR T-resistant leukaemia cells from CAR T-responsive leukaemia cells. One was a pattern of DNA methylation associated with a stem cell-like phenotype.

They observed similar results when they examined the DNA accessibility profiles of the leukaemia cells. The regions of open chromatin characteristic of CAR T-cell resistant leukaemia were associated with stem cell proliferation and resembled patterns found in haematopoietic progenitor cells, including haematopoietic stem cells and progenitors of myeloid cells, a different class of blood cells associated with AML.

“The data support that these leukaemias are relatively plastic and exhibit multi-lineage potential, similar to stem cells, which we suspect allows them to more rapidly adapt to the evolutionary pressures of CD19 CAR T cells,” said Dr Javed Khan, senior author of the study

A switch from a lymphoid to a myeloid lineage has also been observed as a mechanism of resistance to CD19-CAR T therapy, he noted.

“Interestingly, we saw subpopulations of cells expressing both lymphoid and myeloid markers, indicating that the epigenomes of some nonresponsive leukemias may contain a hybrid population of cells with a hybrid of ALL and AML epigenomes,” Dr Khan said.

“Our data suggest that these leukemias, characterised by both lymphoid and myeloid-specific accessible regions, are likely less differentiated than responsive leukemias.”

The researchers also identified decreased expression of genes involved in antigen presentation and processing in cells that did not respond to CAR T therapy.

“We hope that one day, screening for this phenotype could allow clinicians to identify patients whose leukemias are unlikely to respond prior to therapy and provide alternative therapies to improve outcomes for these patients,” said Dr Khan.

New iron formula may avoid GI side effects

A more tolerable formula of oral iron has been developed by researchers at the QIMR Berghofer Medical Research Institute in Brisbane which they believe will overcome the adverse effects of existing iron sulfate formulations for iron deficiency anaemia that lead to many pregnant women stopping taking them.

QIMR Berghofer PhD student Sheridan Helman says early studies have found iron hydroxide adipate tartrate (IHAT) to be a promising alternative because it is just as safe and effective at boosting iron levels in animal studies as existing treatments, but with fewer adverse side effects.

The Head of QIMR Berghofer’s Molecular Nutrition Laboratory, Associate Professor David Frazer, says the next step is trials in pregnant women.

“We have the data showing IHAT is safe and effective in human adults and children, and in pregnant mice, so our next goal is to see if we can reproduce these results in pregnant women. We’re working through the ethical issues involved to move to this next phase,” she said.

“The IHAT treatment is exciting because we’ve found there are less side effects, less stress on the body, and less damage to the microbiome of the gut.”

Pharmaceutical company Nemysis owns the right to develop IHAT.

Antibiotic prescribing halved during pandemic

The number of antibiotics prescribed in Australia fell by as much as 50% during the COVID-19 pandemic, a study has shown.

An analysis of outpatient antibiotic prescriptions issued from January 2014 to April 2021 showed that the number of prescriptions dropped sharply as national restrictions were implemented at the start of the pandemic in March 2020 and remained lower than usual during the period studied.

In winter 2020, there were 1,432,000 prescriptions per month compared to 2,313,000 the same month in 2019, a 38% reduction. Summer 2021 showed a 23% reduction in prescriptions compared to the summers of 2018 , according to Dr Jack Skeggs of Monash Infectious Diseases, Monash Health, who led the research.

The reductions were predominantly in antibiotics such as amoxicillin used to treat community-acquired respiratory infections which showed a 52% reduction in prescribing the winter of 2020 compared to pre-pandemic levels. Prescription of antibiotics such as trimethoprim commonly used for other indications, remained stable.
Some of the reduction is likely to be due to the social distancing measures introduced to curb COVID-19 also reducing the spread of other respiratory infections, Dr Skeggs suggested.

He said it was notable that reductions occurred in all states and territories despite significant differences in COVID-19 case numbers and duration of lockdowns
“This is particularly promising as it suggests that the reductions were not dependent on high case numbers or the most onerous social distancing measures like lockdowns and it may therefore be possible to maintain some of the decreases after the pandemic,” he said.

“Our finding that certain broad-spectrum antibiotics like amoxicillin-clavulanate appear to be being prescribed for community-acquired respiratory infections suggests that antibiotic prescribing for respiratory illness remains a valuable target for future anti-microbial stewardship programs,” he added.

The findings were presented at the European Congress of Clinical Microbiology & Infectious Diseases (ECCMID) in Lisbon, Portugal, 23-26 April.