Jacob Plieth
The private group celebrates a double first for its mRNA-generated Car-T therapy in myasthenia gravis.
Using Car-T therapy in autoimmune disease, beyond its natural habitat of oncology, has gained huge traction of late. But the prospect of having patients undergo burdensome chemo conditioning, while acceptable in cancer, might stifle serious uptake in chronic diseases.
Now Cartesian Therapeutics, a private, Maryland-based biotech, reckons it has cracked the problem by using mRNA to generate Car-T cells, a procedure not dependent on cell engraftment and thus not requiring lymphodepletion. Even better, its myasthenia gravis trial, just published in Lancet Neurology, has shown impressive efficacy in most patients.
The study authors have hailed the data as the first with an RNA Car-T therapy in autoimmune disease, and Cartesian claims that this is the first successful phase 2 trial of an RNA-based cell therapy. The project in question, an anti-BCMA Car the company calls Descartes-08, is now starting a placebo-controlled myasthenia gravis (MG) study.
Promising efficacy… and safety
The Lancet Neurology paper concerns 11 MG patients from the second part of Cartesian’s phase 2 study. Two discontinued early, but the remaining nine showed six to eight-point reductions in MG-ADL scores at weeks 12 to 24.
MG-ADL is the FDA-mandated efficacy measure on which Astrazeneca’s Ultomiris was approved for MG, having shown a mean 3.1-point 26-week reduction, versus 1.4 points for placebo. Meanwhile, QMG score, a secondary Ultomiris endpoint, fell by a mean 10 points in a seven-patient Descartes-08 cohort at week 24, though other subjects saw more modest changes.
At least as impressive as these efficacy signals was the safety of Descartes-08: there were no dose-limiting toxicities, and no cytokine release syndrome or neurotoxicity of any grade. Two serious adverse events, urticaria and myocardial infarction, were noted, with the first being deemed “possibly related” to Descartes-08.
Cartesian puts safety down to use of mRNA, allowing treatment in an outpatient setting and without lymphodepletion. Rather than using a viral vector that causes permanent integration of Car-coding DNA into the T cell genome – standard for current Car-T products – Descartes-08 employs mRNA, delivered using an undisclosed non-viral method.
The advantages include that the Car-encoding mRNA does not replicate with the proliferating T cells, so its effect is transient. T cells are expanded ex vivo, and thus do not need to engraft – making lymphodepletion unnecessary – and thus the given dose of mRNA determines the actual load of Car-T cells.
Repeat dosing
However, transient expression necessitates repeat dosing, and in the trial each patient got six Descartes-08 doses, taken from a single apheresis, frozen, tested and thawed at each infusion.
Descartes-08 was successfully manufactured in all 11 patients apheresed, with a vein-to-vein time of 2.5 to four weeks, according to University of North Carolina-Chapel Hill’s Dr James Howard, one of the study authors. Manufacturing involved additional sorting to eliminate CD4+ T cells, partly because these secrete most of the inflammatory cytokines that could lead to unwanted toxicity, and to yield a “CD8+ T-cell-only product”.
Multiple dosing was specifically tested, with the six doses – a number determined by the availability of cells after a single apheresis – spread over three weeks to six months. The goal is a full therapeutic effect, though it is still unclear what regimen could achieve this. The placebo-controlled trial uses six once-weekly doses, Howard told Evaluate Vantage.
Paradoxically, even though the effect of the RNA is transient, there are hints that after the six initial doses efficacy in MG can persist for months. Howard cited one of his patients, who 14 months after receiving Descartes-08 “is still going strong in clinical remission”.
“The hope was that we would see a small signal. We clearly wanted safety first and foremost, but from efficacy we were not anticipating what we saw,” he told Vantage. “This was a very gratifying surprise.”
Precedent
Groundbreaking though the data might be, this is not the first case of RNA being used to encode a Car construct in humans.
Back in 2013 the University of Pennsylvania ran a trial of a mesothelin-directed Car-T cancer therapy encoded by mRNA via electroporation. However, one patient developed anaphylaxis and cardiac arrest within minutes of a third infusion, and this was cited as a possible “safety issue for mRNA CARs, especially when administered using an intermittent dosing schedule”.
Rival work includes a clinical study of an mRNA-engineered anti-mesothelin Car-T at a Chinese group including UTC Therapeutics, but in immunology all other applications of Car-T involve traditional, DNA-based viral transduction, according to clinicaltrials.gov.
The Descartes-08 study authors tackle the risks directly. They cite a DNA-delivered Car in lupus, where all subjects needed inpatient admission for lymphodepletion, and all developed haematological toxicity and cytokine release. In a neuromyelitis optica study of another DNA-encoded product there were widespread infections, and all patients had grade 3 neutropenia.
For Cartesian the next big catalyst could come with data from the placebo-controlled study, which Howard reckons could start to emerge in 18 months. But he cautions: “In MG trials the placebo response is horrific. This disease fluctuates hour by hour … patients are clamouring for treatment and often overperform. It’s our nemesis.”
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