RNA CAR T therapy offers hope for patients with myasthenia gravis

28th June 2023

A novel approach using RNA CAR T cell therapy improves clinical symptoms in patients with myasthenia gravis according to a recent phase 1b/2a study.

Chimeric antigen receptor (CAR) T cells represent a versatile new class of effective and molecularly precise therapy in oncology. However, CAR T cell treatment has also been trialled with some degree of success in patients with autoimmune diseases such as systemic lupus erythematosus.

While conventional CAR T-cell engineering relies on DNA to express the CAR, an alternative is to engineer these cells with RNA, to produce RNA CAR T cells. The rationale behind using RNA is that because the molecule is not self-replicating, it would confer more predictable pharmacokinetics and consequently a more favourable safety profile.

In a small scale trial of using RNA CAR T cells published in the Lancet Neurology, researchers examined the value of this approach to treat individuals with myasthenia gravis – commonly known as the ‘snowflake disease’ because it affects each individual differently.

This prototypical autoimmune disease is characterised by autoantibodies that target the neuromuscular junction, which causes chronic fluctuating and potentially debilitating weakness and muscle fatigue. The RNA CAR T cell therapy, known as Descartes-08, was used in adults with generalised myasthenia gravis and a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 6 or higher gravis.

The study was undertaken in two phases. Initially, patients with Myasthenia Gravis Foundation of America (MGFA) disease class III-IV generalised myasthenia gravis were given three increasing doses of Descartes-08, to identify the maximum tolerated dose. In the second phase, participants with MGFA disease class II-IV received six infusions of the maximum tolerated dose.

The primary objective was to establish the safety and tolerability of Descartes-08, whereas secondary objectives assessed disease severity. Researchers used four validated scales used to assess disease severity: MG-ADL, Quantitative Myasthenia Gravis (QMG), Myasthenia Gravis Composite (MGC), and Myasthenia Gravis Quality of Life 15-revised (MG-QoL-15r).

RNA CAR T cell therapy outcomes

In total, 14 participants were enrolled, three in phase 1 and 11 in phase 2 and the median follow-up in phase 2 was five months.

Mean improvements from baseline to week 12 were -6 for MG-ADL, -7 for QMG, -14 for MGC and -9 for MG-QoL-15r.

There was no dose-limiting toxicity, cytokine release syndrome or neurotoxicity. Common adverse events were headache, nausea, vomiting and fever, which resolved within 24 hours of the infusion.

Based on these preliminary findings, the researchers suggested that RNA CAR T cell therapy warranted further investigation as a treatment approach for individuals with myasthenia gravis and other autoimmune diseases.

Mosunetuzumab induces high and durable remission in patients with follicular lymphoma

13th December 2021

Mosunetuzumab mono-therapy has been shown to induce both a high and durable response in patients with refractory follicular lymphoma

The use of mosunetuzumab mono-therapy in patients who have refractory follicular lymphoma (FL) gave rise to a high response rate and durable remission. This was the finding from a Phase II trial by a team from the BC Cancer Centre for Lymphoid Cancer and University of British Columbia, Vancouver, Canada, presented at ASH 2021.

FL is a type of non-Hodgkin lymphoma and associated with frequent relapses and decreasing progression-free intervals with successive lines of conventional therapy. Mosunetuzumab (Mosun) is a CD20xCD3 bi-specific antibody that re-directs T cells to eliminate malignant B cells and in the dose-escalation phase of an ongoing Phase I/II study (NCT02500407), Mosun was highly active and well tolerated in relapse-refractory follicular lymphoma (R/R FL) patients who had received 2 or more prior therapies. The Canadian team have now presented pivotal data from the same study from a large expansion cohort of R/R FL patients who received Mosun mono-therapy at the recommended Phase II dose (1/2/60/30mg).

All patients had FL (Grade 1–3a) and had at least 2 prior lines of therapy and the primary endpoint was complete response (CR) rate based on PET/CT scanning and assessed by an independent review facility (IRF) using standard response criteria.

Findings

A total of 90 patients with a median age of 60 years (61.1% male) were enrolled in the study and at entry, 76.7% had stage III or IV disease and the median number of prior lines of therapy was 3 (range: 2–10). In addition to Mosun, alkylators were given to all patients. Overall, 68.9% of patients were refractory to their last therapy, 78.9% to any prior aCD20 Ab, and 53.3% to any prior aCD20 Ab and an alkylator (double refractory).

The median time on mosunetuzumab was 12.9 months and CR rates by IRF was 57.8% and the overall response rate (ORR) was 78.9% with the median time to first response being 1.4 months and the median progression free survival time was 17.9 months. Among patients with at least two prior treatment failures the CR was 48% and the ORR 69%.

Cytokine release syndrome was the most common adverse event, occurring in 44.4% of all patients although this was mostly confined to grade 1 severity. Other common adverse events were fatigue (36.7%), headache (31.1%), neutropenia and pyrexia (28.9% each), hypophosphataemia (22.2%), and pruritus (21.1%).

The authors concluded that Mosun induces deep and durable remissions and with a high response rates that was maintained for ≥12 months in the majority of patients and that it represents an active new therapy for relapse-refractory patients with follicular lymphoma.

Citation

Budde E et al. Mosunetuzumab Monotherapy Is an Effective and Well-Tolerated Treatment Option for Patients with Relapsed/Refractory (R/R) Follicular Lymphoma (FL) Who Have Received ≥2 Prior Lines of Therapy: Pivotal Results from a Phase I/II Study. ASH Conference 2021