Allogenic T-cell-based immunotherapy for PML in development

Australian researchers developed a novel allogeneic T-cell-based immunotherapy, CE-VST01-JC, by expanding JC polyomavirus (JCPyV)-specific T-cells from healthy donors. The clinical safety and efficacy of CE-VST01-JC for patients with progressive multifocal leukoencephalopathy (PML) will be evaluated in the global ASCEND-JC study. If successful, this T-cell-based immunotherapy could become the first PML treatment.

PML is a rare, devastating, and often fatal demyelinating disease of the central nervous system caused by the JCPyV. Risk groups are severely immunosuppressed patients, such as transplant recipients, HIV/aids patients, and patients with multiple sclerosis using specific medications, and the increasing use of immunosuppressive treatments in the past years has caused a rise in the prevalence of PML cases. There is currently no treatment for PML.

First author Dr George Ambalathingal (QIMR Berghofer Medical Research Institute, Australia) emphasised T-cell therapy has been highlighted as a promising approach for PML treatment over the past decade, especially JCPyV-specific or BK polyomavirus (BKPyV)-specific T-cell products [1]. In collaboration with Cellevolve, Dr Ambalathingal's group developed a novel allogeneic, off-the-shelf immunotherapy, CE-VST01-JC, consisting of JCPyV-specific T-cells from healthy donors. These T-cells were expanded using a targeted, highly curated peptide mix, consisting of 36 JCPyV-specific peptides derived from all 5 antigens of JCPyV (i.e., LT, ST, VP1, VP2, and VP3), covering 32 class I and class II human leukocyte antigen (HLA) alleles. The peptide mix was extensively assessed for JCPyV-specificity, allogenicity, and functionally and phenotypically characterised. The results showed high specificity and more immunogenic precision with a minimised risk of graft-versus-host disease (GvHD). The in vitro characterisation indicated that CE-VST01-JC contains highly potent JCPyV-specific T-cells with stem-cell-like memory T-cells, lacking any off-target reactivity.

The clinical safety and efficacy of CE-VST01-JC will be evaluated in the multicentre, randomised, double-blind, phase 2 study ASCEND-JC (NCT05541549), with an adaptive design (see Figure). The FDA recently approved the trial, which should start in late 2023 or early 2024. Up to 60 participants will be randomised 2:1 to 4 infusions of 100 million cells of HLA-matched JCPyV-specific T-cells each, or placebo. Dr Ambalathingal explained it would be the largest trial of a PML treatment ever. Meanwhile, both CE-VST01-JC and T-cell treatments for the BK-virus (CE-VST01-BK) have become available in Australia for compassionate use. He noted that the results in 12 participants were very promising and encouraging.

Figure: Design of ASCEND-JC, a global pivotal phase 2 trial [1]



HLA, human leukocyte antigen; VST, CE-VST01-JC; LFTU, rate of lost to follow up.

1. Ambalathingal GR, et al. CE-VST01-JC: A novel allogeneic T-cell based immunotherapy for the treatment of progressive multifocal leukoencephalopathy (PML). PL4.001, AAN 2023 Annual Meeting, 22–27 April, Boston, USA.

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Posted on 26 June, 2023