Allogenic T cell-based immunotherapy for the treatment of PML in development

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

PML is a very rare, devastating and often fatal demyelinating disease of the central nervous system caused by the JCPyV. Risk groups are severy immunosuppressed patients, e.g., transplant recipients, HIV/aids patients, and multiple sclerosis patients using certain medications. The increasing use of immunosuppressive treatments in the past years has caused an increase in the prevalence of PML cases. There is currently no treatment for PML.

First author Dr George Ambalathingal (QIMR Berghofer Medical Research Institute, Australia) said T cell therapy has been highlighted as a promising approach for PML treatment over the past decade, in particular, JCPyV- or BK polyomavirus (BKPyV)-specific T cell products. In collaboration with the company Cellevolve, Dr Ambalathingal’s group developed a novel allogeneic, off-the-shelf T cell-based immunotherapy, CE-VST01-JC, which consists of JCPyV-specific T cells from healthy donors [1]. These T-cells were expanded using a targeted, highly curated peptide mix, defined by human leukocyte antigens (HLA). According to Dr Ambalathingal, this mixture consisted of 36 JCPyV-specific peptides derived from all 5 antigens of JCPyV: LT, ST, VP1, VP2 and VP3, covering 32 class I and class II HLA-alleles. It has been extensively assessed for JCPyV-specificity and allogenicity and has been functionally and phenotypically characterised. The result has high specificity and more immunogenic precision while minimising the risk of 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.

Clinical safety and efficacy of CE-VST01-JC will be evaluated in the multi-centre, randomised, double-blind, phase 2 study ASCEND-JC (NCT05541549), with an adaptive design. The trial was recently approved by the American FDA and 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 said it will be the largest trial of a PML treatment ever. Meanwhile, both CE-VST01-JC and T cell treatment for the BK-virus (CE-VST01-BK) has been made available in Australia for compassionate use. He concluded that the results in 12 participants were very promising and encouraging.

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

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