Novel MOv18 IgE antibody shows potential as ovarian cancer therapy

27th July 2023

The chimeric first-in-class immunoglobulin E (IgE) antibody MOv18 appears to have a manageable safety profile for cancer therapy, with additional evidence of anti-tumour activity in a patient with ovarian cancer.

Published in the journal Nature Communications, the researchers conducted a Phase I dose escalation trial, with the primary objective of exploring the safety and tolerability of the MOv18 IgE antibody.

The MOv18 antibody targets the human folate receptor-alpha (FRα) that is over-expressed in tumours such as ovarian, breast and lung cancers, but remains at low levels in normal tissue.

Eligible patients were over 16 years of age and had advanced or metastatic solid tumours that were not suitable for alternative standard treatment. In addition, all were required to have a solid tumour expressing FRα, although the majority had advanced ovarian cancer which had become platinum-resistant.

MOv18 IgE safety

A total of 26 patients were enrolled and, overall, MOv18 IgE was generally well tolerated with the majority of adverse events being low grade. The most common events were localised cutaneous toxicities including urticaria, pruritus and rash, which appeared to be dose-related. Furthermore, the urticaria always resolved within hours of dosing, either spontaneously or with the administration of systemic steroids and antihistamines.

Although the primary focus of the study was the safety of MOv18 rather than efficacy, tumour shrinkage and an associated fall in the CA125 tumour marker level, was seen in one patient. Notably, the study authors observed that the anti-tumour activity ‘occurred at doses very much lower than typically observed for IgG antibodies‘, reflecting fundamental differences in Fc-receptor affinity and effector cell biology.

Professor James Spicer, professor of experimental cancer medicine at King’s College London, consultant in medical oncology at Guy’s and St Thomas’ NHS Foundation Trust and the study’s lead investigator, said: ‘IgE is a completely new form of antibody therapy which has shown great promise in this phase I trial. Our findings show that the drug was well tolerated in patients and shrunk a cancerous tumour in a patient with ovarian cancer.

‘The results pave the way to development of an entirely new class of anti-cancer drug for people with chemotherapy-resistant cancers. The immunology expertise in King’s College London laboratories allowed us to undertake this trial of a completely new form of antibody therapy.‘

Potential for faecal microbiota transplantation to enhance immunotherapy in advanced melanoma

11th July 2023

A faecal microbiota transplantation (FMT) from healthy donors prior to PD-1 inhibitor immunotherapy could represent a novel and effective approach to the management of advanced melanoma, according to a recent phase 1 trial.

Published in the journal Nature Medicine, researchers combined healthy donor FMT with the PD-1 inhibitors nivolumab or pembrolizumab in previously untreated patients with advanced melanoma.

The primary outcome of interest was safety, with key secondary endpoints of the objective response rate, changes in gut microbiome composition and systemic immune and metabolomics analyses.

A total of 20 patients with a confirmed diagnosis of unresectable or metastatic cutaneous melanoma and with no previous anti-PD-1 treatment were enrolled.

Patients received a single FMT via capsules containing 80-100 mg of faeces from heavily screened healthy donors. Individuals were required to consume 36-40 capsules under supervision followed by a 30-minute period of observation.

Faecal microbiota transplantation ‘safe and effective’

When considering the primary outcome, eight patients experienced grade 1-2 FMT-related toxicities, mainly diarrhoea, flatulence and abdominal discomfort. However, there were no grade 3 or higher adverse events before receipt of the first dose of anti-PD-1 therapy.

The objective response rate was 65% and this included four patients who experienced a complete response. Microbiome profiling revealed that all of the patients engrafted strains from their respective donors although the acquired similarity between microbiomes increased over time in responders.

The researchers concluded that FMT from healthy donors represents a safe new therapeutic tool that has clinical potential and should be explored further in randomised trials.

Additional approaches are needed in advanced melanoma given that five-year survival even with combination immunotherapy is just over 50%. Previous work suggested that FMT and anti-PD-1 therapy, could overcome resistance to anti-PD-1.

Base-edited CAR7 T cells a potential treatment for relapsed T-cell leukaemia

19th June 2023

The use of base-edited chimeric antigen receptor (CAR) T cells with a specificity for CD7 could become a therapeutic option for children with relapsed T-cell leukaemia, according to the interim findings of a recent phase 1 trial.

A potential problem with CAR T cell therapy is that since both the CAR T cells and the malignant T cells share the same antigen target, there is a risk of fratricide or self-killing of the CAR T cells. One solution is to use base-edited universal and hence ‘off-the-shelf’ CAR T cells. The base-editing process involves making changes to single letters of DNA code, which stop genes being expressed without having to make a cut to the chromosomes.

In the current study, published in the New England Journal of Medicine, researchers investigated the safety of these edited cells. They used base editing to inactivate three genes encoding for CD52 and CD7 receptors, as well as the β chain of the αβ T-cell receptor. Next, they added a CAR, which recognised the CD7 T-cell receptor on leukaemic T cells. The final base-edited CD7-targeted CAR (BE-CAR7) T cells were then given to three children as an infusion.

Safety of BE-CAR7 T cells

The first patient receiving the BE-CAR7 T cells was a 13-year-old girl with relapsed T-cell acute lymphoblastic leukaemia. After 28 days, it was found that BE-CAR7 T cells were the major circulating mononuclear cells. She then received a reduced-intensity (non-myeloablative) allogeneic stem cell transplant from her original donor, with successful immunologic reconstitution and ongoing leukaemic remission.

The other two patients receiving BE-CAR7 T cells had less successful results. One died of a fatal fungal infection-related complication, whereas the other patient underwent allogeneic stem cell transplantation while in remission.

The researchers suggested that these interim results support further investigation of base-edited T cells for patients with relapsed T cell leukaemia and are aiming to recruit 10 children for the initial cohort.