Engineered probiotics for local tumor delivery of checkpoint blockade nanobodies

To the Editor,

I read with very keen interest the article by Gurbatri et al. (1) and titled “Engineered probiotics for local tumor delivery of checkpoint blockade nanobodies”.

Immune checkpoint inhibitors have indeed revolutionised anti-cancer therapeutic strategies with the targeting of programmed cell death-ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated protein-4 (CTLA-4) continuing to demonstrate promising results.

Although combination therapies utilising both anti-PD-L1/PD-1 with anti-CTLA-4 monoclonal antibodies (mAbs) together have clearly demonstrated more efficacious responses when compared with the utility of single therapies, the associated higher toxicity levels observed remain of concern.

This work sought to exploit the attraction and preference of bacteria for tumours, as a means of developing and testing a more natural cancer therapeutic delivery system using microbes.

Of particular interest were the studies referred to that highlighted the preferential and selective bacterial colonization within tumours, when the bacteria was administered systemically, in addition to the finding of widespread prevalence of unharmful bacteria existing within malignant tissues (2) – (8).

Using an intratumoural probiotic bacterial delivery system for the controlled production and intratumoural release of blocking nanobodies able to target PD-L1 and CTLA-4, together with computational modelling and lysis circuit dynamics, the authors were able to determine the optimal parameters needed for maximal therapeutic efficacy in their model.

Testing within syngeneic tumour models demonstrated enhanced therapeutic responses and achievement of tumour regression using their bacterial delivery system to release blocking nanobodies as PD-L1 and CTLA-4 antagonists.

In addition, the engineered and probiotic generated expression of the granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine by the bacteria used in this system, was able to improve anti-tumour immune responses when using a less immunogenic syngeneic tumour model.
An exciting set of carefully executed studies using microbial-based therapeutic platforms, with direct clinical relevance.

Respectfully yours,
Dr Dianne Sika-Paotonu CQS MRSNZ
Associate Dean (Pacific)
Senior Lecturer, Pathology & Molecular Medicine
Head, University of Otago Wellington Pacific Office
Wellington School of Medicine and Health Sciences, University of Otago, New Zealand
Honorary Research Associate, Telethon Kids Institute, Australia
Honorary Research Associate, Victoria University of Wellington, New Zealand
Associate Investigator Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, New Zealand

References:
1. Gurbatri, C. R., Lia, I., Vincent, R., Coker, C., Castro, S., Treuting, P. M., ... & Danino, T. (2020). Engineered probiotics for local tumor delivery of checkpoint blockade nanobodies. Science Translational Medicine, 12(530).

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