Image source - Destruction Of A Cancer Cell. Kateryna Kon/science Photo Library.

EnGeneIC’s EDV™ (EnGeneIC Dream Vector) nanocell drug delivery platform is a targeted cyto-immunotherapy indicated for the treatment of cancer. EDV nanocells deliver cytotoxic drugs directly into tumour cells. These could enable cancer treatment to be more potent and significantly less toxic than current therapies, while also stimulating an innate and adaptive immune anti-tumour response.

A recent publication by Sagnella et al. in Cancer Cell, evaluates EnGeneIC Limited’s clinical-stage novel therapy in which EDV nanocells are used in mouse and human tumour models (Sagnella, S. et al, 2020).

EnGeneIC Dream Vectors (EDV™) are non-viable nanocells, around 400nm in diameter, derived from bacteria that are genetically modified to divide at their cell poles as well as through their centre. This abnormal division causes a portion of the cell to split off without encapsulating chromosomal material creating a non-viable nanocell. These nanocells can then be packaged with high concentrations of a variety of materials such as siRNA, microRNA, or cytotoxic drugs and act as a delivery system to transport these drugs directly to tumour microenvironments (TMEs). The nanocells are attached to engineered bispecific antibodies. One arm of the antibody is attached to the nanocell surface, while the other is directed to any tumour cell surface receptor (MacDiarmid, J. A. et al, 2007).

While EDV nanocells are large enough to be retained in circulation by the blood vessels of healthy tissue, tumour vasculature tends to be structurally disorganised with immature, hyperpermeable vessels which allows nanocells to passively extravasate into interstitial TMEs. The surrounding lymphatic vessels are similarly poorly formed, impairing their ability to effectively drain and remove the nanocells, resulting in their accumulation. This phenomenon is known as the enhanced permeability and retention (EPR) effect and it allows passive and selective build-up of nanocells within TMEs.

Once in the TME, the bispecific antibodies on the EDV target tumour cell surface receptors. This active specific targeting causes nanocell uptake by the tumour via macropinocytosis. This causes the nanocells to be taken into endosomes within the cell, which then fuse with lysosomes causing the breakdown of the nanocell and the subsequent release of the packaged material into the tumour tissue. This results in rapid cell death if the nanocell is packaged with cytotoxic drugs (MacDiarmid, J. A. et al, 2007) (Sagnella, S. et al, 2020).

Minicells: Versatile vectors for targeted drug or si/shRNA cancer ...
Figure 1: EDV nanocells within the TME actively target tumour cells. EDV bispecific antibodies bind to receptors on the tumour cell surface, they are engulfed by the cancer cell, and the toxic payload is released inside. 'Minicell' is an old term for the vector, now referred to more accurately as, ‘nanocell’ as the vector is in the nano size range (400nm).
Source: https://engeneic.com/edv-technology/

EDVs have demonstrated the ability to effectively deliver cytotoxic drugs to tumours resulting in cell death, simultaneously stimulating an anti-tumour, immune response (MacDiarmid, J. A. et al, 2007) (Sagnella, S. et al, 2018). DAMP molecules released by the apoptotic cells stimulate tumour associated macrophages which produce a cytokine response and the maturation of dendritic cells (DCs). Following maturation, antigen presentation of DCs to T cells results in the increased recruitment of CD4+ T helper cells and CD8+ T-cells which induce an adaptive immune response. The CD8+ cells pass into the TME and target the tumour for destruction. The stimulation of several different types of immune cell contributes to a more robust anti-tumour response than seen in other immunotherapies (Sagnella, S. et al, 2020).

Delivering the drug directly into the TME and only releasing the drug once inside the tumour, means that there is limited toxicity from the anti-tumour drug as it is selectively localised to tumour cells. This means that significantly higher doses, or more toxic drugs can be used, enabling enhanced potency and efficacy of treatment (Sagnella, S. et al, 2020).

Clinical trials are currently evaluating the use of EDV technology in phase 1 clinical trials across multiple cancer indications including glioblastoma and CNS cancers, which are traditionally difficult to treat. Provided their outcomes are good, it seems likely that clinical development programs focused on nanocell technologies will only expand over time. The future of EDV nanocell technology is very promising. Its development could one day bring about effective therapies for treating drug-resistant and late-stage cancer, addressing patients with very high clinical unmet needs.

Written by Frances Wise, Healthcare Analyst, Oncology.

References

Sagnella, S. et al. Cyto-Immuno-Therapy for Cancer: A Pathway Elicited by Tumor-Targeted, Cytotoxic Drug-Packaged Bacterially Derived Nanocells. Cancer Cell (2020) 37, 354-370

MacDiarmid, J. A. et al. Bacterially Derived Nanocells for Tumor-Targeted Delivery of Chemotherapeutics and Cell Cycle Inhibitors. Landes Bioscience (2007) 6:17, 2099-2105