Health Science Reviews

By Mrittika Islam

Cancer remains as one of the most notoriously unyielding diseases mankind has ever had to face, accounting for nearly 10 million deaths in 2022 [1]. Its precise pathological profile is still a topic of rigorous debate; it is becoming increasingly clear that what we do not know about cancer is definitively more than what we do know, and the more headway we make to dismantle this disease, the more obstacles seem to appear.

Cancer treatment is no exception. The arsenal of tools used to treat cancer include the augmentation of the body’s own anti-tumour immune response, i.e., the ability to recognize and eliminate cancer cells, referred to as cancer immunotherapeutics. One such therapy offers a unique approach to tumour elimination; the use of naturally occurring and/or genetically modified Oncolytic Viruses (OVs). Infecting and replicating inside tumour cells, OVs induce cell lysis which releases tumour molecular markers that prime immune cells, such as T cells, and activate a new and enhanced adaptive immune response against the tumour. This immunotherapy pioneers the use of viral mechanisms to target tumours, i.e., the induction of cellular lysis after sufficient viral replication – a promising strategy using an unconventional instrument.

The appeal of OVs primarily come from their selectivity; Oncolytic Viruses are genetically engineered to have high selectivity for malignant cells, often exploiting characteristic defects in the tumour’s anti-viral defence system. This therapy therefore minimizes toxicity to normal cells, lowering side effects, while maintaining high tumour lethality – a particularly attractive factor due to the escalation of harmful side effects in the landscape of cancer drugs. In addition to this, OVs can be used to deliver therapeutic payloads to the tumour microenvironment (TME), opening the door to novel mechanisms to supplement or suppress molecular targets to amplify immune infiltration.

Despite the elegance of this therapy, only a handful of oncolytic viruses have been approved for commercial use, often due to shortfalls in clinical progression. One of the main limitations of viral oncotherapy is the inefficacy against immunologically ‘cold’ tumours, i.e., tumours that have established robust immunosuppression by altering the TME to prevent immune recognition, infiltration and function. As the success of OVs rely on immune efficacy, these immune resistant tumours tend to bypass oncolytic destruction. The popular attempt to overcome this by supplementing the OV-mediated immune response – for example, by delivering immune stimulatory payloads – has proven to be inadequate due to the sturdy and, rather unfortunately, ambiguous mechanisms of immune resistance. There is, therefore, much to uncover regarding this delicate immune manipulation sustaining cold tumours and impeding OV treatment.

To this extent, Greg Delgoffe, Ph.D., and his team at the University of Pittsburgh School of Medicine took a new approach to investigating this limitation of viral oncotherapy: focusing on determining and alleviating the mechanisms of immune suppression rather than enhancing the existing immune potency [2]. Briefly, they developed genetically identical pairs of mouse head and neck tumours (MEER) that were either sensitive or resistant/unresponsive to an unmodified form of Oncolytic Vaccinia Virus (VV), and compared the composition of the immune infiltrates in each tumour model. In doing so, they discovered that resistant tumours were characterized by a persistent stability of immunosuppressive T regulatory cells (Treg) in the tumour microenvironment, which was absent in the OV sensitive forms. This was further deduced to be caused by elevated levels of a potent immune inhibitory signalling molecule, Transforming Growth Factor β (TGFβ), in the TME, suggesting that TGFβ plays a direct role in OV resistance. This highlighted an important mechanism of OV resistance – the oncogenic elevation of specific immunoregulatory components to maintain an immunosuppressive TME thereby diminishing the OV mediated immune enhancement.

This discovery provided a new therapeutic target for combating OV resistance: TGFβ. To investigate this, they then genetically engineered the VV to deliver a powerful TGFβ inhibitor. This was met with encouraging results: upon OV treatment, TGFβ inhibition led to significant reduction in the MEER tumours that were initially resistant to the therapy, thus restoring susceptibility to OV. Importantly, oncoviral TGFβ inhibition did not appear to affect non-malignant TGFβ that functions in normal cells. This strategy therefore not only targets oncogenic TGFβ to relieve tumour mediated immunosuppression, but also does so with no notable effect on normal TGFβ functioning.

This study provides new insights into the immunoregulatory mechanism used by cancer cells to curate OV resistance, uncovering a fundamental component – TGFβ – driving this oncogenic phenomenon. Dr Delgoffe and his team further demonstrated the profound effects of TGFβ inhibition in mitigating oncogenic immune suppression and improving OV efficacy. This new take on a familiar battle in the development of cancer therapeutics – i.e., resistance – provides exciting opportunities to deliver therapeutic payloads to dismantle the components sustaining resistance, thus strengthening treatment potency. TGFβ may very well be one amongst a plethora of immunosuppressive components contributing to OV resistance and this study provides a promising vehicle and strategy for their effective neutralisation.

It is worth noting once again that the use of viruses to treat cancer serves as an interesting scientific unorthodox. Even so, with the recent advancements in modern biotechnology and our understanding of cancer biology and virology, the potential of viral oncotherapy seems indefinite. Research on oncolytic viruses as an immunotherapy has come impressively far but still has further to go. This is just the beginning.

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References

1. Cancer (IARC), The International Agency for Research on Cancer. Global Cancer Observatory. https://gco.iarc.fr/ (2022)
2. DePeaux, Kristin et al. “An oncolytic virus-delivered TGFβ inhibitor overcomes the immunosuppressive tumour microenvironment.” The Journal of Experimental Medicine vol. 220,10 (2023).