Arming a virus to fight cancer

Cancer, the big C, or the blip. Although 50% of people are likely to receive a diagnosis at some point in their lives, it doesn’t diminish the emotional turbulence that those afflicted and their loved ones face. Cancer is multifactorial, as it comes down to the individual’s specific genetic profile. In the last decade, scientists have been thinking “outside-of-the-box” to become more creative to abolish this disease. The most promising research has been different methods of immunotherapy, which involves enhancing a patient’s own immune system to seek and destroy or be more powerful against tumours. For example, “immune checkpoint inhibitors” boost T cells (one of the fighters in the immune army) to survive longer and have “more energy” to fight tumours [1][2]. The success of boosting these fighter cells by means of this therapy led to the Nobel Prize in 2018. Another ground-breaking therapy gaining traction is called “CAR T cell therapy” which involves removing a patient’s immune cells, genetically modifying their T cells to seek and destroy their tumours, almost like a GPS tracker [3][4]. This therapy has been widely successful in blood cancers, especially in children with leukemia. In this blog, however, let’s focus on a new study that involves using viruses to fight cancer.

Oncolytic viruses are viruses that infect cancer cells, using them as their host [5]. As a therapy, once the virus infects the host, it uses its machinery to replicate itself inside, then bursts the tumour cells. Once the tumours explode, a concoction of antigens are released that alerts the immune system to hurry to the area. As a consequence, now the immune system is prepped and primed to seek and destroy tumours. Though this was first observed at the turn of the nineteenth century, when cancer patients’ tumours would regress during viral infection, there was little movement in the field until technological advances occurred to harbour this potential to fight cancer. Advancing the field to incorporate oncolytic viruses is just another example of scientists thinking creatively to fight cancer, as it creates an “immunologically hot” environment once the tumours burst, mass activating the immune system, with the added bonus of creating an “in situ” vaccine, as the person’s immune system develops memory to that cancer.???????

Oncolytic viruses are FDA approved, thanks to a Phase 3 trial showing a response rising up to 70% in advanced melanoma patients [5]. Even more so, combining this oncolytic virus with an immune checkpoint inhibitor as mentioned in the first paragraph, has delivered a two-punch in melanoma patients.?Given there is no additional toxicity in combining these two treatments, why not use these in combo to deliver a knock-out blow against cancer?

This is what a research group based at The Institute of Cancer Research (ICR) in London did. The scientists designed and constructed a therapy based on herpes virus, HSV-1 [6]. Why HSV-1? HSV-1 is a super activator of the immune system as it kills by a process known as “necrosis”, and has the potential to infect a broad range of cancer cells. Importantly, HSV-1 has been shown to be safe and effective in cancer patients. In this study, the researchers took an HSV-1 strain to boost its cancer-killing ability by genetically modifying it [7]. The product, called RP2, was combined with the FDA-approved checkpoint inhibitor, nivolumab, to stop T cells from becoming exhausted when fighting cancer.

The clinical trial recruited patients with solid tumours having progressed, and those with advanced metastatic uveal melanoma, non-small cell lung cancer, breast cancer, head and neck cancer or gastrointestinal cancers. A total of 9 patients were evaluated for RP2 alone, and 30 received RP2 in combination with nivolumab. 3 out of the 9 patients treated with RP2 alone had their tumours reduce in size, and 1 saw a complete response and has remained in remission 15 months later. In the combination therapy cohort, 7 of the 30 patients had durable responses. Most importantly, there were no additional toxicities and this study proved the safety of RP2 + nivolumab.?

The early data is very promising, the next step is to observe how patients continue to respond and increasing the number of patients. This study is just another example of the pioneering developments in cancer therapy, where scientists are becoming creative to solve the current setbacks in cancer, to make the incurable now curable.

Bibliography:

[1] D. A. Fennell et al., “Nivolumab versus placebo in patients with relapsed malignant mesothelioma (CONFIRM): a multicentre, double-blind, randomised, phase 3 trial,” Lancet Oncol, vol. 22, no. 11, 2021, doi: 10.1016/S1470-2045(21)00471-X.

[2] C. Robert et al., “Ipilimumab plus Dacarbazine for Previously Untreated Metastatic Melanoma,” New England Journal of Medicine, vol. 364, no. 26, 2011, doi: 10.1056/nejmoa1104621.

[3] D. L. Porter, B. L. Levine, M. Kalos, A. Bagg, and C. H. June, “Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid Leukemia,” New England Journal of Medicine, vol. 365, no. 8, 2011, doi: 10.1056/nejmoa1103849.

[4] S. L. Maude et al., “Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia,” New England Journal of Medicine, vol. 371, no. 16, 2014, doi: 10.1056/nejmoa1407222.

[5] R. H. I. Andtbacka et al., “Talimogene laherparepvec improves durable response rate in patients with advanced melanoma,” Journal of Clinical Oncology, vol. 33, no. 25, 2015, doi: 10.1200/JCO.2014.58.3377.

[6] S. Thomas et al., “Development of a new fusion-enhanced oncolytic immunotherapy platform based on herpes simplex virus type 1,” J Immunother Cancer, vol. 7, no. 1, 2019, doi: 10.1186/s40425-019-0682-1.

[7] F. Aroldi et al., “421 Initial results of a phase 1 trial of RP2, a first in class, enhanced potency, anti-CTLA-4 antibody expressing, oncolytic HSV as single agent and combined with nivolumab in patients with solid tumours,” 2020. doi: 10.1136/jitc-2020-sitc2020.0421.