Cancer immunotherapy has set new standards in cancer care, but many patients are still not responding. RNA modifying enzymes (RME) research could be a way to improve results.

DDW’s Megan Thomas reflects on STORM Therapeutics’ approach for the future of this mechanism of action.  

Turning points and catalysts

March 2011 was a turning point in cancer, with the FDA’s first approval of a checkpoint inhibitor drug. Unlike those drugs that went before it, Bristol-Myers Squibb’s Yervoy (ipilimumab) didn’t work by attacking cancer cells directly. Instead, it flipped a chemical switch known as CTLA-4, which instructs the immune system to mount an attack on the tumour. 

This was followed by Merck & Co’s Keytruda (pembrolizumab) in September 2014, which inhibits the receptor PD-1 to produce a similar effect. The research underpinning the CTLA-4 and PD-1 technologies resulted in the Nobel Prize in Physiology or Medicine 2018 for the researchers and teams who pioneered them – James Allison of the University of California, Berkeley, and Tasuku Honjo at Kyoto University, respectively. 

Allison and Honjo had answered a question that had been puzzling scientists for decades, which is why the body’s immune defences are unable to fight cancer. They revealed that these biochemical ‘brakes’ hold back the influx of T-cells into tumours – and by turning off these brakes the immune system can recognise cancer and begin destroying it. 

But results vary greatly from patient to patient – while a small percentage may experience a complete response and become clear of cancer, many do not. Only around 20%-40% of patients respond to immunotherapy, leaving scientists looking at ways to improve the response, and provide further options for those where immunotherapy treatment is unsuccessful. 

Next-generation checkpoint inhibitors targeting novel pathways like LAG-3 and TIM-3, are showing potential in overcoming resistance to first-generation immune checkpoint inhibitors. Adoptive cell therapies, such as CAR-T cells and tumour-infiltrating lymphocyte (TIL) therapies, are advancing, particularly in hematological malignancies, with ongoing efforts to expand their efficacy in solid tumours. 

Cellular reprogramming through RNA modifications

New mechanisms of action, new receptors, and new modalities are being explored, with one example being the UK’s STORM Therapeutics. Cambridge-based STORM is innovating in the field of cellular reprogramming through RNA modifications, which has led to the discovery of small molecule drugs capable of precisely reprograming cells through RNA biology. 

This could lead to new approaches to immunotherapy: its first-in-class, lead product STC-15 works by inhibiting an RNA modifying enzymes (RME) known as METTL3, its RNA methyltransferase inhibitor. Preclinical data have shown that inhibiting METTL3 stimulates immune cells and

activates interferon pathways, leading to the destruction of tumour cells. 

Jerry McMahon, CEO of STORM Therapeutics, said: “Many patients do not respond to immunotherapy or develop resistance over time. Addressing these challenges requires the development of next-generation treatments that can enhance efficacy, overcome resistance, and reduce side effects.” 

STC-15 is the first molecule specifically targeting an RME to enter clinical development and has been shown to enhance anti-tumour properties of checkpoint inhibitors, by improving the immune response. Its Phase 1 study is progressing well in patients with solid tumours. 

McMahon explains: “STC-15 has the potential to be particularly beneficial for patients who have been previously treated with immunotherapy.” 

One of the biggest challenges in immunotherapy is ensuring that the immune response can penetrate the tumour microenvironment – the area around the cancerous tissue that can prevent T-cells from infiltrating. The environment is often hypoxic, lacking the oxygen needed for T-cells to survive, and the tumour microenvironment itself acts as a physical barrier, preventing immune response. 

McMahon adds: “One of the key challenges in cancer treatment is overcoming resistance, and METTL3 inhibition can modulate the tumour microenvironment and enhance the anti-tumour immune response.” 

There is increasing interest in combining immunotherapies with drugs from different classes to increase efficacy. METTL3 is one example of this, thanks to its ability to stimulate the immune response to cancer. 

“STC-15 could be used in combination with existing immunotherapies to improve their efficacy, particularly in tumours that are resistant to current treatments. By targeting RNA modifications, we are approaching cancer treatment from a completely different angle, which could complement other therapeutic approaches. For patients who have relapsed after immunotherapy, STC-15 offers a novel mechanism of action that could expand the treatment options available to them.” 

Research beyond cancer

Beyond cancer, STORM’s research into RNA-modifying enzymes, particularly METTL3, has broader implications for other therapeutic areas. RNA modifications are implicated in a range of diseases, including inflammatory disorders, neurodegenerative diseases, and viral infections. 

METTL3 inhibitors could be explored for their role in modulating immune responses in chronic inflammatory conditions, such as rheumatoid arthritis or Crohn’s disease.  

In neurodegenerative disorders like Alzheimer’s disease or ALS, dysregulation of RNA processing is a known factor, and modulating RNA methylation could offer new therapeutic avenues.  

“Additionally, RNA modifications play a role in viral replication, suggesting that our technology could be applied to antiviral therapies, particularly in diseases where current treatment options are limited,” McMahon added. 

STORM’s METTL3 research currently has no major competitors in the clinic and little development in the discovery stage. METTL3 inhibition also has potential in Alzheimer’s and central nervous system diseases, where under-activity of the pathway is linked with brain cell death that causes dementia. 

McMahon says: “Our work has the potential to enhance cancer therapy, especially for patients who have undergone immunotherapy, and to impact a broader range of diseases where RNA modifications are crucial. We are committed to advancing our research to improve patient outcomes across multiple therapeutic areas.”