The role of RNA in immunotherapies

Reece Armstrong speaks to Samuel Deutsch, Chief Scientific Officer of Nutcracker Therapeutics about the RNA landscape and how it can benefit the development of immunotherapies. RA: What role does RNA play in the development of effective immunotherapies? SD: The ability of RNA therapies to use the body’s own mechanisms to reprogram cells and tissues towards a healthy state offer a transformative approach to medicine, with early applications in the immunotherapy space. Specifically, at Nutcracker Therapeutics, we’re exploring ways to temporarily reprogram healthy tissues to produce therapeutic molecules that can treat cancer or autoimmune disorders. The transient nature of RNA reduces the risk of permanent damage, reverting tissues back to their normal state after the therapeutic action is completed. An important advantage of RNA in immunotherapies is the fact that manufacturing and formulation can be standardised, potentially accelerating the process of getting new products into the clinic. RA: Are multi-mechanistic or combination immunotherapies therapies better at fighting cancerous tumours? Could you discuss the benefits of encoding for multiple proteins and the associated anti-cancer effects? SD: With mRNA therapy, we can combine different mRNA molecules, each one having a unique mechanism of action within a single drug product. This approach is particularly effective against diseases, such as cancer, in which attacking the disease from multiple therapeutic angles can prevent resistance development. An example of such an approach is our lead asset NTX-250 that comprises three different mRNA molecules. However, drug developers have the extra burden of demonstrating the contribution of each individual component and proving that the combination of different molecules work together as expected and are safe to administer. RA: How challenging is it to develop potent immunotherapies given the complex interplay between tumours and the immune system? SD: This is definitely a challenge. But it all comes down to designing drug products with increased efficacy and broader therapeutic windows. RNA-based approaches allow the design of more complex molecules, as the proteins are freshly produced in the patients’ cells and tissues being delivered as mRNA nanoparticles with standard manufacturing and formulation processes. With our suite of mRNA therapeutic platforms, we can rapidly screen many molecule designs, to get a drug candidate that interacts optimally with our targets and stimulates the immune system effectively and safely. An example of this iterative process is NTX-471, our anti-CD47 preclinical program. We engineered versions of mRNA-encoded, anti-CD47 proteins with differing valencies, and performed in-depth functional characterization to identify candidates with the best exposure, purity, specificity, efficacy and enhanced tolerability. RA: Could you tell us about Nutcracker’s preclinical candidates? (NTX-471 & NTX-250) SD: NTX-250, our lead candidate, targets cervical intraepithelial neoplasia (CIN), which is caused by the human papillomavirus (HPV). CIN is a common precursor to cervical cancer. Currently, surgical removal is the standard of care for women affected by this disease. NTX-250 was developed to target CIN through a multi-modal mechanism. It combines a vaccine component against HPV, an immunomodulator to make the tumour environment more receptive to immune attacks, and a T-cell co-stimulator to establish long-term immune memory against the tumour. The product is differentiated in that it clears both the lesions and the HPV virus, which is the root-cause of the disease. This multifaceted strategy exemplifies how RNA therapies can offer novel and effective treatments for complex diseases. There is potential for NTX-250 to be also used as a therapy for cervical cancer and other tumor types caused by HPV. NTX-471 is one of our early-stage preclinical candidates. It targets CD47 cancerous cells with unique mRNA-encoded compositions that are highly specific to CD47 receptors on cancer cells, whilst minimising binding to healthy cells and tissues. This specificity increases tolerability of the product, mitigating the anemia side effects commonly seen with anti-CD47 therapies, while retaining the anti-tumour activities. RA: What are the benefits of encoding anti-CD47 proteins? SD: CD47 is a receptor that is found on numerous cells in the body, and commonly overexpressed in cancer cells. These CD47 receptors emit a ‘do not eat me’ signal, protecting the cell from engulfment or destruction from specialised immune system cells called macrophages. Although CD47 plays an important role in the body’s normal biological functioning, it is also a part of what makes targeting cancerous cells so difficult. By developing RNA therapeutics that create anti-CD47 proteins, the CD47 receptors on cancer cells can be blocked, leaving them vulnerable to attacks by the immune system. Part of the challenge in creating anti-CD47 drugs is obtaining specificity, and many existing anti-CD47 drugs often bind to normal cells in addition to cancerous cells. Our anti-CD47 candidate, NTX-471, was engineered for higher specificity to tumours, mitigating safety concerns. RA: What lessons for RNA development did we learn from the Covid-19 pandemic? SD: Tackling the Covid-19 pandemic quickly was a crowning achievement for the RNA field and validated the safety and efficacy of this class of molecules at a global scale. Now being at the tail-end of the pandemic, we have a production overcapacity for mRNA manufacturing, while the next clinical uses of therapeutic mRNAs advance through the clinical development process. It is likely that the next mRNA treatments to be commercially approved will require different manufacturing scales ranging from thousands of patients to n-of-1 ‘personalised treatments’. This will shift the RNA manufacturing paradigm. Our peers in the field are starting to realise that we need flexible solutions designed for the next stage of RNA therapies, where precisely matching capacity to demand will be crucial. RA: How versatile is RNA as a tool for indications outside of infectious diseases? Other than cancer, what diseases can we expect RNA to play a role in treating in the near future? SD: The beauty of RNA is that with the appropriate sequence designs and formulations, you can encode virtually any protein imaginable. Because of this, RNA is an incredibly versatile tool across a wide range of modalities and indications, and there are a multitude of different ways that RNA can be utilised to create novel therapeutics. Some areas that are making progress in the clinic include personalised cancer vaccines, protein replacement therapies for rare diseases, and mRNA encoded gene and genome editing drugs. Although the existing RNA therapeutics currently in use have remarkable potential, as our knowledge base and therapeutic readiness continues to evolve, we expect the types and quality of RNA therapeutics to continue to grow at a fast pace. DDW Volume 25 – Issue 2, Spring 2024 Biography Sam Deutsch is Chief Scientific Officer at Nutcracker Therapeutics, leading biological R&D. Deutsch manages the advancements of Nutcracker’s therapeutics pipeline through close interactions between internal R&D, scientific advisors and clinical collaborators. Before Nutcracker, Deutsch led the DNA synthesis platform at the Joint Genome Institute of Lawrence Berkeley National Laboratory.