René, last year you mentioned that the field of geographic precision medicine, where Xilio Therapeutics operates, is yet to be fully explored. Could you remind us what that term means, and can you update us on any new insights in this area over the past year?
Our geographic precision medicines are tumor-selective immunotherapies designed to focus the immune system’s tumor-destroying effect locally in tumor tissue but not in healthy tissues.
By localizing activity to the tumor, we hope to overcome the toxicities of prior generations of immunotherapies and give patients the opportunity to receive higher doses to destroy the tumor.
We have indeed deepened our understanding significantly, thanks in part to our own research and contributions from other companies in the field. For example, this research has shown the potential of leveraging differences in the tumor microenvironment between tumors and normal tissue—specifically using certain enzymes abundant in tumors to achieve selective molecular activation. This move from theory to practical application has been a crucial step forward, not only for us but for the field at large.
Over the past year, we have treated over 100 patients with late-stage advanced cancers using our therapeutic approaches, learning much in the process. For instance, we have discovered that we can activate our first molecule, an anti-CTLA-4 monoclonal antibody, predominantly within the tumor—showing 70 to 90% activity in the tumor environment, while maintaining less than 15% activity in the circulating blood. This targeted activity allows us to minimize side effects significantly, thereby enabling higher dosages and longer treatment durations for responding patients.
Moreover, the insights gained from our clinical-stage research have been invaluable as we advance our research-stage pipeline. For example, our research presented at the American Association of Cancer Research's annual meeting on our bi-specific PD1-IL2 molecule marks a significant milestone, showcasing the potential of combining our experiences with masking antibodies and cytokines to create more effective therapeutic solutions that combine both in a single molecule.
Furthermore, we have initiated combination therapy studies using this molecule with Roche's PD-L1 inhibitor, atezolizumab. We are particularly focused on advancing a Phase 2 combination study for microsatellite stable colorectal cancer (MSS CRC), a major concern increasingly affecting younger populations, as highlighted in recent reports. The increase in younger patients developing late-stage colorectal cancer is alarming, and while the exact causes remain unclear, theories range from lifestyle and diet to environmental factors. No definitive cause has been pinpointed yet, making it a significant area of concern. This backdrop makes our work in immunotherapy even more crucial, as it offers hope for long-term survival and possibly curing cancers previously deemed intractable to such therapies. Our commitment to MSS CRC is driven by the urgent need to address this growing issue effectively.
What advancements have been made in other areas of your pipeline?
Our cytokine programs, specifically IL-2 and IL-12, have shown promising advancements. We have been able to administer significantly higher doses than previously possible, thanks to the tumor-selective activation of these molecules. This approach is designed to not only enhance the efficacy but also enable long-term safety, particularly with IL-2, which we can now administer over extended periods without severe side effects. Importantly, we have observed robust activation of the immune cells directly within the tumors, significantly more so than in the peripheral blood, which is exactly our goal.
IL-2 is ideal for combination therapies, including with TIL cell therapies. Combing a tumor-selective IL-2 with TIL cell therapies has the potential to reduce toxicity dramatically compared to traditional IL-2 therapies, which have been notoriously difficult to manage. Additionally, we have seen encouraging results with our tumor-selective IL-2 in a patient with MSS CRC, which is typically unresponsive to immunotherapy, achieving long-term stable disease with our treatment.
Additionally, our third molecule, a tumor-selective IL-12, is considered a potential game-changer in turning 'cold' tumors 'hot,' enabling unresponsive cold tumors to respond to immunotherapy. IL-12 has been historically challenging due to its toxicity, but in the clinic, our version has reached doses 100-fold higher than previously tolerated levels due to our tumor-selective approach.
This attracted interest from Gilead, and we recently signed a global licensing agreement. Such partnerships underscore the growing interest in our platform, and it’s rewarding to see so many others recognizing the potential of geographic precision medicine.
You have recently secured $11.3 million in financing. How will this funding help Xilio?
The recent financing, in conjunction with our deal with Gilead, is crucial as it extends our operational runway and allows us to reach several important clinical milestones for our anti-CTLA-4 and IL-12 molecules. This funding came from our longstanding investors, Bain Capital and Rock Springs Capital, who have been with us since before our initial public offering. Their continued investment reflects their deep understanding of our technology and their commitment to advancing our initiatives. This financial backing is essential for sustaining our clinical trials and for fostering further partnerships and developments within our pipeline.
Looking forward, what progress would you hope to report three years from now?
In three years, I hope to share transformative results, particularly in applying our immunotherapies to cancer types where such treatments have historically been ineffective. Our goal is to provide long-term, durable responses in cancers like MSS CRC. Additionally, I anticipate our IL-12 molecule will have opened avenues for treating various 'cold' tumors. The ultimate aim is to expand the reach of immunotherapy to manage as many cancers as we can.
