Background Checkpoint inhibition (CPI) therapies have led to large successes in treating certain cancer types, but they are largely ineffective in immunologically ‘cold’ tumors, with an immunosuppressive microenvironment. The immunosuppressive tumor microenvironment (TME) is dominated by Treg and suppressive myeloid cells. Patients who respond well to CPI therapies exhibit a Th1-biased TME driven by IFNg and related genes. Thus, approaches that can safely transform an immunosuppressive TME would be beneficial.
Methods mRNA-based therapies are a rapidly growing class of medications that can redefine how many diseases are treated. These therapies enable the production of biologics directly in the patient and mRNA LNPs are straightforward to manufacture at scale. Despite these key advantages, mRNA therapeutics are yet to show their true potential in oncology. Dose limiting toxicities of mRNA immunotherapies are driven, in part, by systemic payload (encoded protein) toxicity, which can be avoided by engineering the mRNA to improve its onco-selectivity and thereby reduce its on-target off-tumor toxicity. To tackle this challenge, Kernal Biologics has developed onco-selective mRNA LNP therapies that utilize a computational pipeline enabled by machine learning. The aim is to overcome the immunosuppressive conditions within the tumor microenvironment.
Results Previously, we have shown that local onco-selective mRNA LNP therapy via intratumoral injections can results in complete responses in various preclinical models, including those that are resistant to checkpoint inhibitors. Here we report the outcome of in vivo proof-of-concept studies for systemic mRNA LNP administration. In a syngeneic MC38 tumor model, KR-336 was administered intravenously as a monotherapy, resulting in impressive anti-tumor effectiveness. This was evidenced by tumor regression, multiple complete responses, and enhanced overall survival rates. The mRNA LNPs were well-tolerated and prompted immune activation, fostering a pro-inflammatory tumor microenvironment.
Conclusions These findings collectively indicate the viability of systemic onco-selective mRNA LNP therapy as a potential treatment option for cancers characterized by an immunosuppressive tumor microenvironment. Additionally, it has the potential to drastically expand the patient population that can benefit from cancer immunotherapy.
Ethics Approval All in vivo animal studies were performed in accordance with the IACUC number 2021–1309 at CRADL, Cambridge MA
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.