RNA Editing Technology for Enhancing Tumor Immunogenicity and Immune Checkpoint Inhibitors

SUMMARY

Novel RNA editing method to generate a multitude of neoantigens in tumor cells making the cells more recognizable by T cells and enhancing the efficacy of immune checkpoint inhibitors

The problem: Current approaches to further enhance the immunogenicity of tumors fail to counteract the mechanisms deployed by cancer cells to escape detection

• The field of cancer immunotherapy has focused significantly on the development of immune checkpoint inhibitors (ICIs) which target proteins like PD-1 and PD-L1 to enhance the immune system’s ability to detect and attack cancer cells. Despite their success, ICIs have shown efficacy only in a minority of patients as monotherapies.

• This limitation has driven exploration into methods of making tumors more immunogenic and, therefore, responsive to immunotherapies. Current strategies encompass the use of oncolytic viruses, gene therapies, and neoantigen vaccines. These approaches aim to stimulate the immune system more robustly or precisely by increasing the visibility of tumors to immune cells.

• However, each of these strategies has its drawbacks. Oncolytic viruses, while effective in certain cases, pose safety concerns related to viral toxicity, off-target effects, and genetic unpredictability. Gene therapy methods, specifically those involving adeno-associated viruses (AAVs), introduce single genes to enhance immune responses but often fall short in generating a sufficiently robust immune reaction. Neoantigen vaccines, though promising, demand patient-specific customization which is both time-consuming and resource-intensive. These vaccines also face challenges with the genetic variability of tumors, leading to potential immune escape mechanisms. Thus, there are significant technical and logistical hurdles in making these therapies universally effective against a wide array of tumors.

The proposed solution: A method for localized delivery of hyperactive adenosine-to-inosine RNA editing enzymes for induction of neoantigens in tumor cells

• The faculty inventor, Jeffrey Hubbell, developed a novel method to induce a multitude of neoantigens in tumor cells through extensive RNA editing. This is accomplished by locally delivering hyperactive adenosine-to-inosine (A-to-I) RNA editing enzymes, making tumors more recognizable to a patient’s immune system and potentially enhancing the efficacy of ICIs. By inducing thousands of RNA editing events, the therapy could serve as an off-the-shelf treatment, providing broader application across various cancer types.

• Compared to existing therapies, such as oncolytic viruses, gene therapies, and neoantigen vaccines, this method is advantageous in its ability to safely and effectively induce a multitude of neoantigens. The RNA editing approach not only enhances immunogenicity broadly but also avoids the genetic manipulation risks of viral therapies. By using hyperactive ADAR enzymes to introduce widespread neoantigen profiles, this method offers a scalable and potentially more universally effective cancer immunotherapy.

ADVANTAGES

ADVANTAGES

• Generates multitude of neoantigens

• Improves tumor recognition by T cells

• Reduces off-target effects by using hyperactive RNA editing enzymes

• Offers alternative to time-consuming personalized treatments

APPLICATIONS

• Cancer immunotherapy

• Potential for combination with other therapies (oncolytic viruses, gene therapy)

June 3, 2024

Proof of concept

Patent Pending

Licensing,Co-development

Jeffrey Hubbell