Ultra-High Nitric Oxide Priming for Checkpoint Inhibitor Cancer Therapy
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Solution Overview
Problem
The limited effectiveness of cancer treatment using immune checkpoint antibodies and the persistence of antigenic remnants post-tumor ablation hinder effective systemic anti-tumor immune responses.
Innovation Solution
Administering ultra-high concentration gaseous nitric oxide (UNO) to upregulate immune checkpoint protein expression, combined with checkpoint inhibitors and optionally an immune adjuvant, to enhance tumor-specific immune cell responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If tumor ablation is performed to destroy bulk tumor, then local tumor control is improved, but antigenic remnants persist and systemic anti-tumor immune response is insufficient
Solution Approach 1:
The patent applies preliminary action by administering ultra-high concentration gaseous nitric oxide (UNO) to the tumor site before checkpoint inhibitor therapy. This pre-treatment creates oxidative stress and DNA damage in tumor cells, upregulates immune checkpoint proteins, and primes the tumor microenvironment to enhance subsequent immune response, thereby converting local ablation into systemic immunity activation.
Solution Approach 2:
The patent utilizes parameter changes by delivering nitric oxide at ultra-high concentrations (10,000-1,000,000 ppm), which is significantly higher than physiological levels. This extreme parameter change induces oxidative/nitrosative stress and DNA damage that would not occur at normal concentrations, thereby triggering immune checkpoint upregulation and enhanced anti-tumor immunity.
2Productivity
If checkpoint inhibitors are administered to stimulate immune response, then anti-tumor immunity is enhanced, but treatment effectiveness remains limited
Solution Approach 1:
The patent applies preliminary action by administering ultra-high concentration gaseous nitric oxide (UNO) to the tumor site before checkpoint inhibitor therapy. This pre-treatment creates oxidative stress and DNA damage in tumor cells, upregulates immune checkpoint proteins, and primes the tumor microenvironment to enhance subsequent immune response, thereby converting local ablation into systemic immunity activation.
Solution Approach 2:
The patent uses nitric oxide as an intermediary substance that mediates between tumor cells and the immune system. UNO acts as a chemical mediator that damages tumor cells, upregulates checkpoint proteins, and activates immune cells, thereby bridging the gap between direct tumor destruction and immune system activation to enhance checkpoint inhibitor effectiveness.
3Ease of operation
If low dose nitric oxide is administered, then physiological signaling is maintained, but anti-cancer effect is insufficient
Solution Approach 1:
The patent utilizes parameter changes by delivering nitric oxide at ultra-high concentrations (10,000-1,000,000 ppm), which is significantly higher than physiological levels. This extreme parameter change induces oxidative/nitrosative stress and DNA damage that would not occur at normal concentrations, thereby triggering immune checkpoint upregulation and enhanced anti-tumor immunity.
Solution Approach 2:
The patent applies local quality by delivering ultra-high concentration nitric oxide specifically to the tumor site through local administration methods (intra-tumoral injection, intratumoral catheter, or topical application). This ensures that the extreme concentrations are confined to the tumor microenvironment, protecting surrounding healthy tissues while maximizing anti-tumor effect locally.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The combination of UNO with checkpoint inhibitors and immune adjuvants increases tumor-specific immune cell responses, particularly CD8+ T-cells, leading to improved cancer treatment outcomes, including tumor regression and prolonged survival.
Implementation Method 1
high doses of NO were shown to promote oxidative/nitrosative stress and DNA damage
Implementation Method 2
The generation of reactive nitric oxide species, including peroxynitrite can oxidize the DNA and induce single strand breaks
Implementation Method 3
NO can induce cell death via both i) necrosis, and ii) apoptosis
Implementation Method 4
NO can induce cell death via both i) necrosis, and ii) apoptosis
Data Source
AI summary
Cancer treatment using ultra-high concentration gaseous nitric oxide (UNO) and a checkpoint inhibitor and, optionally, an immune adjuvant is provided. Additionally, UNO as a sensitizing treatment to checkpoint inhibitors is provided. Accordingly, there is provided a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of UNO and a checkpoint inhibitor and, optionally, an immune adjuvant.