PD-1 PD-L1 Antagonist Timing with Radiation Therapy
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Solution Overview
Problem
Current radiation therapy for cancer often leads to local recurrence and metastatic disease due to immune escape, despite generating anti-tumor immune responses, highlighting the need for improved treatment strategies that enhance anti-tumor immune responses.
Innovation Solution
Administering fractionated radiation therapy in combination with PD-1 and/or PD-L1 antagonists, such as antibodies like MEDI4736, pembrolizumab, or nivolumab, on the same day or up to 4 days after radiation therapy, to enhance immune responses and overcome immunosuppression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If radiation therapy is used to treat cancer, then local tumor control is improved, but immune escape occurs leading to tumor recurrence
Solution Approach 1:
The patent converts the harmful immune escape mechanism into a beneficial outcome by using radiation-induced upregulation of PD-L1 as a target for subsequent PD-1/PD-L1 antagonist treatment. The radiation therapy initially causes tumor recurrence through immune escape, but this same process upregulates PD-L1 expression, which then becomes the target for the combination therapy that prevents future recurrence
Solution Approach 2:
The patent applies preliminary action by administering radiation therapy first to induce PD-L1 upregulation on tumor cells, then following with PD-1/PD-L1 antagonists to block the immune escape pathway. This sequential approach prepares the tumor microenvironment for the immunotherapy by ensuring high PD-L1 expression levels before antagonist administration
2Reliability
If PD-1 and/or PD-L1 antagonists are administered to block immune escape, then anti-tumor immune response is enhanced, but treatment complexity increases
Solution Approach 1:
The patent merges two distinct treatment modalities (radiation therapy and PD-1/PD-L1 antagonist immunotherapy) into a single coordinated treatment protocol. By combining these therapies with a defined sequential schedule, the patent achieves synergistic anti-tumor effects while managing complexity through protocol standardization
3Reliability
If fractionated radiation therapy is used, then anti-tumor immune response is generated, but treatment duration increases
Solution Approach 1:
The patent employs periodic action through fractionated radiation therapy, delivering radiation in multiple discrete doses (e.g., 5 fractions of 2 Gy each) rather than a single continuous dose. This periodic delivery allows the immune system to respond to each fraction while maintaining cumulative anti-tumor effects, and the standardized fractionation schedule optimizes the timing for subsequent PD-1/PD-L1 antagonist administration
Data Source
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AI summary
This application provides a method of treating cancer in a patient comprising administering at least one dose of radiation therapy and at least one PD-1 and/or PD-L1 antagonist, wherein at least one PD-1 and/or PD-L1 antagonist is administered on the same day as a dose of radiation therapy or up to and including 4 days later.