CD47 Blockade Enhances Radiation Therapy Abscopal Effect
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Solution Overview
Problem
Current cancer treatments, particularly radiation therapy, often fail to effectively address metastatic disease due to inflammatory protumor effects and limited systemic activation of antitumor immune responses, necessitating the development of combination therapies that enhance local and abscopal anti-tumor effects.
Innovation Solution
Combining radiation therapy with a CD47 blocking agent, such as antibodies or small molecules, to inhibit the interaction between CD47 and SIRPα, thereby stimulating macrophage-mediated phagocytosis and promoting potent local and systemic anti-tumor effects, including abscopal effects in non-irradiated tumor sites.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If radiation therapy is used to treat cancer, then local tumor cell death is achieved through DNA damage, but inflammatory protumor effects occur and systemic anti-tumor activation is limited
Solution Approach 1:
The patent introduces CD47 blocking agents as intermediary substances that mediate between radiation therapy and the immune system. These agents block the CD47-SIRPα interaction, preventing macrophages from receiving inhibitory signals, thereby converting protumor inflammatory effects into beneficial antitumor immune activation. The CD47 blocker serves as a mediator that transforms the harmful inflammatory response into a helpful systemic anti-tumor response.
2Reliability
If conventional radiation therapy is applied, then direct cancer cell killing occurs, but metastatic disease is not effectively addressed
Solution Approach 1:
The patent makes radiation therapy universal by combining it with CD47 blocking agents that activate macrophages systemically. This combination allows the treatment to effectively address both local primary tumors and distant metastatic sites. The macrophage activation creates a systemic anti-tumor response that can infiltrate and destroy cancer cells throughout the body, not just at the irradiated site, thereby giving the therapy universal effectiveness across different tumor locations.
3Reliability
If CD47 blocking agent is combined with radiation therapy, then local and abscopal anti-tumor effects are enhanced, but treatment complexity increases
Solution Approach 1:
The patent applies preliminary action by administering the CD47 blocking agent before or concurrently with radiation therapy to prime the macrophage system. This preliminary blocking of the CD47-SIRPα interaction ensures that when radiation induces tumor cell death, the activated macrophages are already ready to respond vigorously, enhancing both local and abscopal effects. The preliminary preparation simplifies the overall treatment mechanism by pre-establishing the immune activation pathway.
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 radiation therapy with CD47 blockade significantly enhances local tumor inhibition and induces abscopal effects, leading to reduced tumor growth and increased macrophage infiltration, particularly in metastatic cancers like small cell lung cancer, without relying on T-cell activation.
Implementation Method 1
The primary mode of action of radiation is the direct induction of cancer cell death through acute damage to the DNA
Implementation Method 2
By binding to signal-regulatory protein α (SIRPα), a receptor expressed on the surface of macrophages, CD47 is able to transduce inhibitory signals that prevent phagocytosis. Blocking the interaction between CD47 and SIRPα with antibodies not only stimulates macrophages to engage cancer cells in vitro but also exerts robust anticancer effects in vivo
Implementation Method 3
Blocking the interaction between CD47 and SIRPα with antibodies not only stimulates macrophages to engage cancer cells in vitro but also exerts robust anticancer effects in vivo
Implementation Method 4
The release of tumor antigens by dead or dying cancer cells further leads to the priming of antenna-specific T cells, thereby activating an adaptive immune response against any remaining cancer cells
Implementation Method 5
cancer cell debris can stimulate the innate immune system, including recruitment of and increased phagocytosis by macrophages
Data Source
AI summary
Methods and compositions are provided for the treatment of cancer with a targeted therapy in combination with radiation. Administration of an effective dose or series of doses of a CD47 blocking agent, i.e. an agent that blocks the interaction between CD47 and SIRPα, is combined with radiation therapy to provide for an abscopal effect. In some embodiments the cancer is a metastatic cancer, or a cancer with a high likelihood of metastasis.