Activated Allogeneic CD4+ T-Cell Priming for ICI-Resistant mCRC
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Solution Overview
Problem
Immune checkpoint inhibitors (ICIs) are ineffective in treating immunologically 'cold' metastatic colorectal cancer (mCRC) tumors, which lack significant immune cell infiltration and are unresponsive to current therapies.
Innovation Solution
Administer activated allogeneic CD4+ T-cells and immune checkpoint inhibitors targeting CTLA-4, PD-1, PD-L1, and/or LAG-3 checkpoint molecules to convert 'cold' tumors to 'hot' lesions, enhancing immune cell infiltration and tumor response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immune checkpoint inhibitors are administered to treat metastatic colorectal cancer, then tumor response is improved in dMMR/MSI-H tumors, but treatment effectiveness deteriorates in pMMR/MSS tumors due to lack of immune cell infiltration
Solution Approach 1:
The patent applies preliminary action by administering activated allogeneic CD4+ T-cells before immune checkpoint inhibitors to pre-condition pMMR/MSS tumors. This preliminary step converts cold tumors to hot tumors by inducing immune cell infiltration and upregulating PD-L1 expression, thereby preparing the tumor microenvironment to respond to subsequent ICI treatment. The sequence is critical: T-cell activation first, then ICI administration.
Solution Approach 2:
The patent uses activated allogeneic CD4+ T-cells as an intermediary to bridge the gap between ICI therapy and pMMR/MSS tumors. These T-cells serve as a mediator that transforms the tumor microenvironment from an ICI-resistant state to an ICI-responsive state by increasing immune cell infiltration and PD-L1 expression, enabling the ICI to then effectively target the tumor.
2Reliability
If activated allogeneic CD4+ T-cells are administered to convert cold tumors to hot tumors, then immune cell infiltration increases, but treatment complexity increases
Solution Approach 1:
The patent merges two separate therapeutic approaches into a unified treatment protocol: allogeneic T-cell therapy and immune checkpoint inhibition. By combining these therapies in a specific sequence (T-cells first, then ICI), the protocol achieves synergistic effects where the T-cells prepare the tumor microenvironment and the ICI amplifies the immune response, creating a more effective overall treatment than either therapy alone.
3Reliability
If multiple treatment modalities are combined to treat pMMR/MSS mCRC, then therapeutic effectiveness improves, but treatment cost and administration complexity increase
Solution Approach 1:
The patent employs periodic action by administering treatments in distinct phases or cycles. The protocol structures therapy as sequential phases: first phase involves T-cell administration and activation, second phase involves ICI administration. This periodic structure allows each therapy to work optimally in its designated phase while maintaining overall treatment effectiveness, and facilitates monitoring and adjustment between phases.
Data Source
AI summary
A method and composition is described of treating metastatic colorectal cancer in a patient, comprises administering activated allogeneic CD4+ T-cells to a patient; and administering at least one immune checkpoint inhibitor to the patient