Intratumoral Expression Vector for Cold Tumor Conversion
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Solution Overview
Problem
Current cancer immunotherapies face challenges in effectively targeting 'cold' tumors that lack preexisting inflammation, necessitating novel combination treatment modalities to convert these tumors into 'hot' ones by enhancing antigen presentation and T-cell activation.
Innovation Solution
Intratumoral delivery of an expression vector encoding a secretable vaccine protein, such as gp96-Ig, combined with a T cell costimulatory fusion protein like OX40L-Ig, to stimulate antigen-specific T-cell responses and promote tumor inflammation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional cancer immunotherapies are used, then they work effectively on tumors with preexisting inflammation, but they fail to treat 'cold' tumors that lack preexisting inflammation
Solution Approach 1:
The treatment approach is segmented into two distinct components: (1) intratumoral delivery of expression vectors encoding vaccine proteins and costimulatory molecules to convert cold tumors, and (2) subsequent systemic immunotherapy administration. This segmentation allows the treatment to be tailored to the specific immunogenicity status of the tumor, resolving the contradiction between effectiveness on hot tumors and applicability to cold tumors.
Solution Approach 2:
Before administering conventional immunotherapies, the patent performs preliminary action by intratumorally delivering expression vectors that encode vaccine proteins and costimulatory molecules. This preliminary step converts cold tumors into hot tumors by inducing inflammation and enhancing antigen presentation, thereby creating the necessary preexisting inflammation state that makes subsequent immunotherapy effective.
2Reliability
If allogeneic vaccine cell lines secreting Gp96-Ig and Fc-OX40L are used, then antigen-specific CD4+/CD8+ anti-tumor responses are generated, but the approach requires complex combination of multiple proteins
Solution Approach 1:
Multiple functional proteins (vaccine antigen, Gp96-Ig chaperone, and Fc-OX40L costimulatory molecule) are merged into a single allogeneic vaccine cell line through genetic engineering. This consolidation maintains the complex multi-protein functionality required for robust anti-tumor immune responses while simplifying the delivery system to a single cellular vehicle rather than requiring separate administrations of multiple proteins.
Solution Approach 2:
The allogeneic vaccine cell line is engineered to simultaneously perform multiple functions: presenting tumor antigens via MHC molecules, chaperoning antigens through secreted Gp96-Ig, and providing costimulatory signals via secreted Fc-OX40L. This multi-functionality within a single cell type achieves reliable anti-tumor responses without requiring complex combination therapies of separate protein administrations.
3Adaptability or versatility
If intratumoral delivery of expression vectors is performed, then tumor inflammation is enhanced and cold tumors are converted to hot tumors, but the treatment requires precise intratumoral administration
Solution Approach 1:
The intratumorally delivered expression vectors enable the tumor microenvironment to self-convert from a cold to hot state by locally producing vaccine proteins and costimulatory molecules. This self-service mechanism enhances inflammation and antigen presentation directly at the tumor site without requiring ongoing external intervention, thereby achieving tumor conversion while minimizing the complexity of repeated precise administrations.
Data Source
AI summary
The present disclosure relates to, inter alia, a method for treating a tumor by intratumorally delivering an effective amount of a composition comprising an expression vector that comprises a first nucleotide sequence encoding a secretable vaccine protein, and a second nucleotide sequence encoding a T cell costimulatory fusion protein.