Cytokine-Expressing Parainfluenza Vector for Solid Tumor Infiltration
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing immune checkpoint inhibitors and CAR-T therapy have limited efficacy in increasing the response rate for solid cancers due to defective angiogenesis and stressful conditions in the tumor microenvironment, which inhibit the infiltration of tumor-infiltrating lymphocytes and reduce the antitumor effect.
Innovation Solution
An anticancer agent containing human parainfluenza virus type 2 expressing cytokines such as IL-2, IL-7, IL-12, IL-15, IL-18, or chemokines like CCL19 and CCL21, or their mutants, combined with immune activators and checkpoint inhibitors, is administered intratumorally to enhance tumor infiltration and immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immune checkpoint inhibitors and CAR-T therapy are used for solid cancer treatment, then the response rate for hematological cancers increases, but the infiltration of tumor-infiltrating lymphocytes into solid cancer tissues is inhibited and the antitumor effect is reduced
Solution Approach 1:
The patent segments the immune response enhancement into multiple components: cytokine expression (IL-2, IL-7, IL-12, IL-15, IL-18) to activate and recruit immune cells, chemokine expression (CCL19, CCL21) to guide lymphocyte infiltration, and checkpoint inhibitor administration to remove suppression. This multi-component approach overcomes the limitation of single-therapy infiltration inhibition in solid cancers.
Solution Approach 2:
The patent creates a composite therapeutic approach by combining viral vectors (adenovirus or AAV) that co-express multiple cytokines and chemokines with checkpoint inhibitors. This composite system simultaneously addresses multiple barriers to effective solid cancer immunotherapy: recruitment, activation, infiltration, and suppression removal.
2Adaptability or versatility
If the tumor microenvironment with defective angiogenesis and hypoxia is present, then cancer cells develop drug resistance and aggression, but the infiltration of immune cells is hindered by matrix formation
Solution Approach 1:
The patent uses chemokines CCL19 and CCL21 as intermediary signals that create a chemical gradient through the tumor matrix, guiding lymphocytes to navigate and infiltrate through the obstructive stromal matrix. The cytokines serve as intermediary activators that prepare the immune microenvironment before infiltration occurs, overcoming the physical and immunological barriers created by the tumor matrix.
3Reliability
If CAR-T cells are administered for solid cancer treatment, then the therapy shows effectiveness in mice, but the infiltration into human cancer tissues is inhibited and the antitumor effect is reduced
Solution Approach 1:
The patent applies preliminary action by first administering the viral vector to express cytokines and chemokines that prepare the tumor microenvironment, then subsequently administering checkpoint inhibitors to remove suppression. This sequential preparation creates a favorable environment before CAR-T cell infiltration is attempted, addressing the infiltration barrier that prevents mouse-to-human translation of efficacy.
Data Source
Figure 1~2
Figure 3~4
Figure 5~6
AI summary
An anticancer agent for solid cancer contains, as an active ingredient, human parainfluenza virus type 2 expressing: at least one kind of cytokine selected from the group consisting of IL-2, IL-7, IL-12, IL-15, and IL-18; or a combination of the cytokine and CCL 19 and/or CCL21; or a mutant of either the cytokine or the combination, the mutant having the same function.