CAR T Cells With Disrupted IFNAR Resist Interferon Apoptosis
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Solution Overview
Problem
Chimeric antigen receptor (CAR) modified T cells face challenges in infiltrating solid tumors due to unfavorable chemokine gradients and immune suppressive mechanisms, leading to exhaustion and apoptosis, while oncolytic viruses' efficacy is limited by their sensitivity to type I interferon, which promotes CAR T cell attrition.
Innovation Solution
Administering oncolytic viruses that induce type I interferon expression in combination with genetically modified T cells that have reduced expression or disruption of the type I interferon receptor, such as IFNAR, to enhance CAR T cell persistence and function within the tumor microenvironment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If oncolytic viruses are administered to treat cancer, then tumor cells are lysed and therapeutic transgenes are expressed, but type I interferon promotes CAR T cell apoptosis and reduces T cell persistence
Solution Approach 1:
The patent converts the harmful effect of type I interferon on CAR T cells into a beneficial selectivity mechanism. By engineering CAR T cells with disrupted IFNAR receptors, the patent makes these T cells resistant to type I interferon-mediated apoptosis while normal cells remain sensitive. This allows the oncolytic virus to safely induce type I interferon for its antiviral and antitumor effects without causing CAR T cell exhaustion, effectively converting a harmful factor into a selective advantage for the modified T cells.
Solution Approach 2:
The patent changes the sensitivity parameter of CAR T cells to type I interferon by disrupting the IFNAR receptor signaling pathway. This parameter change allows CAR T cells to maintain functionality in the presence of high type I interferon concentrations produced by oncolytic virus infection, while normal cells remain responsive to this antiviral cytokine. The genetic modification fundamentally alters the interaction between the T cells and the interferon environment.
2Reliability
If CAR T cells are administered to treat solid tumors, then tumor cells are targeted, but unfavorable chemokine gradients and immune suppressive mechanisms limit infiltration and drive dysfunction
Solution Approach 1:
The patent converts the immune suppressive tumor microenvironment, particularly type I interferon signaling, into a selective pressure that benefits the engineered CAR T cells. By disrupting IFNAR receptors, the patent makes CAR T cells resistant to the suppressive effects of type I interferon while normal T cells remain vulnerable. This transforms the hostile tumor environment into a setting where modified CAR T cells gain a survival advantage, effectively converting harm into benefit for therapeutic efficacy.
3Reliability
If type I interferon is produced to stimulate immune response, then tumor reactive T cells are primed, but CAR T cell attrition is profoundly increased
Solution Approach 1:
The patent resolves this contradiction by making CAR T cells selectively resistant to type I interferon through IFNAR disruption. This allows the oncolytic virus to safely produce high levels of type I interferon to stimulate innate immunity and prime tumor-reactive T cells, while the engineered CAR T cells remain protected from interferon-mediated attrition. The harmful effect on T cell numbers is converted into a beneficial selective pressure that spares the modified CAR T cells while eliminating wild-type T cells that cannot withstand the interferon environment.
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
This approach promotes a favorable chemokine gradient for CAR T cell trafficking and reduces tumor burden by making CAR T cells less sensitive to type I interferon-mediated apoptosis, thereby improving therapeutic efficacy in treating various cancers.
Implementation Method 1
OVs initiate targeted infection and lysis of tumor beds and therefore can directly mediate debulking. OVs can be used to specifically express therapeutic transgenes in the tumor milieu. In addition, OV nucleic acids can activate Toll-like receptors (TLRs) and innate immune response pathways to initiate a pro-inflammatory cascade that stimulates the production of chemokines and cytokines
Implementation Method 2
genetically modified T cells in which expression of the type I IFN receptor (e.g., interferon-α/β receptor (IFNAR)), or expression of another receptor that can signal T cell apoptosis or dysfunction upon expression of anti-viral innate factors following OV infection, has been disrupted
Implementation Method 3
interferon-α/β receptor knockout (IFNAR KO) CAR T cells were partially resistant to apoptosis induced by VSVmIFNβ in vivo
Data Source
AI summary
This document relates to methods and materials involved in treating cancer. For example, methods and materials for using one or more oncolytic viruses (OVs) in combination with an adoptive cell therapy (e.g., a chimeric antigen receptor T cell therapy) to alter one or more functions of a T cell and/or to enhance T cell expansion to treat cancer in a mammal (e.g., a human) are provided.