Oncolytic Virus Expressing CD19t for Solid Tumor Immunotherapy
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Solution Overview
Problem
Current immunotherapies for solid tumors, such as CAR T cell therapies and bispecific T cell engagers, face challenges due to limited and heterogeneously expressed tumor targets, as well as the complexity of the solid tumor microenvironment, which hinders effective and durable anti-tumor responses.
Innovation Solution
The use of oncolytic viruses (OV) expressing a truncated CD19 (CD19t) in combination with CD19-targeted bispecific T cell engagers (TCEs) to redirect endogenous T cells and target solid tumors effectively.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR T cell therapies or bispecific T cell engagers are used to treat solid tumors, then anti-tumor responses can be achieved, but the limited and heterogeneous expression of tumor targets reduces effectiveness and durability
Solution Approach 1:
The patent uses a universal tumor-agnostic approach by engineering oncolytic viruses to express a standardized CD19t antigen across all solid tumor types, regardless of their native antigen expression. This allows a single TCE therapy to target multiple solid tumor types (breast, lung, colorectal, pancreatic, ovarian cancers) that otherwise lack suitable targets, resolving the contradiction between reliable anti-tumor response and limited target availability
Solution Approach 2:
The patent introduces an intermediary oncolytic virus that infects solid tumor cells and forces them to express CD19t, which is not naturally present on these tumors. This intermediary virus acts as a bridge, creating a common target (CD19t) that the TCE can recognize and attack, thereby enabling effective therapy against tumors that would otherwise be inaccessible due to lack of suitable targets
2Reliability
If conventional immunotherapies are administered, then some anti-tumor activity can be achieved, but the complex solid tumor microenvironment hinders effective and durable responses
Solution Approach 1:
The oncolytic virus performs multiple functions simultaneously: it lyses infected tumor cells to release antigens, stimulates innate immune responses through viral components, and delivers the CD19t transgene to create new target antigens. This self-service approach overcomes the suppressive tumor microenvironment by actively transforming it into an immunogenic site that recruits and activates T cells, thereby achieving durable responses despite microenvironmental complexity
Solution Approach 2:
The patent applies preliminary action by first administering the oncolytic virus to infect and transform tumor cells before administering the TCE. This preliminary viral infection ensures that CD19t is expressed on the tumor cell surface and that the tumor microenvironment is primed with viral antigens and inflammatory signals, creating optimal conditions for subsequent TCE-mediated T cell activation and durable anti-tumor immunity
Data Source
AI summary
Described herein, inter alia, are oncolytic viruses expressing a truncated human CD19 (CD19t) and methods for treating a patient suffering from a solid tumor by administering an oncolytic virus expressing truncated human CD19 (OV19t), and optionally a T cell engager targeted to CD19.