PVR-Targeting CAR T Cells With BiTE Secretion for FRα Heterogeneity

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Cancer immunotherapies, such as adoptive T cell transfer, have limited efficacy in treating ovarian cancer and other cancers due to the heterogeneity in the expression of Folate Receptor alpha (FRα) on cancer cells, leading to immune escape and ineffective targeting.

Innovation Solution

Modified T cells expressing a chimeric antigen receptor (CAR) that binds to Poliovirus Receptor (PVR) without a CD8 hinge, combined with a BiTE that binds to FRα and CD3ε, enhance cancer cell killing by increasing PVR expression on FRα-low cells, thereby targeting a broader range of cancer cells.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If CAR T cells are used to target ovarian cancer, then cancer cell killing is enhanced, but efficacy is limited due to FRα heterogeneity

Engineering Contradiction:

Improvecancer treatment efficacyVSAvoidtargeting capability across heterogeneous cancer cells

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The modified T cells are engineered to perform multiple functions: they express a PVR-targeting CAR for direct killing of PVR+ cells, and simultaneously secrete a BiTE that binds FRα and CD3ε to kill FRα+ cells. This multi-functional design allows the therapy to target both FRα-positive and FRα-negative cancer cells, overcoming the limitation of FRα heterogeneity and improving adaptability across heterogeneous tumor populations.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Solution Approach 2:

The BiTE acts as an intermediary molecule that bridges the T cell (via CD3ε binding) and the FRα-positive cancer cells. By secreting this BiTE, the modified T cells can indirectly target and kill FRα-positive cancer cells that would otherwise escape detection by the PVR CAR, thereby extending the therapeutic coverage to heterogeneous cell populations.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Adaptability or versatility

If T cells are modified to express CAR and secrete BiTE, then broader cancer cell targeting is achieved, but device complexity increases

Engineering Contradiction:

Improverange of targeted cancer cellsVSAvoidcell modification complexity

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The invention combines the CAR expression and BiTE secretion capabilities into a single modified T cell product. Rather than using separate therapies (CAR T cells plus BiTE administration), both functions are merged into one cell product that can simultaneously perform direct killing via CAR and indirect killing via secreted BiTE, simplifying the overall treatment protocol while maintaining broad targeting capability.

Inventive Principle:

Principle #5Merging (Combining)

Data Source

PatentUS20260077046A1Targeting the PVR axis using car t cell therapy and combinations

Publication Date: 2026.03.19 ROSWELL PARK CANCER INSTITUTE CORPORATION

AI summary

Provided is a method of treating cancer in an individual by administering to the individual modified cells that express a chimeric antigen receptor (CAR) that contain a TIGIT extracellular domain that can bind to poliovirus receptor (PVR), a CD28 segment, and a CD3ζ segment. The modified cells may co-express and secrete a Bi-specific T cell engager (BiTE). The BiTE includes a segment that can specifically bind to human Folate Receptor alpha (FRα) and a segment that that can specifically bind to a human CD3ε segment. Modified cells that express the CAR, and may also express and secrete the BiTE, and polynucleotides encoding the CAR and the BiTE, are also provided.