PD-1 Switch Receptor and FAS Blockade for Persistent ACT T Cells

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Solution Overview

Problem

Adoptive cell therapies (ACT) face suppressive mechanisms in the tumor microenvironment (TME) that limit the efficacy of T cells, including immune checkpoint receptor activation, sub-optimal costimulatory molecule expression, and FAS/FASL interactions, leading to T cell apoptosis and reduced persistence.

Innovation Solution

A synthetic Immune Checkpoint Switch (ICS) transgene cassette expressing a PD-L1 targeting third-generation chimeric costimulatory receptor, a FAS dominant negative receptor, and a safety switch (truncated EGFR) in T cells to overcome these suppressive mechanisms.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If T cells are adoptively transferred to treat cancer, then anti-tumor immune response is enhanced, but T cell persistence is reduced due to FAS/FASL-mediated apoptosis in the tumor microenvironment

Engineering Contradiction:

Improveanti-tumor immune response efficacyVSAvoidT cell persistence

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent applies preliminary anti-action by pre-engineering T cells to express a dominant-negative FAS receptor before adoptive transfer. This modified FAS receptor binds to FASL on tumor cells but prevents apoptotic signaling, proactively blocking the harmful FAS/FASL interaction pathway before it can eliminate the T cells in the tumor microenvironment.

Inventive Principle:

Principle #9Preliminary anti-action

2Reliability

If T cells are engineered to resist PD-1 checkpoint inhibition, then T cell activation is improved, but device complexity increases due to genetic engineering requirements

Engineering Contradiction:

ImproveT cell activationVSAvoidgenetic engineering complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent merges multiple functions into a single genetic engineering approach: the engineered T cells simultaneously express (1) a dominant-negative FAS receptor to block apoptosis, and (2) an antigen-specific receptor (TCR or CAR) for tumor targeting. This consolidation achieves both T cell persistence and activation in one engineered cell product, reducing overall system complexity.

Inventive Principle:

Principle #5Merging (Combining)

3Reliability

If multiple genetic engineering modifications are applied to T cells to overcome multiple suppressive mechanisms, then T cell efficacy is enhanced, but safety control becomes more difficult

Engineering Contradiction:

ImproveT cell efficacyVSAvoidsafety control

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent introduces a safety switch mechanism as an intermediary control system. The engineered T cells include a suicide gene (e.g., herpes simplex virus thymidine kinase) that can be activated by a specific drug (ganciclovir) to induce rapid T cell death. This intermediary safety mechanism allows external control of potentially overactive or adverse T cell responses without affecting the therapeutic anti-tumor function.

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS20250352581A1Combination therapies comprising functional components of PD-1 switch receptor and fas dominant negative receptor

Publication Date: 2025.11.20 NEOMICS PHARMACEUTICALS LLC

AI summary

The present application relates to PD-1 switch receptors, e.g., chimeric PD-1 switch receptors, in combination with a FAS dominant negative receptor, optionally in combination with a safety switch, e.g., truncated EGFR, which can be used in adoptive cell therapy to treat human diseases and disorders.