NKT Cell CAR Platform for Off-the-Shelf Immunotherapy

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Solution Overview

Problem

Current cancer immunotherapy using CAR-T cells faces limitations due to reduced proliferative capacity of T cells from lymphoma patients, leading to low infusion rates, and the risk of graft-versus-host disease (GvHD) with allogeneic cells.

Innovation Solution

The use of Natural Killer T (NKT) cells, which are genetically modified to express a chimeric antigen receptor (CAR) and have reduced expression of beta-2 microglobulin (B2M) and/or MHC class II-associated invariant chain (Ii), allowing them to avoid GvHD and immune rejection.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If T cells are obtained from lymphoma patients for CAR-T therapy, then tumor-specific immunity is improved, but proliferative capacity is reduced leading to low infusion rates

Engineering Contradiction:

Improvetumor-specific immunityVSAvoidinfusion rate

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent uses healthy donor T cells as an intermediary source instead of directly using patient T cells. These healthy donor cells are genetically modified with CAR to provide tumor-specific immunity without the proliferative limitations of patient-derived cells, thereby achieving both high reliability and productivity

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent changes the source parameter of T cells from patient-derived to healthy donor-derived. This parameter change allows the cells to maintain tumor-specific CAR-mediated immunity while avoiding the reduced proliferative capacity that limits infusion rates in patient-derived CAR-T cells

Inventive Principle:

Principle #35Parameter changes

2Productivity

If allogeneic T cells from healthy donors are used to overcome low proliferation, then cell availability is improved, but graft-versus-host disease and immune rejection occur

Engineering Contradiction:

Improvecell availabilityVSAvoidGvHD and immune rejection

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent extracts and eliminates the T cell receptor (TCR) from the allogeneic T cells through genetic modification. By removing the TCR while retaining the CAR, the cells lose their ability to recognize host MHC and cause GvHD, while maintaining their tumor-targeting capability through the CAR

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent converts the potential harm of allogeneic T cells causing GvHD into a benefit by selectively removing TCR function. This allows the use of highly proliferative healthy donor cells while preventing the harmful alloreactive responses that would otherwise occur

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

3Object-affected harmful factors

If TCR is deleted from T cells to avoid GvHD, then GvHD risk is reduced, but off-target genetic alterations occur with TALEN technology

Engineering Contradiction:

ImproveGvHD riskVSAvoidgenetic safety

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The patent replaces the TALEN gene editing system with a viral vector-based CAR expression system. Instead of using TALEN to delete TCR (which causes off-target effects), the viral vector delivers CAR that functionally replaces TCR-mediated recognition, achieving GvHD prevention through functional substitution rather than genomic disruption

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

Data Source

PatentUS12291558B2CD1D-restricted NKT cells as a platform for off-the-shelf cancer immunotherapy

Publication Date: 2025.05.06 BAYLOR COLLEGE OF MEDICINE

AI summary

An isolated human NKT cell or a plurality of cells thereof, having reduced or no detectable expression of endogenous beta-2-microglobulin (B2M); endogenous MHC class II-associated invariant chain (Ii); or both. Methods to generate the cell or cells, and methods of treatment using the cell or cells are also provided.