VPS39 Knockout Enhances CAR-T Cell Antitumor Activity

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Solution Overview

Problem

Adoptive immune cell therapies, such as CAR-T cell therapy, face challenges in efficacy due to sustained activation of late endosomal mTORC1 in older adults, leading to lysosomal dysfunction and impaired T cell expansion and function, particularly in cancer treatment.

Innovation Solution

Engineering immune cells, like CAR-T cells or tumor-infiltrating lymphocytes, to reduce VPS39 expression, which is part of the HOPS complex, to inhibit late endosomal mTORC1 activation, thereby promoting lysosomal function and T cell expansion and antitumor activity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If adoptive immune cell therapy is applied in older adults, then cancer treatment is provided, but efficacy is reduced due to sustained activation of late endosomal mTORC1 and lysosomal dysfunction

Engineering Contradiction:

Improveefficacy of adoptive immune cell therapyVSAvoidlysosomal dysfunction and impaired T cell expansion

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent extracts and removes the harmful VPS39 component from the HOPS complex in immune cells through genetic modification. By specifically knocking out or reducing VPS39 expression in adoptive immune cells (such as CAR-T cells or TILs), the patent eliminates the source of sustained mTORC1 activation while preserving the overall cellular structure and function. This extraction approach directly addresses the harmful factor without disrupting other essential cellular processes.

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent changes the expression level parameter of VPS39 in immune cells from normal physiological levels to reduced or absent levels. This parameter modification alters the functional state of the HOPS complex, thereby changing the activation status of late endosomal mTORC1 from sustained to regulated, and ultimately improves lysosomal function and T cell expansion capability in the context of cancer therapy.

Inventive Principle:

Principle #35Parameter changes

2Productivity

If VPS39 expression is reduced in immune cells, then lysosomal function and T cell expansion are improved, but immune cell engineering complexity increases

Engineering Contradiction:

ImproveT cell expansion and antitumor activityVSAvoidimmune cell engineering

Core Design Contradiction:

ProductivityVSDevice complexity

Solution Approach 1:

The patent converts the potentially harmful effect of VPS39 (which causes sustained mTORC1 activation and lysosomal dysfunction) into a beneficial outcome by selectively removing it. The genetic modification that eliminates VPS39, which initially appears as a complex engineering challenge, actually simplifies the overall system by removing a pathological component and restoring normal cellular function, thereby improving T cell expansion and antitumor activity.

Inventive Principle:

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

Data Source

PatentUS20240197874A1Materials and methods for improving efficacy of adoptive immune cell therapy

Publication Date: 2024.06.20 MAYO FOUNDATION FOR MEDICAL EDUCATION & RESEARCH

AI summary

Methods and materials for treating cancer (e.g., melanoma) in a subject and for improving efficacy of adoptive immune cell therapy are described. The methods can include administering immune cells (e.g., chimeric antigen receptor T cells or tumor-infiltrating lymphocytes) having reduced expression of a VPS39 polypeptide to the subject.