Engineered Immune Cells With L-Type Cav Channels for Enhanced Cytotoxicity
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Solution Overview
Problem
Current immune cell therapies, such as those using cytotoxic T lymphocytes and natural killer cells, lack sufficient methods to enhance their cytotoxicity against cancer and infectious agents, necessitating improved effectiveness.
Innovation Solution
Engineering immune cells to overexpress L-type voltage-gated calcium channels or introduce gain-of-function mutations in these channels, combined with manipulating the Hedgehog signaling pathway through components like PTCH1, to increase GLI1 expression and activity, thereby enhancing cytotoxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immune cell therapies are used to treat cancer and infectious diseases, then clinical benefits are demonstrated, but the cytotoxicity effectiveness is insufficient
Solution Approach 1:
The patent changes the physiological parameters of immune cells by modulating calcium channel activity and calcium signaling pathways. Specifically, it uses L-type calcium channel agonists (like FPL 64176 and Bay K 8644) to increase calcium influx, and manipulates the Hedgehog signaling pathway to enhance Gli1 expression, thereby altering the cytotoxicity parameters of CTLs and NK cells to improve their killing effectiveness against tumor and infected cells
2Productivity
If L-type Cav channel expression is increased to enhance cytotoxicity, then cell killing capacity is improved, but the complexity of cell engineering increases
Solution Approach 1:
The patent uses pharmacological agents (L-type calcium channel agonists) and signaling pathway modulators as intermediaries to achieve the desired effect without direct genetic engineering of calcium channels. These small molecules mediate the enhancement of calcium signaling and Gli1 expression, providing a less complex alternative to direct channel overexpression while still achieving improved cytotoxicity
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The engineered immune cells demonstrate enhanced cytotoxicity against cancer cells and infectious agents, including increased cell killing capacity and efficacy in both in vitro and in vivo conditions.
Implementation Method 1
L-type voltage-gated calcium (Cav) channels
Implementation Method 2
the Hedgehog (Hh) signaling pathway. Induction of Hh leads to enhanced expression of the Hh transcription factor Gli1
Data Source
AI summary
The invention provides an engineered immune cell, wherein the engineered immune cell comprises a gain-of-function mutation in a Cav channel and/or overexpresses an L-type voltage-gated calcium (Cav) channel. Also provided are related engineered immune cells for use in medicine. Also provided are L-type Cav channel agonists for use in a method of stimulating cell killing activity of an immune cell in a subject having a proliferative disorder. Pharmaceutical compositions and methods are also provided.