Integrin Stabilizers Enhance T Cell Infiltration in Solid Tumors
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Solution Overview
Problem
Adoptive cell therapy (ACT) for cancer treatment faces challenges in achieving high intratumoral bioavailability of effector cells, such as T cells and NK cells, due to barriers in tumor vasculature that hinder their infiltration into solid tumors, reducing the effectiveness of immunotherapy.
Innovation Solution
The use of small molecule stabilizers, like AEC1, that enhance integrin-ligand interactions between effector cells and tumor endothelial cells, specifically targeting α4β1-VCAM-1, α4β7/MedCam-1, and αLβ2-ICAM-1, to improve the adhesion and transmigration of T cells across the tumor endothelium.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If effector cells are infused into patients to treat cancer, then antitumor activity is improved, but intratumoral bioavailability is reduced due to vascular barriers
Solution Approach 1:
The patent uses integrin ligands (such as ICAM-1, VCAM-1, fibronectin) as intermediary molecules that facilitate the interaction between effector cells and tumor endothelium. These ligands act as mediators that bridge the gap caused by vascular barriers, enabling effector cells to adhere to and migrate across the endothelium into the tumor stroma, thereby improving intratumoral bioavailability while maintaining antitumor activity.
2Reliability
If effector cells are activated to increase potency, then antitumor efficacy is improved, but transmigration across tumor endothelium is reduced
Solution Approach 1:
The patent changes the biochemical parameters of the endothelial barrier by introducing exogenous integrin ligands that bind to activated integrins on effector cells. This parameter change in the endothelial surface properties enables activated effector cells to recognize and bind to the modified barrier, facilitating transmigration without reducing their activation state or antitumor efficacy.
3Stability of the object's composition
If tumor vasculature barriers are present to maintain endothelial function, then vascular integrity is preserved, but effector cell adhesion and infiltration are hindered
Solution Approach 1:
The patent applies preliminary action by pre-coating the endothelial surface with integrin ligands before effector cell infusion. This preliminary modification of the vascular barrier creates pre-formed binding sites that guide and facilitate effector cell adhesion and transmigration, thereby improving infiltration productivity without compromising the structural integrity of the vascular system.
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
This approach increases the intratumoral bioavailability and potency of T-cell therapies by facilitating greater adhesion and migration of effector cells into tumors, enhancing antitumor activity and therapeutic outcomes.
Implementation Method 1
integrin-ligand stabilizer... capable of stabilizing integrin receptor-ligand interactions between integrins and their cognate ligands
Implementation Method 2
increase the intratumoral bioavailability of effector cells... facilitate transmigration across the tumor endothelium
Data Source
AI summary
Compositions and methods of enhancing the potency and efficacy of adoptive cell therapy using integrin-ligand stabilizers, wherein the integrin is selected from the group consisting of α4β1, α5β1, α4β7, αvβ3 and αLβ2, and contacting the effector cells ex vivo with agonists or stabilizers having the general Formula (I); methods of treating integrin-expressing cells with such stabilizers to enhance tumor infiltration; and therapeutic methods comprising administering stabilizer or agonist-treated cells to a mammal requiring treatment of solid tumors, hematologic cancers.