Fractionated CAR T Cell Dosing for Solid Tumors
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Solution Overview
Problem
Current CAR T-cell therapies for solid tumors face challenges such as non-specific targeting due to shared antigens with normal tissues, an immunosuppressive tumor microenvironment, and increased toxicity risks like cytokine release syndrome, which limit their effectiveness and safety.
Innovation Solution
A novel dosing strategy involving a fractionated administration of CAR T cells, where a first dose of 30% of the total cells is followed by a second dose of 70% at least five days later, along with lymphodepleting chemotherapy and the use of dominant negative receptors like truncated TGFβ receptor variants to mitigate toxicity and enhance persistence.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a high dose of CAR T cells is administered to improve anti-tumor efficacy, then the therapeutic effect is enhanced, but the risk of toxicities such as cytokine release syndrome increases
Solution Approach 1:
The total dose of CAR T cells is divided into multiple fractions administered at different time points. The patent describes administering initial lower doses followed by additional doses, which allows the immune system to respond in a controlled manner while accumulating sufficient therapeutic effect over time, thereby reducing the risk of severe acute toxicities associated with high-dose single administrations
2Reliability
If CAR T cells are administered to target solid tumors, then anti-tumor activity is achieved, but the cells fail to persist optimally in the tumor microenvironment
Solution Approach 1:
The patent employs lymphodepleting chemotherapy administered before CAR T cell infusion to clear suppressive elements from the tumor microenvironment and create a more favorable conditions for CAR T cell persistence and expansion, thereby enhancing the durability of the anti-tumor response
Solution Approach 2:
Multiple dosing administrations are given at periodic intervals, allowing CAR T cells to establish persistence in the tumor microenvironment over time, with each subsequent dose building upon the persistence established by previous doses
3Reliability
If CAR T cells are used to treat solid tumors, then therapeutic intervention is provided, but on-target off-tumor toxicities occur due to shared antigens with normal tissues
Solution Approach 1:
The patent employs fractionated dosing where lower initial doses are administered first, allowing for monitoring and control of on-target off-tumor toxicities while still achieving therapeutic effect. This partial action approach enables better safety management compared to full-dose single administration
Data Source
AI summary
The present disclosure provides methods for the administration of engineered cells, such as T cells, to subjects for adoptive cell therapy. Also provided are compositions and articles of manufacture for use in the methods. The cells express chimeric antigen receptors (CARs) and/or T cell receptors (TCRs), and optionally, other molecules to overcome the immunosuppressive tumor microenvironment. Methods provided herein may employ a fractionated dosing regimen which may further comprise monitoring the development of a toxicity and managing the symptoms thereof.