Dual-CAR Allogeneic T Cells for Host Rejection Resistance
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Solution Overview
Problem
Allogeneic CAR-modified cell therapies face rejection by the host's immune system, limiting their persistence and efficacy in treating conditions like cancer.
Innovation Solution
Engineered immune cells, such as CAR-T cells, are modified to express a first antigen binding protein targeting a therapeutic antigen and a second antigen binding protein, specifically binding to CD70 on recipient immune cells, thereby enhancing their persistence and survival.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If allogeneic CAR-modified cells are administered to multiple patients, then cost is reduced and product robustness is improved, but the cells face rejection by the host immune system limiting persistence
Solution Approach 1:
The patent converts the harmful host immune response into a beneficial targeting mechanism by engineering CAR-T cells to express a second CAR that specifically recognizes CD70 on activated host immune cells. This transforms the rejection problem into a self-defense mechanism where the allogeneic cells can selectively eliminate the very immune cells attempting to reject them, thereby resolving the contradiction between manufacturing efficiency and cell persistence
Solution Approach 2:
The patent creates a composite CAR-T cell with dual functionality: a first CAR for therapeutic antigen recognition and a second CAR for CD70 recognition on host immune cells. This composite structure combines tumor-killing activity with immune evasion capability, allowing the cells to maintain both manufacturability and prolonged persistence in the host
2Reliability
If a second CAR targeting CD70 is added to the engineered cell, then persistence against host immune rejection is improved, but device complexity increases
Solution Approach 1:
The patent implements multi-functionality by designing a single engineered CAR-T cell that performs two distinct functions: (1) recognizing and killing tumor cells via the first CAR, and (2) recognizing and eliminating activated host immune cells via the second CAR targeting CD70. This universal design allows one cell type to handle both therapeutic and protective functions, managing complexity through functional integration rather than separate cell populations
3Reliability
If deep lymphodepletion regimens are used, then allogeneic cell persistence is improved, but patient toxicity and treatment complexity increase
Solution Approach 1:
The patent enables the allogeneic CAR-T cells to self-regulate the host immune response by equipping them with a second CAR that autonomously targets and eliminates CD70-expressing activated immune cells. This self-service mechanism replaces the need for aggressive external lymphodepletion, allowing the therapeutic cells to create their own favorable environment without subjecting the patient to severe toxicity from high-dose chemotherapy or radiation
Data Source
AI summary
Provided herein are CD70-binding proteins comprising a CD70-binding domain and a transmembrane domain, engineered immune cells comprising the CD70-binding proteins, and methods of making and using the same. Also provided herein are engineered immune cells e.g. CAR (chimeric antigen receptor) T cells for administration to patients to treat cancer (e.g., solid tumors and hematologic tumors) and other unwanted conditions. The cells are engineered to functionally express a first antigen binding molecule e.g. a CD70 CAR and a second antigen binding molecule e.g. a second CAR that binds a target molecule characteristic of the cancer or other disease or unwanted condition. The cells may be further engineered to reduce the functional expression level of one or more of TRAC, CD52 and CD70. Also provided are methods of making and using the engineered cells, compositions and kits comprising them, and methods of treating by administering them.