CD70 CAR-T Cells Secreting CD33 TEAMs Against Antigen Escape
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Solution Overview
Problem
Antigen escape occurs in cancer cells treated with CD70-targeted CAR-T therapy, leading to relapse in CD70-negative cancers.
Innovation Solution
Engineer CD70 CAR-T cells to express and secrete a T-cell engaging antibody molecule (TEAM) that targets CD33, allowing binding to cancer cells or myeloid-derived suppressor cells independent of CD70 expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CD70-targeted CAR-T therapy is used, then cancer cells expressing CD70 are effectively treated, but cancer cells that escape by reducing or losing CD70 expression are not treated
Solution Approach 1:
The treatment strategy is segmented into two complementary components: CD70-targeted CAR-T cells for initial treatment and CD33-targeted TEAM molecules for addressing antigen escape. This segmentation allows the system to handle different subsets of cancer cells through specialized mechanisms, resolving the contradiction between effective treatment of CD70+ cells and coverage of CD70-negative escape cells.
Solution Approach 2:
The TEAM (T-cell engaging antibody molecule) acts as an intermediary that bridges the gap between CAR-T cells and cancer cells. The TEAM binds to CD33 on cancer cells and engages T-cells to kill the cancer, serving as a mediator that overcomes the limitation of direct CD70 dependency and addresses antigen escape mechanisms.
2Ease of manufacture
If a single target antigen (CD70) is used for CAR-T therapy, then the treatment is simple and effective against CD70+ cells, but the treatment fails against CD70-negative or low-expression cells
Solution Approach 1:
The therapy system is designed with multi-functionality to address multiple cancer cell phenotypes. The CD70 CAR-T cells provide initial treatment effect, while the secreted TEAM molecules provide a secondary function to target CD33+ cells, including CD70-negative escape cells. This multi-functional approach maintains treatment durability without significantly complicating the manufacturing process.
Solution Approach 2:
The CAR-T cells perform preliminary action by initially targeting and killing CD70+ cancer cells. The TEAM molecules are prepared in advance within the CAR-T cell construct and are secreted to immediately begin targeting CD33+ cells, including those that have escaped CD70 targeting. This preliminary preparation and sequential action ensures comprehensive coverage while maintaining therapeutic simplicity.
3Adaptability or versatility
If CD70 CAR-T cells are engineered to also express CD33 TEAM, then dual targeting capability is achieved, but the cell engineering complexity increases
Solution Approach 1:
The CD70 CAR and CD33 TEAM targeting capabilities are merged into a single CAR-T cell construct. The CAR-T cell simultaneously expresses the CD70 CAR on its surface and secretes the CD33 TEAM molecule, combining two targeting functions into one cellular system. This merging achieves dual targeting capability while managing engineering complexity through integrated construct design.
Solution Approach 2:
The CAR-T cell performs self-service by autonomously producing and secreting the TEAM molecules as part of its normal function. The TEAM expression is driven by the same promoter that drives CAR expression, allowing the cell to self-regulate and maintain appropriate levels of both components without requiring external control mechanisms, thereby managing complexity through autonomous operation.
Data Source
AI summary
The disclosure is directed to methods and compositions for treating cancers characterized by cells comprising chimeric antigen receptors (CARs) that bind CD70 and T-cell engaging antibody molecules (TEAMs) that bind CD33, nucleic acid molecules encoding chimeric antigen receptors (CARs) that bind CD70 and/or TEAMs that bind CD33, and compositions and methods related thereto.