CAR-MAIT Cells Targeting CD4 for Allogeneic Tumor Therapy
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Solution Overview
Problem
Current CAR-T cell therapies are limited in treating T-cell malignancies due to autologous transfusion issues, on-target/off-tumor toxicity, and low efficacy in solid tumors, and existing methods for expanding MAIT cells are difficult to scale and contaminated with other cell subsets, making them unsuitable for allogeneic adoptive transfer.
Innovation Solution
Development of novel genetic constructs and methods to isolate and expand highly purified MAIT cells, which are then engineered into CAR-MAIT cells capable of targeting CD4 or TCR-Vbeta 7.1, allowing for allogeneic transfer and improved tumor infiltration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional CAR-T therapy is used, then autologous transfusion is possible, but graft-versus-host disease occurs and on-target/off-tumor toxicity increases
Solution Approach 1:
The patent extracts and eliminates the problematic T-cell subsets (conventional αβ T cells and γδ T cells) from the immune cell population, retaining only MAIT cells. This selective extraction removes the cells responsible for graft-versus-host disease and on-target/off-tumor toxicity while preserving the therapeutic anti-tumor activity of MAIT cells.
Solution Approach 2:
The patent changes the composition parameter of the adoptive transfer cell population by selectively expanding MAIT cells and eliminating other T-cell subsets. This parameter change transforms the cell population from a mixed T-cell composition to a purified MAIT cell population, thereby improving safety while maintaining efficacy.
2Quantity of substance
If existing MAIT cell expansion methods are used, then MAIT cells can be obtained, but the cells are contaminated with other cell subsets and difficult to scale
Solution Approach 1:
The patent segments the T-cell population by using specific surface markers (CD161, TCR Va7.2, CD3) to identify and isolate MAIT cells from other T-cell subsets. This segmentation approach enables precise purification of MAIT cells through flow cytometry sorting, achieving high purity while maintaining scalability.
Solution Approach 2:
The patent replaces conventional mechanical cell separation methods with flow cytometry-based sorting using fluorescently labeled antibodies. This substitution enables precise identification and isolation of MAIT cells based on their unique surface marker profile, achieving both high purity and scalability.
3Reliability
If conventional CAR-T therapy is used, then T-cell malignancies can be targeted, but efficacy in solid tumors is low due to inadequate tumor infiltration
Solution Approach 1:
The patent employs MAIT cells as intermediary effectors that recognize tumor cells through the MR1 antigen presentation pathway. This intermediary recognition mechanism enables MAIT cells to effectively infiltrate and kill tumor cells, including solid tumors, overcoming the limitations of conventional CAR-T cells that rely on MHC-restricted recognition.
4Ease of manufacture
If allogeneic adoptive transfer is attempted, then off-the-shelf therapy is possible, but conventional T cells cause graft-versus-host disease
Solution Approach 1:
The patent extracts and removes the cells responsible for graft-versus-host disease (conventional αβ T cells and γδ T cells) from the donor cell population, leaving only MAIT cells. This extraction enables safe allogeneic adoptive transfer by eliminating the harmful cells while preserving the therapeutic potential of MAIT cells.
Solution Approach 2:
The patent changes the immunological parameter of the donor cell population by selectively purifying MAIT cells and eliminating other T-cell subsets. This parameter change transforms the cell population into a safe allogeneic product that can be manufactured off-the-shelf without causing graft-versus-host disease.
Data Source
AI summary
The present invention relates to chimeric antigen receptor (CAR)-T cells, and particularly, although not exclusively, to anti-CD4 CARs, and to their use in immunotherapy, and for treating, preventing or ameliorating cancer, such as T-cell lymphomas, various microbial infections, such as HIV and TB, and also autoimmune disease. The invention is especially concerned with the use of CAR-engineered mucosal-associated invariant T (MAIT) cells, and to novel methods for stimulating, isolating and expanding highly purified MAIT cells, which can then be engineered into such CAR-MAIT cells. The invention extends to genetic constructs per se, and to their use in generating the CAR-MAIT cells, and to transduced CAR-MAIT cells per se. The invention also extends to various medical uses of the constructs and transduced CAR-MAIT cells, and to pharmaceutical compositions comprising these constructs and CAR-MAIT cells.