Allogeneic CAR-T Cells with HLA Knockout for Repeated Immunotherapy
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current adoptive immunotherapy protocols using autologous or allogeneic engineered T-cells face challenges such as undesired immune reactions, graft-versus-host disease, and logistical hurdles, which limit their efficacy and safety.
Innovation Solution
A method for preparing a set of pharmaceutical unit doses comprising engineered cells and a pharmaceutically acceptable vehicle, involving genotyping and phenotyping of HLA molecules, selecting donor cells with optimal HLA matching, and modifying cells with CARs or TCRs to reduce anamnestic responses and graft-versus-host disease.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If autologous engineered T-cells are used for immunotherapy, then the therapy can be personalized to the patient, but it induces undesired immune reactions including cytokine storm and GVHD
Solution Approach 1:
The patent uses allogeneic T-cells from healthy donors as copies of autologous T-cells, which lack the patient's personal HLA markers. These donor T-cells are engineered with CARs to perform the same anti-tumor function without triggering anamnestic responses or GVHD, since they don't recognize the patient's HLA molecules.
Solution Approach 2:
The patent extracts the HLA markers from the donor T-cells through genetic engineering (knockout of HLA-A, HLA-B, HLA-C, HLA-DR, HLA-DQ genes), removing the problematic self-recognition elements that would cause GVHD and anamnestic responses, while preserving the CAR-mediated anti-tumor function.
2Object-affected harmful factors
If allogeneic T-cells from healthy donors are used, then undesired immune reactions are reduced, but graft-versus-host disease occurs due to HLA disparities
Solution Approach 1:
The patent extracts and removes the HLA markers from donor T-cells through gene knockout (HLA-A, HLA-B, HLA-C, HLA-DR, HLA-DQ), eliminating the molecular basis for GVHD while preserving the CAR-mediated anti-tumor activity. This creates T-cells that can't recognize host HLA molecules, preventing GVHD.
Solution Approach 2:
The patent fundamentally changes the HLA expression parameter of donor T-cells from normal expression to complete knockout (zero expression). This parameter change eliminates the immunogenicity that would cause GVHD while maintaining the therapeutic function through CARs.
3Productivity
If repeated administrations of immunotherapy are performed, then tumor mass is controlled, but anamnestic immune responses are triggered
Solution Approach 1:
The patent uses a bank of allogeneic donor T-cells with different HLA profiles as copies. By selecting donors with rare or unique HLA combinations, the patent ensures that repeated administrations do not trigger anamnestic responses, as each donor T-cell population lacks the specific HLA markers that would be recognized by the patient's immune system.
Solution Approach 2:
The patent changes the HLA expression parameter of the T-cells to complete knockout (zero expression) for all classical HLA molecules. This parameter change ensures that repeated administrations of engineered T-cells cannot trigger anamnestic responses, as there are no HLA markers for the patient's immune system to recognize as foreign.
4Adaptability or versatility
If autologous cell preparation is performed for each patient, then therapy is personalized, but substantial variations in efficacy and safety result
Solution Approach 1:
The patent creates a bank of standardized allogeneic donor T-cells with consistent engineering (CAR transduction, HLA knockout). These standardized copies provide reliable and consistent therapy across different patients, eliminating the variability inherent in autologous preparations while maintaining personalization through donor selection based on patient-specific HLA typing.
Solution Approach 2:
The patent standardizes the T-cell engineering parameters across all donor cells (same CAR construct, same HLA knockout protocol, same expansion conditions). This standardization ensures consistent efficacy and safety across different patient treatments, while personalization is achieved through selective donor matching based on patient HLA genotype.
Data Source
AI summary
The present invention provides composition kits and methods for treating cancer in a human by immunotherapy using successive doses of CAR-T cells with no or reduced anamnestic immune reaction in one individual (P).