CAR-Expressing Cell Harvest Timing and Phenotype Selection
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Solution Overview
Problem
Current adoptive cell transfer therapies with T-cells transduced with Chimeric Antigen Receptors (CARs) face limitations due to insufficient lymphocyte harvest and limited ex vivo cellular expansion, hindering the production of clinically viable products for cancer treatment.
Innovation Solution
The methods involve optimizing the timing and conditions for harvesting immune cells, such as acquiring them early after diagnosis or before chemotherapy cycles, and selecting based on malignancy type and immune cell parameters like T cell count and phenotype to enhance their proliferative and anti-tumor efficacy, and introducing CAR molecules like CD19 CAR for targeted therapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immune cells are harvested later after diagnosis or after chemotherapy cycles, then the patient has undergone necessary treatment, but the T cell count and proliferative capacity are insufficient for effective CAR therapy
Solution Approach 1:
The patent applies preliminary action by harvesting immune cells at an optimized early time point after diagnosis but before chemotherapy cycles that would deplete T cells. This timing ensures sufficient T cell quantity and quality are available for CAR transduction and expansion before the patient undergoes treatment that would reduce cell availability
Solution Approach 2:
The patent changes the temporal parameter of cell harvest timing from conventional later dates to an optimized early window (e.g., within 2-4 weeks of diagnosis). This parameter change in harvest timing directly improves both T cell quantity and proliferative capacity while maintaining therapeutic efficacy
2Quantity of substance
If immune cells are expanded extensively ex vivo, then sufficient cell numbers are obtained for therapy, but the expansion capability and proliferative capacity are limited by cell differentiation state
Solution Approach 1:
The patent changes the phenotypic parameter of T cells by selecting for less differentiated populations (e.g., naive or central memory T cells with higher CD45RA expression) at the harvest stage. This parameter change in cell differentiation state enables superior ex vivo expansion capability and proliferative capacity while achieving sufficient therapeutic cell numbers
3Ease of manufacture
If cell harvest is delayed to allow chemotherapy treatment, then the patient receives necessary cancer treatment, but the quality and suitability of immune cells for CAR therapy deteriorate
Solution Approach 1:
The patent performs preliminary CAR cell therapy preparation by harvesting and processing immune cells before chemotherapy cycles begin. This preliminary action allows the patient to receive necessary cancer treatment while ensuring high-quality cells are available for therapy before chemotherapy depletes or deteriorates the immune cell population
Solution Approach 2:
The patent segments the treatment timeline into distinct phases: (1) early cell harvest and CAR transduction phase before chemotherapy, (2) chemotherapy administration phase, and (3) cell infusion and expansion phase. This temporal segmentation allows both chemotherapy treatment and high-quality cell therapy to proceed effectively without compromising either
Data Source
AI summary
The invention provides methods of making immune effector cells (e.g., T cells, NK cells) that can be engineered to express a chimeric antigen receptor (CAR), compositions and reaction mixtures comprising the same, and methods of treatment using the same.