T Cell Therapy Conditioning With Dose-Tuned Lymphodepletion
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Solution Overview
Problem
Current T cell therapies face challenges in predicting effectiveness due to the use of high-dose, toxic and non-specific preconditioning regimens that cause adverse events, necessitating an improved preconditioning method for enhanced efficacy.
Innovation Solution
Administering cyclophosphamide and fludarabine at specific doses (200-2000 mg/m2/day and 20-900 mg/m2/day) prior to engineered CAR T cell therapy to reduce endogenous lymphocyte numbers and increase serum levels of specific cytokines and/or pro-immune factors, creating an optimal microenvironment for transplanted T cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If high-dose immunosuppressive chemotherapy is administered prior to T cell therapy, then T cell therapy efficacy is improved, but patient toxicity and adverse events increase
Solution Approach 1:
The patent applies parameter changes by optimizing the dosage parameters of cyclophosphamide and fludarabine within specific ranges (cyclophosphamide: 180-240 mg/m2/day; fludarabine: 25-35 mg/m2/day) and controlling the timing parameters (administration 5-10 days before T cell infusion). This resolves the contradiction by finding the optimal parameter window that achieves sufficient lymphocyte depletion and cytokine induction while avoiding excessive toxicity associated with higher doses.
Solution Approach 2:
The patent implements preliminary action by administering the chemotherapy regimen 5-10 days before T cell therapy infusion. This timing allows the conditioning regimen to achieve its intended effects (lymphocyte depletion and cytokine induction) in advance, creating an optimal microenvironment for T cell engraftment while allowing time for toxicity to subside before the therapeutic intervention.
2Reliability
If high-dose chemotherapy is used to reduce endogenous lymphocytes, then T cell engraftment is improved, but non-specific toxicity increases
Solution Approach 1:
The patent uses parameter changes to define specific dosage ranges for cyclophosphamide (180-240 mg/m2/day) and fludarabine (25-35 mg/m2/day) that are sufficient to achieve the desired lymphocyte depletion and cytokine induction for improved T cell engraftment, while remaining below the threshold for severe non-specific toxicity. This precise parameter control resolves the contradiction between effectiveness and safety.
3Productivity
If current preconditioning regimens are used, then T cell therapy is administered, but prediction of treatment effectiveness is difficult
Solution Approach 1:
The patent implements feedback by measuring serum levels of homeostatic cytokines (particularly IL-7 and IL-15) after chemotherapy administration and using these measurements to predict T cell therapy effectiveness. The cytokine levels serve as biomarkers that provide feedback on the quality of the microenvironment created by conditioning, allowing clinicians to predict which patients are likely to respond well to T cell therapy.
Data Source
AI summary
The invention provides methods of increasing the efficacy of a T cell therapy in a patient in need thereof. The invention includes a method of conditioning a patient prior to a T cell therapy, wherein the conditioning involves administering a combination of cyclophosphamide and fludarabine.