Sequential CAR-T Cell Dosing for Toxicity Reduction
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Solution Overview
Problem
Current adoptive cell therapy methods using engineered cells expressing recombinant receptors, such as chimeric antigen receptors (CARs), face challenges in reducing toxicity and improving efficacy, particularly in increasing exposure and persistence of cells in subjects, while minimizing risk of cytokine release syndrome (CRS) and neurotoxicity.
Innovation Solution
The method involves administering multiple doses of cells, with a first low-dose 'debuling' dose followed by consecutive doses at specific timing to reduce disease burden and minimize toxicity, using genetically engineered cells expressing CARs or other antigen receptors, where the timing and number of cells are optimized to avoid immune response and toxicity, and the doses are adjusted based on disease burden.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a high dose of cells is administered to increase exposure and improve efficacy, then therapeutic effectiveness is improved, but toxicity and risk of cytokine release syndrome increase
Solution Approach 1:
The total cell dose is divided into multiple sequential administrations (first dose and consecutive doses). The first dose serves as a debulking dose to reduce tumor burden, followed by consecutive consolidating doses to maintain therapeutic effect while reducing peak toxicity associated with single high-dose administration.
Solution Approach 2:
The first dose is administered as a preliminary debulking action before consecutive consolidating doses. This preliminary reduction of disease burden creates a more favorable environment for subsequent doses, reducing the risk of severe toxicity while maintaining efficacy.
2Reliability
If multiple doses are administered to increase cell exposure, then efficacy is improved, but risk of host immune response and toxicity increases
Solution Approach 1:
Consecutive doses are administered at specific time intervals after the first dose, creating a periodic dosing schedule. This timing strategy allows the host immune system to recover between exposures while maintaining sufficient cell presence for therapeutic effect, thereby reducing cumulative toxicity and immune response risk.
3Object-affected harmful factors
If a low first dose is used to reduce toxicity, then safety is improved, but initial therapeutic impact is reduced
Solution Approach 1:
The therapeutic process is segmented into a debulking phase (first dose) and a consolidating phase (consecutive doses). The first dose, while lower than single-dose alternatives, is optimized to provide sufficient initial therapeutic impact for debulking, with subsequent doses providing the necessary consolidation to achieve complete remission without excessive toxicity.
Data Source
AI summary
Provided are methods for administering multiple doses of cells, such as T cells, to subjects for cell therapy. Also provided are compositions and articles of manufacture for use in the methods. The cells generally express recombinant receptors such as chimeric receptors, e.g., chimeric antigen receptors (CARs) or other transgenic receptors such as T cell receptors (TCRs). The methods generally involve administering a first and at least one consecutive dose of the cells. Timing of the doses relative to one another, and/or size of the doses, in some embodiments provide various advantages such as lower or reduced toxicity and improved efficacy, for example, due to increased exposure of the subject to the administered cells. In some embodiments, the first dose is a relatively low dose, such as one that reduces tumor or disease burden, thereby improving the efficacy of consecutive or subsequent doses, and the consecutive dose is a consolidating dose.