IL-10 Agents Modulating CAR-T Cell Toxicity
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Solution Overview
Problem
CAR-T cell therapy for cancer is limited by antigen-specific toxicities and extreme potency, leading to life-threatening cytokine-release syndromes due to high affinity T-cell receptor interactions with significant antigen burden, necessitating the development of methods to enhance therapeutic efficacy while minimizing adverse events.
Innovation Solution
The use of IL-10 agents in conjunction with CAR-T cell therapy to modulate T-cell-mediated immune responses, where IL-10 is administered to the subject either prior to, simultaneously with, or subsequent to CAR-T cell administration, or contacted with CAR-T cells ex vivo, to enhance cytotoxic activity and immunomodulatory effects, thereby reducing toxicity and improving treatment outcomes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If high affinity T-cell receptor interactions are used to enhance therapeutic efficacy, then cancer cell killing ability is improved, but antigen-specific toxicities and cytokine-release syndromes increase
Solution Approach 1:
IL-10 acts as an intermediary immunomodulatory agent that mediates between the CAR-T cell therapeutic effect and the harmful immune response. It suppresses excessive cytokine release and modulates the immune microenvironment, allowing high-affinity CAR-T cells to function effectively while reducing toxicities to normal tissues expressing target antigens
Solution Approach 2:
The invention changes the immunological parameters of the system by introducing IL-10 to alter the cytokine profile and immune cell activation state. This parameter change allows the system to achieve high therapeutic efficacy while operating in a modified immune environment that reduces harmful effects
2Productivity
If high dosage CAR-T cells are administered to overcome immune suppression, then tumor clearance is improved, but adverse events and cytokine-release syndromes increase
Solution Approach 1:
IL-10 serves as a protective intermediary that enables the administration of higher CAR-T cell dosages by buffering the immune system's response. It prevents runaway immune activation while allowing sufficient CAR-T cell activity to achieve complete tumor clearance
Solution Approach 2:
IL-10 provides beforehand cushioning by pre-modulating the immune microenvironment to accommodate high-dose CAR-T cell therapy. This cushioning effect prevents excessive immune activation and cytokine release that would otherwise occur with high-dose administration
3Reliability
If CAR-T cell therapy is administered to treat cancer, then therapeutic potential is improved, but treatment complexity and monitoring requirements increase
Solution Approach 1:
The invention merges two therapeutic agents (CAR-T cells and IL-10) into a coordinated treatment regimen. This combination approach simplifies the overall treatment strategy by addressing both tumor elimination and immune toxicity management through a unified therapeutic framework
Data Source
AI summary
The present invention relates to methods of modulating the activity of CAR-T cells in the treatment of diseases, disorders and conditions by the administration of an IL-10 agent. The invention further provides engineered CAR-T cells to express additional therapeutically effective agents. The present invention further provides improved pharmaceutical and therapeutic compostions and methods relating to the use of CAR-T cell therapies in the treatment of disease in mammalian subjects.