CD26high T Cell Activation via ICOS Costimulation
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Solution Overview
Problem
Current methods for identifying human CD4+ T cell subsets with durable antitumor memory responses are inadequate, as traditional approaches focus on IFN-α-secreting Th1 cells, while recent studies suggest Th17 cells may be more effective against tumors, but the human equivalent remains unclear.
Innovation Solution
The development of CD26high immune effector cells, specifically T cells, which are activated through ICOS costimulation and co-stimulated with agents like 41BB, CD28, and cytokines such as IL-2, IL-7, and IL-12, to enhance their antitumor capabilities, including expression of chimeric antigen receptors targeting tumor-associated antigens.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional IFN-α-secreting Th1 cell approaches are used to identify antitumor T cell subsets, then established immune response enhancement is achieved, but identification of human CD4+ T cell subsets with durable antitumor memory responses remains insufficient
Solution Approach 1:
The patent changes the identification parameters from traditional Th1/Th2/Th17 cytokine profiles to CD26 surface marker expression levels. By sorting CD4+ T cells into CD26low and CD26high subsets and activating them with ICOS, the patent identifies a novel CD26high T cell subset with superior antitumor memory responses, resolving the contradiction between reliable memory formation and tumor killing effectiveness
2Productivity
If Th17 cells are used for tumor targeting based on murine model results, then enhanced tumor killing is achieved, but the human equivalent subset with durable memory responses remains unclear
Solution Approach 1:
The patent introduces CD26 surface marker expression as an intermediary parameter to bridge the gap between murine Th17 findings and human T cell subset identification. By using CD26 expression levels combined with ICOS activation, the patent successfully identifies human CD26high T cell subsets that replicate the tumor-killing effectiveness of murine Th17 cells while establishing durable human antitumor memory responses
3Reliability
If ICOS costimulation is applied to activate CD26high T cells, then durable antitumor memory responses are achieved, but additional co-stimulatory agents and cytokines are required to enhance antitumor capabilities
Solution Approach 1:
The patent applies preliminary ICOS costimulation during the activation phase to pre-establish durable antitumor memory responses in CD26high T cells before further expansion or therapy. This preliminary action with ICOS creates a foundation of memory-capable cells that can then be enhanced with additional co-stimulatory agents (41BB, CD28, OX40) and cytokines (IL-2, IL-7, IL-12) without compromising the already-established memory potential, thereby resolving the contradiction between memory response reliability and culture system complexity
Data Source
AI summary
Provided herein are methods for the production of activated CD26high T cells by co-stimulation with inducible coactivator (ICOS). Further provided are methods for treatment of cancer by administration of the of activated CD26high T cells as an adoptive T cell therapy.