Adoptive Immune Cell Composition for Solid Tumor Immunosuppression
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing adoptive cell therapies, such as CAR-T and TCR-based treatments, face challenges with limited persistence, antigen escape, and toxicity, particularly in treating solid tumors, and fail to effectively revive exhausted T cells due to immunosuppressive tumor microenvironments.
Innovation Solution
An adoptive cell therapy composition comprising modified immune cells, enriched for CD4+ Th1 cells and optionally depleted of CD8+ T cells, with specific inhibition or genetic modification of BTK, ITK, PI3Kδ, and other pathways to promote Th1 CD4+ T cell differentiation and enhance anti-tumor activity, while reducing graft-versus-host disease risk.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-T or TCR-based cell therapies are used to treat solid tumors, then tumor-specific immune response is enhanced, but the therapies fail due to immunosuppressive tumor microenvironment and physical barriers
Solution Approach 1:
The patent introduces a two-stage cell therapy approach where first-stage cells (such as myeloid-derived suppressor cells or regulatory T cells) are administered to temporarily modify the tumor microenvironment, followed by second-stage CAR-T or TCR-based cells. The first-stage cells act as intermediaries that reduce immunosuppression and facilitate the survival and function of the second-stage therapeutic cells, enabling them to overcome the harmful tumor microenvironment.
2Reliability
If CAR-T therapy is administered to achieve tumor cell destruction, then cytotoxic activity is enhanced, but toxicity including cytokine release syndrome and neurotoxicity occurs
Solution Approach 1:
The patent employs a sequential administration strategy where first-stage cells are given before the second-stage CAR-T cells. This preliminary action allows the first-stage cells to prepare the immune system and tumor microenvironment, reducing the risk of severe cytokine release syndrome and neurotoxicity when the highly cytotoxic second-stage cells are subsequently administered.
Solution Approach 2:
The two-stage approach allows for controlled, partial activation of the immune system in the first stage, followed by targeted excessive cytotoxic action in the second stage against specific tumor antigens. This staged partial action reduces overall systemic toxicity while maintaining effective tumor cell destruction capability.
3Adaptability or versatility
If TIL therapy is used to overcome tumor heterogeneity, then multiple TCRs recognize tumor antigens, but physical barriers and immunosuppression still limit effectiveness
Solution Approach 1:
The patent uses first-stage cells as intermediaries that temporarily modify the tumor microenvironment to reduce physical barriers and immunosuppression. This facilitates the infiltration and function of TILs with diverse TCRs, allowing them to effectively recognize and attack heterogeneous tumor antigens despite the challenging microenvironment.
Data Source
AI summary
The disclosure relates to adoptive cell therapy compositions including a population of isolated immune cells that are obtained from a donor subject. The immune cells can be modified to suppress Bruton's tyrosine kinase (BTK), interleukin-2-inducible T cell kinase (ITK), delta isoform of phosphoinositide 3-kinase (PI3Kδ), helios, blimp1, SOCS1, GATA3, IL-10, STAT3, TOX, CD25, foxp3, Ezh2, TGF-beta Receptor II, LAG-3, PD-1, TNF-alpha, or combinations thereof. The immune cells are optionally depleted of CD8+ T cells by about 10-fold or greater relative to un-depleted leukocytes.