Modified T Cells Expressing SIGLEC-15 scFv to Overcome Immune Suppression
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Solution Overview
Problem
T cell therapies for cancer, such as CAR T cell therapy, are limited by the immunosuppressive microenvironment induced by immune inhibitors like PD-1, which hampers their efficacy.
Innovation Solution
Development of modified cells expressing a polynucleotide encoding a secretable scFv binding SIGLEC-15 and/or a dominant negative form of CD44, combined with a fusion protein comprising an scFv binding SIGLEC-15, a linker, a transmembrane domain, and a cytoplasmic domain, to overcome immune inhibition and enhance T cell activation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If T cell therapy is used to treat cancer, then anti-tumor efficacy is improved, but immune suppression induced by immune inhibitors like PD-1 reduces therapeutic effectiveness
Solution Approach 1:
The patent applies preliminary anti-action by pre-engineering T cells to resist immune suppression before they encounter the tumor microenvironment. The modified T cells are equipped with engineered receptors that block PD-1 signaling and enhance activation, so when these cells are infused into the patient, they are already prepared to overcome the immunosuppressive effects of PD-1 and other inhibitors in the tumor microenvironment, rather than waiting for the suppression to occur and then attempting to counteract it
Solution Approach 2:
The patent applies parameter changes by fundamentally altering the functional parameters of T cells through genetic modification. The T cells are engineered to express modified receptors with altered signaling properties that change their activation threshold, cytokine production levels, and resistance to suppression. This transforms the T cells from a naturally suppressible state to an engineered resistant state, changing key functional parameters to overcome immune inhibition
2Ease of operation
If immune inhibitors like PD-1 are present in the microenvironment, then T cell activation is inhibited, but removing or blocking these inhibitors requires additional therapeutic interventions
Solution Approach 1:
The patent applies merging by combining multiple functions into a single engineered T cell product. Rather than requiring separate therapies for T cell activation and immune suppression blockade, the modified T cells integrate both capabilities: they maintain enhanced activation properties while simultaneously resisting PD-1-mediated suppression. This merges what would otherwise require multiple separate interventions into one unified cellular therapy
Solution Approach 2:
The patent applies self-service by engineering T cells that autonomously counteract immune suppression without requiring external intervention. The modified T cells possess built-in mechanisms to block PD-1 signaling and maintain activation in the presence of immune inhibitors, making them self-sufficient in overcoming suppression. This eliminates the need for additional therapeutic interventions to block PD-1 or other inhibitors, as the T cells handle this themselves
Data Source
AI summary
The present disclosure relates to a modified cell comprising a polynucleotide encoding a secretable scFv binding SIGLEC-15 and/or encoding a dominant negative form of CD44. In embodiments, the modified cell further comprises an antigen-binding molecule, which for example, is a CAR comprising an antigen-binding domain, a transmembrane domain, and an intracellular signaling domain.