cGAS Variant Lymphocytes Enhance Solid Tumor Killing
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Solution Overview
Problem
Current anti-tumor therapies, such as immune checkpoint inhibitors and chimeric antigen receptor T cells, have limitations in effectively targeting solid tumors and require further options to enhance anti-tumor immunity.
Innovation Solution
Development of anti-tumor lymphocytes engineered with a variant cyclic GMP-AMP synthase (cGAS) carrying specific amino acid substitutions at positions 255 and 236, or 254 and 258, which are constitutively active and produce cGAMP, enhancing immune response and tumor cell killing.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immune checkpoint inhibitors and chimeric antigen receptor T cells are used to enhance anti-tumor immunity, then T-cell responses are improved, but effectiveness against solid tumors is limited
Solution Approach 1:
The patent applies parameter changes by modifying the cGAS enzyme through specific amino acid substitutions (R255A/R236A or R255A/K258A) to create a constitutively active variant with enhanced enzymatic activity. This parameter modification enables the engineered lymphocytes to produce higher levels of cGAMP, thereby overcoming the limited effectiveness against solid tumors while maintaining T-cell response enhancement
2Power
If STING agonists are used to activate immune response, then immune activation is enhanced, but therapeutic potency against solid tumors is insufficient
Solution Approach 1:
The patent uses cGAMP as an intermediary substance produced by the engineered cGAS variant within the lymphocytes. This intermediary activates the STING pathway indirectly through endogenous cGAMP production rather than direct administration of external STING agonists, thereby enhancing both immune activation and therapeutic potency against solid tumors
3Object-affected harmful factors
If cGAS is anchored to nucleosome to prevent autoreactivity, then self-DNA binding is prevented, but immune activation is reduced
Solution Approach 1:
The patent extracts the cGAS enzyme from its nucleosome-anchored state through specific amino acid substitutions that disrupt the nucleosome interaction. This extraction allows cGAS to become constitutively active and produce cGAMP without being restrained by nucleosome anchoring, thereby enhancing immune activation while the engineered lymphocytes maintain controlled autoreactivity through targeted expression
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The engineered cGAS variant lymphocytes, known as cGAMP CAR-T cells, effectively reduce tumor burden and enhance anti-tumor activity by activating immune cells, overcoming limitations of STING agonists and improving therapeutic potency against solid tumors.
Implementation Method 1
cGAS initiates innate immune responses following microbial infection, cellular stress and cancer. Upon activation by double-stranded DNA, cytosolic cGAS produces 2′3′ CGMP-AMP
Data Source
AI summary
The present invention relates to anti-tumor lymphocytes, and a variant cyclic GMP-AMP synthase (cGAS) carrying an amino acid substitution of one or both arginines at amino acid positions 255 and 236 and/or an amino acid substitution of one or both lysines at amino acid positions 254 and 258; or a nucleic acid molecule encoding said variant cGAS for use in the treatment of a tumor in a subject.