VGLL1-Specific T Cell Receptors for PDAC Tumor Targeting
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Solution Overview
Problem
Current immunotherapies, such as cytotoxic T lymphocyte (CTL)-based treatments, have not shown significant impact on pancreatic ductal adenocarcinoma (PDAC) due to the highly immune suppressive tumor microenvironment and low mutational burden, limiting the effectiveness of targeting neo-antigens, and existing therapies face challenges like low prevalence of target antigen expression and induction of toxicities in non-tumor tissues.
Innovation Solution
Development of VGLL1-specific T cell receptors (TCRs) that bind to Vestigial-like 1 (VGLL1), a novel tumor-associated antigen, to generate antigen-specific cytotoxic T lymphocytes (CTLs) capable of recognizing and killing PDAC and other cancer cells, including engineered TCRs, multivalent complexes, and expression vectors for T cell modification.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If checkpoint inhibitor therapies are used to activate T lymphocytes, then long-term patient survival is improved in highly mutated tumor types, but the therapy has limited impact on pancreatic ductal adenocarcinoma due to low mutational burden and immune suppressive microenvironment
Solution Approach 1:
The patent applies local quality by engineering T cells with tumor-specific TCRs that are customized for each patient's unique neoantigens. Instead of using a universal immunotherapy approach, the treatment is locally adapted to target specific molecular characteristics of the patient's tumor, thereby overcoming the limitations of checkpoint inhibitors in low-mutation tumors like PDAC
Solution Approach 2:
The patent changes the parameter of T cell specificity by introducing engineered TCRs with enhanced affinity and specificity for patient-specific neoantigens. This parameter change allows the immune system to recognize and respond to tumors with low mutational burden that would otherwise be invisible to standard checkpoint inhibitor therapies
2Productivity
If TIL therapy is used to infuse polyclonal T cells, then regression of bulky tumors is induced, but the therapy does not show significant impact on PDAC due to the immune suppressive tumor microenvironment
Solution Approach 1:
The patent applies preliminary anti-action by pre-engineering T cells with high-affinity TCRs before infusion, equipping them with enhanced capabilities to resist and overcome the immune suppressive microenvironment of PDAC. The engineered T cells are pre-armed with molecules and properties that counteract suppression mechanisms before they encounter the tumor
Solution Approach 2:
The patent uses composite materials by combining engineered T cells with multiple functional components including high-affinity TCRs, costimulatory molecules, and cytokine receptors. This composite structure creates T cells with enhanced functionality that can operate effectively in the hostile PDAC microenvironment
3Reliability
If TCR-T cells are engineered to target specific TAAs, then clinical responses are induced in melanoma, but toxicities occur in non-tumor tissues and self-tolerance mechanisms hinder high-affinity CTL generation
Solution Approach 1:
The patent applies segmentation by dividing the T cell population into highly specific subsets engineered to recognize individual patient-specific neoantigens. This segmentation allows for precise targeting of tumor cells while sparing normal tissues that do not express these unique antigenic determinants
Solution Approach 2:
The patent uses copying by creating artificial TCR sequences that replicate and amplify the specificity of naturally occurring T cells for patient-specific neoantigens. These engineered TCR copies are designed with enhanced binding affinity while maintaining strict specificity for the target antigen, reducing off-target effects
Data Source
AI summary
Provided herein are tumor-antigen VGLL1 specific T cell receptors. The TCR may be utilized in various therapies, such as autologous cell transplantation, to treat a cancer. Methods for expanding a population of T cells that target VGLL1 are also provided.