ALK-Specific T Cell Receptors for Resistant Cancer Immunotherapy
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Solution Overview
Problem
Current treatments for ALK-positive cancers, including ALK-positive lung cancers and anaplastic large cell lymphoma, face challenges such as acquired resistance to ALK tyrosine kinase inhibitors and primary resistance to immune-checkpoint blockade, necessitating novel therapeutic strategies.
Innovation Solution
Development of T cell receptors (TCRs) that specifically bind ALK peptides, encoded by heterologous polynucleotides and expressed in transgenic effector cells, to target and eliminate ALK-positive neoplastic cells, including those resistant to ALK tyrosine kinase inhibitors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If ALK tyrosine kinase inhibitors are used to treat ALK-positive cancers, then survival is extended compared to standard chemotherapies, but acquired resistance develops within a few years of treatment
Solution Approach 1:
The patent segments the treatment approach by combining ALK TKI therapy with immune checkpoint blockade or adoptive T cell transfer, creating a multi-modal treatment strategy that addresses both the oncogenic driver and the immune evasion mechanisms, thereby extending durable response beyond what either modality achieves alone
Solution Approach 2:
The patent employs composite therapeutic regimens that integrate small molecule inhibitors (ALK TKIs) with biological therapies (immune checkpoint inhibitors or engineered T cells), creating a composite treatment approach that targets cancer through multiple mechanisms simultaneously to prevent resistance development
2Reliability
If immune checkpoint inhibitors are used to treat ALK-positive cancers, then some patients achieve response, but primary resistance and hyper-progression occur at high rates
Solution Approach 1:
The patent applies preliminary anti-action by using ALK TKIs to reduce tumor burden and modulate the tumor microenvironment before administering immune checkpoint inhibitors, thereby preemptively reducing factors that contribute to primary resistance and hyper-progression while enhancing immune response
Solution Approach 2:
The patent introduces adoptive T cell transfer as an intermediary therapy that bridges ALK TKI treatment and immune checkpoint blockade, providing a cell-mediated mechanism to directly recognize and eliminate ALK-positive cells while modulating the immune microenvironment to prevent resistance
3Reliability
If adoptive T cell transfer with ALK-specific TCRs is used to treat ALK-positive cancers, then treatment efficacy is enhanced in resistant patients, but the complexity of the therapeutic strategy increases
Solution Approach 1:
The patent creates universal ALK-specific T cell receptors that can recognize multiple ALK-positive cancer types (NSCLC, ALCL, and other ALK-rearranged tumors) across different HLA backgrounds, allowing a single therapeutic approach to address diverse malignancies and reducing the need for patient-specific customization
Solution Approach 2:
The patent engineers T cell receptors with modified affinity parameters and specificity profiles to optimize recognition of ALK peptides while maintaining safety, and adjusts T cell expansion and infusion parameters to achieve effective therapeutic doses, thereby managing complexity through standardized parameter optimization
Data Source
AI summary
The invention features polypeptides and/or transgenic effector cells including T cell receptors (TCRs) which specifically bind anaplastic lymphoma kinase (ALK) antigens or peptide sequences, and the use of such polypeptides and/or transgenic effector cells and TCRs specific to anaplastic lymphoma kinase (ALK) antigens or peptide sequences in compositions and methods for treating ALK-positive neoplasias such as Non-Small Cell Lung Cancers (NSCLCs).