Vδ1+ Gamma Delta T-Cell Therapy for Chemoresistant AML Relapse
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Solution Overview
Problem
Current therapeutic strategies for acute myeloid leukemia (AML), particularly relapsed or refractory AML, face challenges due to chemoresistance and high relapse rates, necessitating a safe and effective treatment option.
Innovation Solution
Administration of a therapeutically effective amount of an allogeneic composition comprising Vδ1+ gamma delta (γδ) T cells, which can recognize and target malignant cells without MHC-mediated antigen presentation, providing a novel immunotherapy for AML.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If chemotherapy with cytarabine and anthracyclin is used, then complete remission is induced, but chemoresistant clones are selected leading to refractory relapses
Solution Approach 1:
The patent converts the harmful effect of chemotherapy-induced chemoresistance into a benefit by using the selective pressure to enrich for gamma delta T cells that are inherently resistant to chemotherapy. These cells are then expanded and used as therapy to attack the cancer without being affected by the same chemoresistance mechanisms, turning the chemotherapy's harmful selection pressure into a beneficial enrichment process.
Solution Approach 2:
The patent introduces gamma delta T cells as an intermediary between the patient's cancer and the treatment. These cells serve as a mediator that recognizes and attacks cancer cells through non-MHC mechanisms, bypassing the chemoresistance pathways that conventional chemotherapy triggers. The gamma delta T cells act as a biological intermediary that transfers immune-mediated cytotoxicity without direct chemical interaction with the cancer cells.
2Reliability
If stem cell transplantation is performed, then relapse is reduced, but substantial portion of patients still develop relapsed AML with poor prognosis
Solution Approach 1:
Instead of using conventional chemotherapy or stem cell transplantation as the primary treatment approach, the patent inverts the strategy by using the patient's own gamma delta T cells as the therapeutic agent. This inversion shifts the treatment paradigm from external chemical or cellular intervention to leveraging the patient's inherent immune system components that are already present and functional, thereby avoiding the relapse issues associated with conventional approaches.
Solution Approach 2:
The patent applies self-service by utilizing and expanding the patient's own gamma delta T cells to fight their cancer. These cells are harvested from the patient, expanded in culture, and then returned to the patient to provide sustained anti-cancer activity. This self-service approach eliminates the need for external donors or conventional treatments, and the cells maintain their cytotoxic function without inducing the harmful effects of chemotherapy or transplantation.
3Adaptability or versatility
If alpha beta T cells are used for immunotherapy, then MHC-mediated antigen presentation is required, but response is delayed and limited by MHC restriction
Solution Approach 1:
The patent extracts the MHC restriction requirement from the T cell activation process by using gamma delta T cells that recognize cancer antigens through non-MHC mechanisms. Specifically, gamma delta T cells can directly bind to stress ligands, pAgs, and lipid antigens on cancer cell surfaces without requiring MHC presentation, thereby removing this limiting factor and enabling faster, more versatile antigen recognition across different cancer types and stages.
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
GDX012 therapy exhibits high cytotoxic activity against AML blasts, homing to bone marrow and persisting for prolonged cytotoxic effect, effectively reducing leukemic blasts and improving patient outcomes.
Implementation Method 1
Vδ1+ γδ T cells recognize malignant cells through expression of a diverse repertoire of natural cytotoxicity receptors (NCRs) that interact with stress ligands, pAgs, lipid Ags and many other non-peptide molecules specifically upregulated on diseased cells
Implementation Method 2
gamma delta T lymphocytes do not require major histocompatibility complex (MHC)-mediated antigen presentation to exert their cytotoxic effect, thus the initial responsiveness of γδ T cells precede that of αβ T cells
Implementation Method 3
GDX012 shows homing to the bone marrow and is detected for at least 28 days. GDX012 therapy exhibits high cytotoxic activity against AML blasts, homing to bone marrow and persisting for prolonged cytotoxic effect
Data Source
AI summary
The present disclosure provides, among other things, methods for treating relapsed or refractory acute myeloid leukemia by administering to a subject in need thereof a therapeutically effective amount of an allogeneic composition comprising VDelta1+ (Vδ1+) gamma delta (γδ) T cells such that one or more symptoms or biomarkers is improved after treatment. The present disclosure also provides suitable doses of compositions comprising allogeneic Vδ1+gamma delta (γδ) T cells for administration to a subject suffering from relapsed or refractory AML. In some embodiments, the Vδ1+gamma delta (γδ) T cells are untransduced.