Therapeutic Cell Survival Modulation via Apoptosis Control
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Solution Overview
Problem
Cellular therapies, such as CAR T-cell therapies, can cause severe side effects like cytokine release syndrome and neurological toxicities due to the activation and proliferation of therapeutic cells, leading to adverse events and risks of neoplasm, immune rejection, and unintended physiological consequences.
Innovation Solution
Modulating the survival of therapeutic cells by administering heterologous apoptosis modulating agents, including BCL2 family proteins, to enhance or decrease cell survival, using molecular circuits that allow conditional or constitutive expression of anti-apoptotic and pro-apoptotic proteins to control apoptosis and prevent off-target effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If therapeutic cells are administered to treat a condition, then therapeutic efficacy is improved, but severe side effects and adverse events occur
Solution Approach 1:
The patent introduces suicide gene systems (e.g., herpes simplex virus thymidine kinase, cytosine deaminase) as intermediary mechanisms that enable controlled elimination of therapeutic cells. These genetic systems act as mediators between the therapeutic cells and the host, providing a safety switch that can be activated by external agents (ganciclovir, 5-fluorocytosine) to terminate cell activity and prevent severe adverse events while maintaining therapeutic efficacy during the treatment period
Solution Approach 2:
The patent employs inducible expression systems that allow dynamic control of therapeutic cell behavior by changing molecular parameters. Promoters responsive to specific inputs (tetracycline, doxycycline, progesterone, light, temperature) enable reversible modulation of cell survival, proliferation, and activity. This parameter control allows the system to maintain high therapeutic efficacy when activated and rapidly terminate cell function when adverse events occur, effectively resolving the contradiction between sustained therapy and safety
2Productivity
If therapeutic cells are activated and proliferated to enhance treatment effect, then therapeutic efficacy is improved, but cytokine release syndrome and neurological toxicities occur
Solution Approach 1:
The patent implements feedback control mechanisms through inducible gene expression systems that respond to external molecular or environmental signals. When adverse events occur, administration of inducing agents (tetracycline derivatives, progesterone, light exposure, temperature change) triggers feedback signals that activate suicide genes or inhibit proliferation genes, thereby reducing cell numbers and cytokine production. This feedback loop enables real-time adjustment of therapeutic cell activity to prevent severe toxicities while maintaining productivity during normal treatment
Solution Approach 2:
The patent transforms static therapeutic cell populations into dynamic, controllable systems. By incorporating inducible promoters and suicide gene systems, the cell population size and activity level can be dynamically adjusted in response to treatment progression and adverse events. This dynamic control allows rapid expansion when therapeutic benefit is needed and rapid contraction when cytokine release syndrome or neurological toxicities occur, resolving the contradiction between productivity and harmful effects
3Duration of action of stationary object
If survival of therapeutic cells is enhanced to improve treatment duration, then therapeutic persistence is improved, but risk of neoplasm and long-term adverse events increases
Solution Approach 1:
The patent introduces suicide gene systems as intermediary safety mechanisms that decouple long-term persistence from cancer risk. The therapeutic cells can persist and proliferate normally during the treatment period, but the embedded suicide genes (thymidine kinase, cytosine deaminase) act as intermediary safety switches that can be activated by administering specific prodrugs (ganciclovir, 5-fluorocytosine). This intermediary system allows long-term persistence when needed while providing a reliable method to eliminate cells if neoplastic transformation or long-term adverse events occur
Solution Approach 2:
The patent applies preliminary action by pre-installing suicide gene systems and inducible control mechanisms into therapeutic cells before administration. These safety features are built in advance, allowing rapid response to adverse events without requiring complex ex vivo manipulation. The preliminary incorporation of control elements enables long-term persistence while maintaining the capacity for rapid cell elimination if neoplasm or long-term toxicity develops, resolving the contradiction between duration and reliability
Data Source
AI summary
Provided are methods of modulating the survival of therapeutic cells as well as cells and nucleic acids and vectors useful in such methods. Such survival modulation may include enhancing survival and/or enhancing death of the therapeutic cells. The provided methods include administering a therapeutic cell, nucleic acid and/or vector to a subject, the administered therapeutic cells, nucleic acids and/or vectors including one or more heterologous apoptosis modulating agents and/or one or more encoding sequences thereof. Cells of the disclosure include or encode one or more heterologous apoptosis modulating agents.