Immune Cell Conditioning Regimens for In Vivo CAR-T Engineering
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Solution Overview
Problem
Current lymphodepleting chemotherapy regimens used in CAR-T cell therapy are not suitable for in vivo immune cell engineering, as they eliminate the very cells sought to be engineered, necessitating the development of alternative conditioning methods compatible with in vivo immune cell engineering.
Innovation Solution
Administration of biological response modifiers (BRMs) such as low-dose cyclophosphamide, γ-chain receptor cytokines, inflammatory chemokines, immune checkpoint inhibitors, and nanoparticle-delivered nucleic acids encoding these agents, either systemically or targeted to tumor sites, to condition the immune system for in vivo engineering.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If lymphodepleting chemotherapy is administered to improve CAR-T therapy efficacy, then the expansion and function of engineered cells is enhanced, but the cells sought to be engineered in vivo are eliminated
Solution Approach 1:
The patent administers lymphodepleting chemotherapy before in vivo immune cell engineering to eliminate immunosuppressive cells and create a favorable microenvironment, but this creates a timing conflict where the same chemotherapy would eliminate the target cells if administered after engineering. The solution is to sequence the actions: first deplete lymphocytes, then introduce the engineering agent to engineer the remaining immune cells.
Solution Approach 2:
The patent divides the treatment into distinct phases: (1) lymphodepleting chemotherapy phase to eliminate suppressive cells, (2) in vivo engineering phase to modify remaining immune cells, and (3) recovery phase where engineered cells expand. This segmentation allows each phase to achieve its purpose without interfering with the others.
2Duration of action of stationary object
If lymphodepleting chemotherapy is used to eradicate immunosuppressive cells, then the persistence of engineered cells is improved, but the overall immune cell population is reduced
Solution Approach 1:
The patent converts the harmful effect of lymphodepleting chemotherapy (elimination of immune cells) into a beneficial outcome by timing it to occur before in vivo engineering. The chemotherapy eliminates suppressive cells and creates space, which then benefits the engineered cells that are introduced afterward, allowing them to persist longer without competition from suppressive cells.
Data Source
AI summary
Disclosed are methods of conditioning subjects who receive, are receiving, or have received an agent for in vivo reprogramming of immune cells in order to improve the efficiency of the in vivo reprogramming and/or the overall therapeutic effect of the treatment. Also disclosed are nanoparticle compositions for providing the conditioning agent(s). The conditioning agent can be provided prior to, concurrently with, or after administration of the in vivo reprogramming agent depending on the conditioning agent. The conditioning regimens are useful in combination with in vivo reprogramming of immune cells to treat hematologic cancers and solid tumor, fibrotic disorders, and B cell or T cell mediated autoimmunity, chronic infection. Some conditioning regimens are also useful in combination with other cancer treatments.