CD19 CAR-NK Dosing Cycles for Lower-Toxicity Blood Cancer Therapy
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Solution Overview
Problem
Current cancer treatments, such as chemotherapy, affect both healthy and diseased cells, while immunotherapies using engineered immune cells face challenges in effectively targeting cancer cells without significant adverse effects.
Innovation Solution
A dosing regimen involving genetically engineered natural killer (NK) cells expressing a chimeric antigen receptor (CAR) directed against CD19, administered in cycles with lymphodepletion and optionally combined with anti-CD20 agents, to specifically target and eliminate cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If chemotherapy is used to treat cancer, then cancer cells are eliminated, but healthy cells are also damaged
Solution Approach 1:
The patent segments the immune system into specific engineered NK cells that are divided and directed to target only cancer cells expressing CD19, rather than affecting all cells uniformly like chemotherapy. The dosing regimen further segments treatment into cycles with lymphodepletion phases to enhance specificity.
Solution Approach 2:
The patent introduces chimeric antigen receptors (CARs) as intermediaries that enable NK cells to specifically recognize and bind to CD19 on cancer cells. This intermediary mechanism allows selective targeting without the non-specific damage caused by chemotherapy.
2Measurement precision
If immunotherapy with engineered immune cells is used to specifically target cancer cells, then specificity is improved, but adverse effects still occur
Solution Approach 1:
The patent changes the dosing parameters by administering multiple doses of engineered NK cells at specific intervals (e.g., days 1, 8, and 15) rather than a single high dose. This dosing schedule allows the immune system to recover between treatments, reducing adverse effects while maintaining targeting specificity.
Solution Approach 2:
The patent implements periodic dosing cycles where engineered NK cells are administered at regular intervals, allowing the immune system to reset and reducing cumulative toxicity. The lymphodepletion phase between cycles further helps manage adverse effects by temporarily reducing immune cell populations.
3Reliability
If multiple doses of engineered NK cells are administered, then treatment efficacy is improved, but treatment complexity increases
Solution Approach 1:
The patent employs the patient's own immune system as a self-service mechanism, where engineered NK cells naturally proliferate and persist in the body over time. This self-sustaining approach reduces the need for complex continuous dosing while maintaining treatment efficacy.
Solution Approach 2:
The patent incorporates monitoring and evaluation phases between dosing cycles to assess treatment response. This feedback mechanism allows clinicians to adjust subsequent dosing based on patient response, optimizing efficacy while managing complexity through data-driven decision making.
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
The regimen achieves high response rates, including complete responses, with minimal adverse effects, effectively treating cancers like leukemia and lymphoma by specifically targeting CD19-positive cells.
Implementation Method 1
a chimeric antigen receptor comprising a CD19-targeting extracellular domain, a transmembrane domain, and a cytotoxic signaling complex. In several embodiments, the CD19-targeting extracellular domain binds to CD19.
Implementation Method 2
a plurality of NK cells that have been expanded in culture
Implementation Method 3
the first dosing cycle is initiated after the subject has undergone a lymphodepletion process in order to reduce native immune cell numbers
Implementation Method 4
a dosing regimen for cancer immunotherapy, comprising at least a first dosing cycle, wherein the first dosing cycle comprises a first dose of genetically engineered natural killer (NK) cells, a second dose of genetically engineered NK cells, and a third dose of genetically engineered NK cells
Data Source
AI summary
Several embodiments of the methods and compositions disclosed herein relate to immune cells that are engineered to express cytotoxic chimeric receptors and various dosing regimens for administering such cells. In several embodiments, the immune cells express a chimeric receptor that targets CD19 on tumor cells. In several embodiments, the cancer is a blood cancer, for example, B cell malignancy. In several embodiments, the immune cells engineered to express a CD 19-directed CAR are administered in combination (prior to, after or concurrently) with an antibody therapy, such as an anti-CD20 directed antibody.