Utilization of CD39 and CD103 for identification of human tumor reactive T cells for treatment of cancer
Inventors
Weinberg, Andrew D. • Montier, Ryan • Duhen, Thomas • Duhen, Rebekka
Assignees
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Publication Number
US-11572541-B2
Publication Date
2023-02-07
Expiration Date
Abstract
Methods are disclosed for treating a subject with a tumor. These methods include administering to the subject a therapeutically effective amount of CD8+CD39+CD103+ T cells. Methods also are disclosed for isolating a nucleic acid encoding a T cell receptor (TCR) that specifically binds a tumor cell antigen. These methods include isolating CD8+CD39+CD103+ T cells from a sample from a subject with a tumor expressing the tumor cell antigen, and cloning a nucleic acid molecule encoding a TCR from the CD8+CD39+CD103+ T cells. In addition, methods are disclosed for expanding CD8+CD39+CD103+ T cells. In additional embodiments, methods are disclosed for determining if a subject with a tumor will respond to a checkpoint inhibitor. The methods include detecting the presence of CD8+CD39+CD103+ T cells in a biological sample from a subject.
Core Innovation
The disclosure describes treating a subject with a tumor by administering a therapeutically effective amount of CD8+CD39+CD103+ T cells. The treatment is performed by adoptive transfer of these cells, and higher frequencies of CD39+CD103+ CD8 T cells in tumors are linked to improved overall survival.
The disclosure further describes using the presence of CD8+CD39+CD103+ T cells in a patient sample as a predictive biomarker for response to checkpoint inhibition or other cancer therapies and surgery. It also describes isolating and cloning T cell receptor (TCR) nucleic acids from CD8+CD39+CD103+ T cells that bind tumor antigens.
The disclosure additionally describes expanding such cells in vitro, including feeder cell and cytokine-based culture, to provide expanded T cells for use in the treatment.
Claims Coverage
The independent claim covers a method of treating a subject with a tumor by administering a therapeutically effective amount of CD8+CD39+CD103+ T cells. The dependent claim set adds 5 inventive features, including tumor type limitations, biomarker/predictive use context, and combination regimens with immune checkpoint antagonists or 4-1BB agonists, optionally using antibody formats and human monoclonal or humanized monoclonal antibodies.
Treating a subject with a tumor by administering CD8+CD39+CD103+ T cells
A method of treating a subject with a tumor comprising administering to the subject a therapeutically effective amount of CD8+CD39+CD103+ T cells, thereby treating the subject with the tumor.
Combination with immune checkpoint antagonists or 4-1BB agonist
The method further administering to the subject a therapeutically effective amount of one or more immune checkpoint antagonists selected from PD-1, PD-L1, CTLA-4, BTLA, TIM-3, and LAG3 antagonists or a 4-1BB agonist.
Checkpoint agents as target-binding antibodies or antigen-binding fragments
The method wherein the PD-1, PD-L1, CTLA-4, BTLA, TIM-3, and LAG3 antagonists are antibodies, or antigen-binding fragments, that specifically bind their respective targets.
Human monoclonal or humanized monoclonal antibody format
The method wherein the specified antibodies are human monoclonal or humanized monoclonal antibodies.
Autologous CD8+CD39+CD103+ T cells
The method wherein the CD8+CD39+CD103+ T cells are autologous.
Overall, the claims center on adoptive administration of therapeutically effective CD8+CD39+CD103+ T cells for tumor treatment, with dependent refinements specifying autologous cell source and optional combination therapy using immune checkpoint antagonists or 4-1BB agonists in antibody or antigen-binding-fragment formats, including human monoclonal or humanized monoclonal antibodies.
Stated Advantages
Higher frequencies of CD39+CD103+ CD8 T cells in tumors are linked to improved overall survival.
Use of the presence of CD8+CD39+CD103+ T cells in a patient sample as a predictive biomarker for response to checkpoint inhibition.
Predicting response to other cancer therapies and surgery based on the presence of CD8+CD39+CD103+ T cells in a patient sample.
Documented Applications
Treating a subject with a tumor by administering CD8+CD39+CD103+ T cells.
Predicting response to checkpoint inhibition using the presence of CD8+CD39+CD103+ T cells in a patient sample.
Predicting response to other cancer therapies and surgery using the presence of CD8+CD39+CD103+ T cells in a patient sample.
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