Engineering Immune Cells For Therapeutic Benefit

Development of tractable methods for CRISPR-based reprogramming of human immune cells opens the door to application of reprogrammed cellular therapies to cancer, HIV, primary immune deficiencies, and autoimmune diseases.
Engineering Immune Cells For Therapeutic Benefit

Our lab previously discovered, with Jennifer Doudna, a Cas9 ribonucleoprotein (RNP) technology for robust genome editing in primary human T cells. We have since developed a CRISPR genome-targeting system independent of viral vectors, allowing rapid and efficient insertion of large DNA sequences at specific loci in primary human T cells. This strategy allows for correction of pathogenic mutations as well as replacement of loci such as the TCR to redirect human T cells to custom antigens. This methodology is being optimized and expanded to additional cell types, such as B cells, NK cells, and HSPCs.

Combining technology development with functional genomic discovery, the lab has developed methods for genome-wide CRISPR screens in human T cells (SLICE) as well as a complementary strategy to barcode and track targeted integrations of large DNA templates, enabling pooled knock-in screens. Broadly, these technologies are allowing us to probe DNA sequences that control cells of the human immune system, understand disease genetics, and enhance cellular immunotherapies. We are using these platforms to design next-generation chimeric antigen receptor (CAR) and TCR-engineered T cells to treat solid tumors refractory to current therapies, autoimmune diseases and infectious diseases.

Selected Publications

Polymer-stabilized Cas9 nanoparticles and modified repair templates increase genome editing efficiency
Nature Biotechnology, 2020
Pooled Knockin Targeting for Genome Engineering of Cellular Immunotherapies
Cell, 2020
Orthotopic replacement of T-cell receptor alpha and beta chains with preservation of near-physiological T-cell function
Nature Biomedical Engineering, 2019
Reprogramming human T cell function and specificity with non-viral genome targeting
Nature, 2018

News

Media highlights of Alex and the lab’s research.
How CRISPR Tools are Unlocking New Ways to Fight Disease
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Crispr: Breakthrough announced in technique of 'editing' DNA to fight off deadly illnesses
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CRISPR-Based “Discovery Engine” for New Cell Therapies to Advance Cancer Treatments
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With new genes and an electric shock, scientists turn immune cells against cancer
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Swift Gene-Editing Method May Revolutionize Treatments for Cancer and Infectious Diseases
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First Human Trial of Engineered T cells
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Engineering the Next Generation of Cell Therapies
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Once Science Fiction, Gene Editing is Now a Looming Reality
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Why DNA is the Most Exciting Programming Language Today
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