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.
GIGIM001_MarsonLab-Research-Feature-topic4

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

Modular pooled discovery of synthetic knockin sequences to program durable cell therapies
Cell, 2023
Peptide-mediated delivery of CRISPR enzymes for the efficient editing of primary human lymphocytes
Nature Biomedical Engineering, 2023
Advancing T cell–based cancer therapy with single-cell technologies
Nature Medicine, 2022
High-yield genome engineering in primary cells using a hybrid ssDNA repair template and small-molecule cocktails
Nature Biotechnology, 2022
RASA2 ablation in T cells boosts antigen sensitivity and long-term function
Nature, 2022
Polymer-stabilized Cas9 nanoparticles and modified repair templates increase genome editing efficiency
Nature Biotechnology, 2020

News

Media highlights of Alex and the lab’s research.
Lego-Like Gene Editing Tool Lets Researchers Improve Cancer Immunotherapy
Read More >>
New Approach to CRISPR Delivery Opens the Door to Editing Multiple Genes Safely
Read More >>
A Cellular Engineering Breakthrough: High-Yield CRISPR Without Viral Vectors
Read More >>
A gene not previously known to regulate immunity could turn tired T-cells around
Read More >>
Giving Immunotherapy Cells Resilience to Pass the ‘Stress Test’
Read More >>
Living Therapeutics Initiative Will Accelerate Development and Delivery of Revolutionary Treatments
Read More >>
Gene Editing Expands to New Types of Immune Cells
Read More >>
How CRISPR Tools are Unlocking New Ways to Fight Disease
Read More >>
Crispr: Breakthrough announced in technique of 'editing' DNA to fight off deadly illnesses
Read More >>
CRISPR-Based “Discovery Engine” for New Cell Therapies to Advance Cancer Treatments
Read More >>
With new genes and an electric shock, scientists turn immune cells against cancer
Read More >>
Swift Gene-Editing Method May Revolutionize Treatments for Cancer and Infectious Diseases
Read More >>
First Human Trial of Engineered T cells
Read More >>
Engineering the Next Generation of Cell Therapies
Read More >>
Once Science Fiction, Gene Editing is Now a Looming Reality
Read More >>
Why DNA is the Most Exciting Programming Language Today
Read More >>