CRISPR Based T Cell Editing, Theodore Roth, Ph.D., UCSF

09/24/19 • 25 min

Genome editing technologies have proliferated in recent years as have different types of immunotherapies. What possibilities exist at the intersection of these advances? In this episode Tracy interviews Theo Roth, Marson Lab at UCSF.

Theo is the first author on a recent paper in Nature entitled Reprogramming Human T-Cell Function and Specificity With Non Viral Genome Targeting.

In recent episodes of this podcast we have discussed manipulating the stemness of T-cells as well as identifying populations of T-cells that are reactive to tumor neo-antigens. Here, we are talking about rapidly engineering immune cell genomes. How quickly can in be done (in terms of helping a patient) and what are the limitations on the scale of changes that could be made? Can it be done without the use of viral vectors?

Theo describes the work to "knock-in" new sequences and ensure they integrate in the correct locations, under the correct regulation.

Theo is the first author on a recent paper in Nature entitled Reprogramming Human T-Cell Function and Specificity With Non Viral Genome Targeting.

Theo describes the work to "knock-in" new sequences and ensure they integrate in the correct locations, under the correct regulation.

Previous Episode

TIL Frequency & Tumor Reactivity? Anna Pasetto, Ph.D., Karolinska Institutet

There is already some evidence that successful immunotherapy is probably connected with reactivity against neo-antigens. But can we identify a population of T-cells whose receptors are specific to those antigens and take further advantage of those to create more effective immunotherapies for individuals?

Anna Pasetto is the first author on a recent publication in Cancer Immunology Research titled Tumor and Neo-Antigen Reactive T-cell Receptors Can be Identified Based on their Frequency in Fresh Tumor.

She and her co-authors hypothesized that the predominant clonotypes within a population of T-cells may indicate its tumor reactivity.

Anna describes for Tracy the strategy they used to identify the candidate clonotypes using deep sequencing of TCRB, single cell PCR and statistical analysis in figuring out which alpha chain was paired with which beta chain in the predominant receptor class.

This research is promising for increasing the effectiveness of cell based immuno-therapies.

Next Episode

HIF-independent synthetic lethality, Hilary Nicholson, Ph.D., Dana-Farber Cancer Institute

On Oct. 7th, 2019, the Nobel Assembly announced that William G. Kaelin, Jr., Dana-Farber Cancer Institute, shares the 2019 Nobel Prize in Physiology or Medicine with Sir Peter J. Ratcliffe of Oxford University and the Francis Crick Institute, and Gregg L. Semenza of Johns Hopkins University, for their discoveries of how cells sense and adapt to oxygen availability.

In this episode Tracy interviews Hilary Nicholson, Ph.D., a postdoc research fellow in Kaelin Lab at Dana-Farber Cancer Institute. Hilary talked about her perspectives of Dr. Kaelin receiving the Nobel Prize, how Dr. Kaelin mentors and inspires her, and how her work is built upon this textbook discovery.

Hilary is the first author of a recent publication on Science Signaling, "HIF-independent synthetic lethality between CDK4/6 inhibition and VHL loss across species". Kidney cancer is one of the top ten most common forms of cancer in developed countries, and the most common type of kidney cancer is clear cell renal cell carcinoma (ccRCC). The von Hippel-Lindau tumor suppressor gene (VHL) inactivation is associated with ccRCC development, and hypoxia-inducible factor 2 alpha (HIF-2 alpha) is accumulated.

Hilary talks about synthetic lethality between CDK4/6 inhibition and VHL loss in two species and across various human ccRCC cell lines in culture and xenografts; The study also shows that HIF-2 alpha was not required for the synthetic lethality. "These findings support testing CDK4/6 inhibitors as treatment for ccRCC, alone and in combination with HIF-2 alpha inhibitors".

In addition, Hilary introduced the Science Cheer leaders, a non-profit organization comprised of 300+ current and former NFL, NBA and college cheerleaders pursuing STEM careers.