MedicalResearch.com Interview with:
Dr. J Joseph Melenhorst, PhD
Director, Product Development & Correlative Sciences laboratories (PDCS)
Adjunct Associate Professor
Center for Cellular Immunotherapies
University of Pennsylvania
MedicalResearch.com: What is the background for this study? Would you briefly explain what is meant by CLL and CAR T cells?
Response: We started treating patients with a form of blood cancer called CLL (chronic lymphocytic leukemia) using a form of gene therapy wherein we engineer the patient’s own immune cells – T cells – with a tumor targeting molecule: The CAR, which stands for chimeric antigen receptor. When we engineer the patient’s immune cells we use a vehicle, in this case virus, that inserts the payload – the CAR – into the patient’s DNA. The virus disappears, and the CAR stays. Where this CAR inserts itself is unpredictable, but we always get stably engineered cells.
MedicalResearch.com: What are the main findings?
Response: We had seen dramatic, complete responses following CAR T cell treatments. Most patients would have signs of CAR T cell activity within days or weeks after infusion. This patient had received a first dose and seemed to respond but that was only short lived. Since we still had his second dose in the freezer we decided to infuse those cells two months after the first. But nothing happened for almost two months and then suddenly we noted dramatic anti-tumor response. That was quite unusual and we wanted to understand the response and process. That was in 2013. Four years of research has now shown that this patient experienced what I called “a series of fortunate events”: The CAR had inserted itself into a gene that, as a consequence of this event, was no longer functional. Since we all carry two copies of each gene we wanted to know what happened with the other copy. It turned out to carry a natural variant that rendered that second, intact copy severely crippled. The net effect was that the function of this gene called “TET2” was almost absent due to this engineering event. Laboratory studies confirmed that the dramatic reduction of TET2 levels in donor T cells gave those cells very similar properties to the patient’s CAR T cells, leading us to conclude that TET2 disruption was responsible for the dramatic anti-tumor activity of this CAR T cell clone.
MedicalResearch.com: What should readers take away from your report?
Response: This month we published in Nature Medicine that the baseline health of T cells, meaning T cells from cancer patients that are used for cell therapy, greatly impacts the success of the therapy. What this current study in Nature on TET2 now shows is that the integration site can also, and quite dramatically, affect the ability of the immune cells to target cancer, even to the point that a single cell can eliminate a very, very large tumor population.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: Our study shows that with the right cells and engineering tools we can enhance the immune system’s ability to target cancer, an amazing tribute to the field of synthetic biology I would say.
MedicalResearch.com: Is there anything else you would like to add?
Response: With findings like this we should examine the CAR integration sites more carefully to identify sites that similarly enhance the in vivo potency of CAR T cells and guide novel cell engineering development.
Joseph A. Fraietta, Christopher L. Nobles, Morgan A. Sammons, Stefan Lundh, Shannon A. Carty, Tyler J. Reich, Alexandria P. Cogdill, Jennifer J. D. Morrissette, Jamie E. DeNizio, Shantan Reddy, Young Hwang, Mercy Gohil, Irina Kulikovskaya, Farzana Nazimuddin, Minnal Gupta, Fang Chen, John K. Everett, Katherine A. Alexander, Enrique Lin-Shiao, Marvin H. Gee, Xiaojun Liu, Regina M. Young, David Ambrose, Yan Wang, Jun Xu, Martha S. Jordan, Katherine T. Marcucci, Bruce L. Levine, K. Christopher Garcia, Yangbing Zhao, Michael Kalos, David L. Porter, Rahul M. Kohli, Simon F. Lacey, Shelley L. Berger, Frederic D. Bushman, Carl H. June, J. Joseph Melenhorst. Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature, 2018; DOI: 10.1038/s41586-018-0178-z
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