From The Editors:
A Decade of Success … With More to Come
Russell Y. Cruz, MD, PhD
Children’s National Medical Center
Washington, United States
To quote advice from Nicholas Haralambous[i] to the young: “Plan in decades. Think in years. Work in months. Live in days.”
This is something worth remembering, especially for young scientists: progress can often be seen only after a significant amount of time has passed. The daily grind and long hours all will add up to success a decade from now, and most likely not in the short term.
Indeed, we have recently seen evidence that has been a decade in the making about the success of CAR T cell therapies. In an article out this month, J. Joseph Melenhorst and Carl June report that two of the initial recipients of CTL019 cells (CD19-specific chimeric antigen receptor T cells) remain in remission more than a decade after receiving their cells.[ii] Their infused cells persisted for more than a decade, giving investigators the ability to further characterize the dynamic changes that happen in vivo. Additional highlights of the paper included: (1) two anti-tumor waves were seen – an early one mediated by CD8 T cells and gamma delta T cells, and a longer one by CD4 CAR T cells; and (2) the persistence of active, cytotoxic CD4 CAR T cells.
This article, besides giving an update on the status of these two patients, gives a glimpse into the critical role of cytotoxic CD4 T cells, which do not appear exhausted. Evidence for their functionally activated phenotype can be seen in the expression of cytotoxic granules and genes as well as cytolytic function in response to CAR stimulation. CAR T cells appear to have ongoing proliferation, which does not appear to be clonotype-specific.
“These findings offer intriguing new insights into the nature of long-term CAR T cell signalling and persistence in these unique patients,” concludes Drs. Melenhorst, June, and their coauthors.
While CAR T cells have been among the most studied therapeutic platforms, much remains to be known, including a comprehensive understanding of the biological underpinnings of persistence (which, in turn, is the key to long term, favorable clinical outcomes).
CAR T cell therapies currently are being investigated all over the world, including in the UK,[iii] China,[iv] Brazil,[v] Japan,[vi] Israel,[vii] Australia,[viii] and Spain.[ix]
Speaking of decades, it has now been nearly three decades since the Telegraft (then the ISHAGE Telegraft) first served as the official newsletter of the society. In those three decades, ISHAGE/ISCT and its members have seen, and participated in, the great successes as well as the painful failures of the field.
In preparation for the decades to come, the Telegraft is transitioning to a permanent web presence as Telegraft Hub, and is available to the public on Twitter, LinkedIn, and the ISCT webpage.
This will be the place for all things cell and gene therapy: browse the latest research referenced in Cytotherapy Corner, go through the past by visiting the Archives, keep yourself posted with regulatory news in the various regional Legal and Regulatory Affairs updates, get to know the people making cell and gene therapy advances in Member Spotlight, keep abreast of the Foundation for the Accreditation of Cellular Therapies updates, and contribute your ideas/share your thoughts!
We invite you to witness the exciting new advances in cell and gene therapy with us! Check us out at https://www.isctglobal.org/telegrafthub, or follow us on Twitter (@telegraft) or at LinkedIn https://www.linkedin.com/company/isctglobal/.
[ii] Melenhorst, J.J., Chen, G.M., Wang, M. et al. Decade-long leukaemia remissions with persistence of CD4+ CAR T cells. Nature 602, 503–509 (2022). https://doi.org/10.1038/s41586-021-04390-6
[iii] Ghorashian S, Kramer AM, Onuoha S, Wright G, Bartram J, Richardson R, Albon SJ, Casanovas-Company J, Castro F, Popova B, Villanueva K, Yeung J, Vetharoy W, Guvenel A, Wawrzyniecka PA, Mekkaoui L, Cheung GW, Pinner D, Chu J, Lucchini G, Silva J, Ciocarlie O, Lazareva A, Inglott S, Gilmour KC, Ahsan G, Ferrari M, Manzoor S, Champion K, Brooks T, Lopes A, Hackshaw A, Farzaneh F, Chiesa R, Rao K, Bonney D, Samarasinghe S, Goulden N, Vora A, Veys P, Hough R, Wynn R, Pule MA, Amrolia PJ. Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR. Nat Med. 2019 Sep;25(9):1408-1414. doi: 10.1038/s41591-019-0549-5. Epub 2019 Sep 2. PMID: 31477906.
[iv] Wei, J., Guo, Y., Wang, Y. et al. Clinical development of CAR T cell therapy in China: 2020 update. Cell Mol Immunol 18, 792–804 (2021). https://doi.org/10.1038/s41423-020-00555-x
[viii] Velickovic ZM, Rasko JEJ. Establishing a robust chimeric antigen receptor T-cell therapy program in Australia: the Royal Prince Alfred Hospital experience. Cytotherapy. 2022 Jan;24(1):45-48. doi: 10.1016/j.jcyt.2021.06.005. Epub 2021 Sep 11. PMID: 34521574.