Dr. Gattinoni is an Earl Stadtman investigator at the Experimental Transplantation and Immunology Branch, NCI. He is interested in uncovering the cellular and molecular mechanisms regulating T cell differentiation and the formation and maintenance of immunological memory. Specifically, his laboratory is focused on understanding the transcriptional, metabolic, and microRNA-mediated regulation of T cell self-renewal and multipotency with the goal of developing new T cell-based immunotherapies for the treatment of patients with advanced cancer and hematologic malignancies.
Our research is focused on the development of novel T-cell based immunotherapies for the treatment of patients with advanced cancer. In the past years, we made several discoveries that have shaped our understanding of how the differentiation state affects the ability of CD8+ T cells to destroy tumors in vivo upon adoptive transfer. We found that, counter to what it was previously thought, CD8+ T cells that acquired terminal effector properties and displayed increased antitumor activity in vitro were poorly effective at triggering tumor regression in vivo because they had impaired abilities to proliferate and survive (Gattinoni, L. et al. J Clin Invest, 2005).
These results prompted us to study ways of withholding CD8+ T cell differentiation. We focused our research on uncovering molecular pathways that regulate the differentiation of CD8+ T cells with the goal of improving the efficacy of adoptive T cell therapies (Gattinoni, L. et al. Nature Med, 2009 and Ji, Y. et al. Nature Immunol, 2011). These studies also led us to the identification of a new memory T cell subset in mouse and human, termed T memory stem cells (TSCM). TSCM cells have an enhanced capacity for self-renewal and the multipotent ability to derive central memory, effector memory and effector T cells. More importantly, these cells are capable of mediating profound anti-tumor responses in preclinical models of adoptive immunotherapy (Gattinoni, L. et al. Nature Med, 2009, and Gattinoni, L. et al. Nature Med, 2011). We have now developed a manufacturing procedure to generate clinical grade CD19-specific CAR modified TSCM cells (Sabatino, M et al. Blood, 2016) and initiated a phase I clinical trial for the treatment of patients with B cell malignancies refractory to prior allogeneic HSC transplantation (NCI-10-C-0054).
We have recently built a database containing global gene expression, microRNA and metabolomic profiles of TSCM cells compared to those of the well-characterized T cell subsets. This database is serving as a hypothesis generator to test transcription factors, microRNAs, and metabolic checkpoints involved in the induction and maintenance of ‘stemness’ in CD8+ T cells. Results from these studies will provide a framework for designing the next generation of T cell-based immunotherapies.
Selected Key Publications
- Nat Med. 23(1): 18-27, 2017. [ Journal Article ]
miR-155 augments CD8+ T-cell antitumor activity in lymphoreplete hosts by enhancing responsiveness to homeostatic γc cytokines.Proc Natl Acad Sci U S A. 112: 476-481, 2015. [ Journal Article ]
- J Clin Invest. 123: 4479-4488, 2013. [ Journal Article ]
Repression of the DNA-binding inhibitor Id3 by Blimp-1 limits the formation of memory CD8(+) T cells.Nat Immunol. 12: 1230-7, 2011. [ Journal Article ]
- Nat Med. 17: 1290-7, 2011. [ Journal Article ]
Dr. Gattinoni received his M.D. from the Universita' degli Studi of Milan, Italy. Following the completion of his residency in medical oncology at the Istituto Nazionale Tumori in Milan, he joined the NCI in 2003 as a Visiting Fellow and became a Staff Scientist in 2008. In 2013, Dr. Gattinoni was appointed as an Earl Stadtman Tenure-Track Investigator at the Experimental Transplantation and Immunology Branch. His honors include the 2004 SITC Presidential Award, the 2012 Wilson S. Stone Memorial Award and the 2013 NCI Director’s Intramural Innovation Award.
|Stephen Calderon||Postbaccalaureate Fellow (CRTA)|
|Jessica Fioravanti Ph.D.||Postdoctoral Fellow (Visiting)|
|Sanjivan Gautam Ph.D.||Postdoctoral Fellow (Visiting)|
|Jinhui Hu Ph.D.||Postdoctoral Fellow (Visiting)|
|Yun Ji, Ph.D.||Staff Scientist|
|Neal Lacey||Postbaccalaureate Fellow (CRTA)|
|John Le Gall M.D.||Clinical Fellow|