Description of Research Expertise
Research Interests
Elucidating the mechanistic basis of T cell dysfunction in human cancer; designing and testing the next generation of genetically-directed CAR T cells as immunotherapy for patients with cancer; epigenetic programming of immune cells; dissecting the signaling/molecular requirements for generation of effective memory and effector T cell responses
Keywords
Adoptive T cell therapy, cancer, chimeric antigen receptor (CAR), epigenetics, T cell dysfunction, immunotherapy biomarkers, tumor microenvironment, genome editing, cellular engineering, lymphoid leukemia, chronic lymphocytic leukemia, prostate cancer, pancreatic cancer, glioblastoma.
Research Summary
Research in the Fraietta laboratory focuses on the generation of innovative immunotherapy strategies involving T cells and their impact on immunity, tumor biology and the tissue/tumor microenvironment in the setting of translatable preclinical studies. We use primary patient samples, in vitro systems and cutting-edge animal models to 1) understand the factors and mechanisms associated with successful adoptive transfer of T cells, with the goal of improving the functions of both endogenous and gene-modified T cells, 2) develop mechanism-based strategies to enhance the survival, expansion and potency of infused T cell products directed against tumors and viral pathogens, and 3) devise methods to modulate the host immune environment to optimally activate T cells.
The current direction within the laboratory is to address both basic and clinical research questions on the role of human T cells in mediating effective anti-tumor immune responses. Our specific areas of interest are as follows:
Next-generation Synthetic Biology: We use a variety of genetic engineering approaches to redirect T cells to recognize and destroy tumors, while sparing healthy tissues. These efforts include the development of CARs and other synthetic immunoreceptors/signaling systems with more potent effector activity, enhanced durability and improved safety, compared to conventional cellular therapeutics. From these studies we have developed expertise in multiple aspects of genome editing to target the major mechanisms of resistance and toxicity in CAR T cell therapy, with the objective of increasing the efficacy of this already transformational approach.
Epigenetic Modulation of Immune Cell Function: Cell fate determination programs encoded in DNA are interpreted, modified, transmitted and expanded as chromatin. Memory and effector CD8+ T cell differentiation from naive precursors requires broad chromatin changes, leading to global or site-specific reprogramming of gene expression. The diversity of signals encountered by T cells requires a matching capacity for transcriptional outcomes provided by the dynamic nature of the epigenome. Important gaps remain in our understanding of the epigenetic landscape of functional and defective T cells in cancer. In this vein, our goals are to investigate epigenetic variation that influences the efficacy of CAR T cell immunotherapy, use epigenetic therapeutics to overcome resistance, identify genes that can be targeted for stable epigenetic programming and develop methods for modifying these programs to reinvigorate the cells in way that improves their anti-tumor potency. These efforts hold great promise for answering long-standing questions as well as generating the most robust antigen-specific T cells for highly effective adoptive cell transfer therapies.
Biomarkers of Response and Resistance to Cellular Immunotherapy: Our main endeavor in this area is the phenotypic and functional characterization of T cells directly isolated and expanded from cancer patients. We are also interested in determining how tumor antigen-specific lymphocytes in hematological malignancies and solid tumors change following CAR T cell infusion or treatment of patients with immunomodulatory agents. These efforts will elucidate the critical determinants of successful CAR T cell-mediated anti-tumor responses in individuals responding to the therapy, and may reveal several actionable ways to overcome resistance in subjects who do not respond. Such predictive biomarkers can be utilized by physicians to prescribe CAR T cell therapy only to the responding patient population, thus eliminating the unnecessary expense and risk of immune-related adverse events for non-responders. Given the intensive cell manufacturing process required for CAR T cell generation, the potential toxicity, and possible new alternative treatments, the ability to use immunological biomarkers to identify which patients are most likely to respond would greatly benefit these individuals and lead to an optimal personalized approach to therapy. Our investigations will ultimately allow us to intervene and generate maximally active CAR T cell products for most, if not all, future patients.
Rotation Projects
Please contact Dr. Fraietta concerning current rotation projects.
Laboratory Personnel (Alphabetical Order)
Alexander Dimitri, Ph.D. Student (DSRB)
Caitlin Hopkins, Ph.D. Student (GTV)
In-Young Jung, Ph.D. Student (GTV)
Weimin Kong, Ph.D., Staff Scientist
Julia Han Noll, Ph.D. Student (GTV)
Erik Williams, Research Specialist
Jennifer Bailey, Administrative Coordinator
Douglas Steiner, Business Administrator
Alumni
Steven Feins, Graduate Student
Anish Vora, Medical Student Intern
Selected Publications
Fraietta Joseph A, Nobles Christopher L, Sammons Morgan A, Lundh Stefan, Carty Shannon A, Reich Tyler J, Cogdill Alexandria P, Morrissette Jennifer J D, DeNizio Jamie E, Reddy Shantan, Hwang Young, Gohil Mercy, Kulikovskaya Irina, Nazimuddin Farzana, Gupta Minnal, Chen Fang, Everett John K, Alexander Katherine A, Lin-Shiao Enrique, Gee Marvin H, Liu Xiaojun, Young Regina M, Ambrose David, Wang Yan, Xu Jun, Jordan Martha S, Marcucci Katherine T, Levine Bruce L, Garcia K Christopher, Zhao Yangbing, Kalos Michael, Porter David L, Kohli Rahul M, Lacey Simon F, Berger Shelley L, Bushman Frederic D, June Carl H, Melenhorst J Joseph: Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature 558(7709): 307-312, May 2018. Ruella Marco, Xu Jun, Barrett David M, Fraietta Joseph A, Reich Tyler J, Ambrose David E, Klichinsky Michael, Shestova Olga, Patel Prachi R, Kulikovskaya Irina, Nazimuddin Farzana, Bhoj Vijay G, Orlando Elena J, Fry Terry J, Bitter Hans, Maude Shannon L, Levine Bruce L, Nobles Christopher L, Bushman Frederic D, Young Regina M, Scholler John, Gill Saar I, June Carl H, Grupp Stephan A, Lacey Simon F, Melenhorst J Joseph: Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell. Nature Medicine 24(10): 1499-1503, Oct 2018. Fraietta Joseph A, Lacey Simon F, Orlando Elena J, Pruteanu-Malinici Iulian, Gohil Mercy, Lundh Stefan, Boesteanu Alina C, Wang Yan, O'Connor Roddy S, Hwang Wei-Ting, Pequignot Edward, Ambrose David E, Zhang Changfeng, Wilcox Nicholas, Bedoya Felipe, Dorfmeier Corin, Chen Fang, Tian Lifeng, Parakandi Harit, Gupta Minnal, Young Regina M, Johnson F Brad, Kulikovskaya Irina, Liu Li, Xu Jun, Kassim Sadik H, Davis Megan M, Levine Bruce L, Frey Noelle V, Siegel Donald L, Huang Alexander C, Wherry E John, Bitter Hans, Brogdon Jennifer L, Porter David L, June Carl H, Melenhorst J Joseph: Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nature Medicine 24(5): 563-571, May 2018. Long Kristen B, Young Regina M, Boesteanu Alina C, Davis Megan M, Melenhorst J Joseph, Lacey Simon F, DeGaramo David A, Levine Bruce L, Fraietta Joseph A: CAR T cell therapy of non-hematopoietic malignancies: detours on the road to clinical success. Frontiers in Immunology 9: 2740, Dec 2018. Long Kristen B, Gladney Whitney L, Tooker Graham M, Graham Kathleen, Fraietta Joseph A, Beatty Gregory L: IFNγ and CCL2 cooperate to redirect tumor-infiltrating monocytes to degrade fibrosis and enhance chemotherapy efficacy in pancreatic carcinoma. Cancer Discovery 6(4): 400-413, Apr 2016. Kawalekar Omkar U, O'Connor Roddy S, Fraietta Joseph A, Guo Lili, McGettigan Shannon E, Posey Avery D, Patel Prachi R, Guedan Sonia, Scholler John, Keith Brian, Snyder Nathaniel W, Snyder Nathaniel, Blair Ian A, Blair Ian, Milone Michael C, June Carl H: Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells. Immunity 44(2): 380-90, Feb 2016. Fraietta Joseph A, Beckwith Kyle A, Patel Prachi R, Ruella Marco, Zheng Zhaohui, Barrett David M, Lacey Simon F, Melenhorst Jan Joseph, McGettigan Shannon E, Cook Danielle R, Zhang Changfeng, Xu Jun, Do Priscilla, Hulitt Jessica, Kudchodkar Sagar B, Cogdill Alexandria P, Gill Saar, Porter David L, Woyach Jennifer A, Long Meixiao, Johnson Amy J, Maddocks Kami, Muthusamy Natarajan, Levine Bruce L, June Carl H, Byrd John C, Maus Marcela V: Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia. Blood 127(9): 1117-27, Mar 2016. Johnson Laura A, Scholler John, Ohkuri Takayuki, Kosaka Akemi, Patel Prachi R, McGettigan Shannon E, Nace Arben K, Dentchev Tzvete, Thekkat Pramod, Loew Andreas, Boesteanu Alina C, Cogdill Alexandria P, Chen Taylor, Fraietta Joseph A, Kloss Christopher C, Posey Avery D, Engels Boris, Singh Reshma, Ezell Tucker, Idamakanti Neeraja, Ramones Melissa H, Li Na, Zhou Li, Plesa Gabriela, Seykora John T, Okada Hideho, June Carl H, Brogdon Jennifer L, Maus Marcela V: Rational development and characterization of humanized anti-EGFR variant III chimeric antigen receptor T cells for glioblastoma. Science Translational Medicine 7(275): 275ra22, Feb 2015. Fraietta Joseph A, Mueller Yvonne M, Yang Guibin, Boesteanu Alina C, Gracias Donald T, Do Duc H, Hope Jennifer L, Kathuria Noshin, McGettigan Shannon E, Lewis Mark G, Giavedoni Luis D, Jacobson Jeffrey M, Katsikis Peter D: Type I interferon upregulates Bak and contributes to T cell loss during human immunodeficiency virus (HIV) infection. PLoS Pathogens 9(10): e1003658, Oct 2013. Gracias Donald T, Stelekati Erietta, Hope Jennifer L, Boesteanu Alina C, Doering Travis A, Norton Jillian, Mueller Yvonne M, Fraietta Joseph A, Wherry E John, Turner Martin, Katsikis Peter D: The microRNA miR-155 controls CD8(+) T cell responses by regulating interferon signaling. Nature Immunology 14(6): 593-602, Jun 2013.
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Last updated: 05/02/2021
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