Joseph A. Fraietta, Ph.D.

faculty photo
Assistant Professor of Microbiology
Department: Microbiology
Graduate Group Affiliations

Contact information
Center for Cellular Immunotherapies
Perelman Center for Advanced Medicine South Tower (SPE)
University of Pennsylvania
3400 Civic Center Boulevard
Laboratory: 9-309 Office: 9-104
Website: https://hosting.med.upenn.edu/fraietta-lab/
Philadelphia, PA 19104-5156
Office: 215-746-4083
Fax: 215-573-8590
Lab: 215-573-1880
B.S. (Bioscience and Biotechnology )
Drexel University (Mary K. Howett, mentor), 2007.
Ph.D. (Microbiology and Immunology)
Drexel University College of Medicine (Peter D. Katsikis, mentor), 2012.
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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

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
The Fraietta Laboratory pioneers immunotherapy strategies, emphasizing the role of T cells in immunity, tumor biology, and host-cancer interactions. We use patient samples, advanced in vitro systems, and sophisticated animal models to enhance the functionality and adoptive transfer of T cells, whether endogenous or gene-modified. We aim to augment the potency of T cells against tumors and viral pathogens, while innovating techniques to optimize the immune environment for T cell activation.

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. These efforts include the development of CARs and other synthetic immunoreceptors 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. Notably, our laboratory co-led the groundbreaking study that pioneered the introduction of multiplex CRISPR/Cas9-edited T cells into humans for the first time.

Epigenetic Modulation of Immune Cell Function: Differentiation from naive precursors to memory and effector CD8+ T cells entails comprehensive chromatin modifications and gene expression reprogramming. Despite this, our understanding of the epigenetic landscape of functional and defective T cells in cancer remains incomplete. Our lab, which first demonstrated that a single epigenetically programmed CAR T cell could induce long-term remission in a patient with chronic lymphocytic leukemia, continues to explore this frontier. We investigate epigenetic influences on CAR T cell immunotherapy, harness epigenetic therapeutics to tackle resistance, and target genes for stable epigenetic programming to boost anti-tumor efficacy. This work holds promise for generating more potent antigen-specific T cells, thus enhancing adoptive cell transfer therapies.

Biomarkers of Response and Resistance to Cellular Immunotherapy: Our research in this area aims to identify critical factors for successful CAR T cell-mediated responses and to develop strategies for overcoming resistance in non-responsive subjects. These findings could lead to predictive biomarkers that guide CAR T cell therapy application, minimizing unnecessary costs and risks for non-responders. Given the complexities of CAR T cell generation and potential toxicity, identifying responsive patients can optimize personalized treatment. In support of these goals, Dr. Fraietta directs the Translational and Correlative Sciences Laboratory (TCSL) in the Center for Cellular Immunotherapies, where a primary objective is to translate these findings into actionable therapeutic strategies.

Rotation Projects
Please contact Dr. Fraietta concerning current rotation projects.

Laboratory Personnel
Gregory Chen, M.D., Ph.D. (Post-doctoral Fellow)
Fengjuan (Jane) Zhang, Ph.D. (Post-doctoral Fellow)
Ángel Ramírez-Fernández, PharmD., Ph.D. (Post-doctoral Fellow)
Caitlin Hopkins (Ph.D. Student)
Alexander Dimitri (Ph.D. Student)
Julia Han Noll (Ph.D. Student)
Erik Williams (Ph.D. Student)
Owen Koucky (Ph.D. Student)
Robert Bartoszek (Research Specialist)
Maya Lavorando (Research Specialist)
Kevin Amses, Ph.D. (Collaborative Bioinformatician)
Brittney Wilson (Administrative Coordinator)
Derrick Bowman (Business Administrator)

Laboratory Alumni
In-Young (Ethan) Jung, Ph.D.
Weimin Kong, Ph.D.

Selected Publications

Jung IY, Bartoszek RL, Rech AJ, Collins SM, Ooi SK, Williams EF, Hopkins CR, Narayan V, Haas NB, Frey NV, Hexner EO, Siegel DL, Plesa G, Porter DL, Cantu A, Everett JK, Guedan S, Berger SL, Bushman FD, Herbst F, Fraietta JA.: Type I Interferon Signaling via the EGR2 Transcriptional Regulator Potentiates CAR T Cell-Intrinsic Dysfunction. Cancer Discov 13: 1636-1655, Jul 2023.

Jung IY, Noguera-Ortega E, Bartoszek R, Collins SM, Williams E, Davis M, Jadlowsky JK, Plesa G, Siegel DL, Chew A, Levine BL, Berger SL, Moon EK, Albelda SM, Fraietta JA.: Tissue-resident memory CAR T cells with stem-like characteristics display enhanced efficacy against solid and liquid tumors. Cell Rep Med 4: 101053, Jun 2023.

Jung IY, Narayan V, McDonald S, Rech AJ, Bartoszek R, Hong G, Davis MM, Xu J, Boesteanu AC, Barber-Rotenberg JS, Plesa G, Lacey SF, Jadlowsky JK, Siegel DL, Hammill DM, Cho-Park PF, Berger SL, Haas NB, Fraietta JA.: BLIMP1 and NR4A3 transcription factors reciprocally regulate antitumor CAR T cell stemness and exhaustion. Sci Transl Med 14: eabn7336, Nov 2022.

Narayan V, Barber-Rotenberg JS, Jung IY, Lacey SF, Rech AJ, Davis MM, Hwang WT, Lal P, Carpenter EL, Maude SL, Plesa G, Vapiwala N, Chew A, Moniak M, Sebro RA, Farwell MD, Marshall A, Gilmore J, Lledo L, Dengel K, Church SE, Hether TD, Xu J, Gohil M, Buckingham TH, Yee SS, Gonzalez VE, Kulikovskaya I, Chen F, Tian L, Tien K, Gladney W, Nobles CL, Raymond HE; Prostate Cancer Cellular Therapy Program Investigators; Hexner EO, Siegel DL, Bushman FD, June CH, Fraietta JA,* Haas NB.* *Co-corresponding author; authors contributed equally. : PSMA-targeting TGFβ-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1 trial. Nat Med 2022.

Kong W, Dimitri A, Wang W, Jung IY, Ott CJ, Fasolino M, Wang Y, Kulikovskaya I, Gupta M, Yoder T, DeNizio JE, Everett JK, Williams EF, Xu J, Scholler J, Reich TJ, Bhoj VG, Haines KM, Maus MV, Melenhorst JJ, Young RM, Jadlowsky JK, Marcucci KT, Bradner JE, Levine BL, Porter DL, Bushman FD, Kohli RM, June CH, Davis MM, Lacey SF, Vahedi G, Fraietta JA.: BET bromodomain protein inhibition reverses chimeric antigen receptor extinction and reinvigorates exhausted T cells in chronic lymphocytic leukemia. J Clin Invest 131: e145459, Aug 2021.

Stadtmauer EA*, Fraietta JA*, Davis MM, Cohen AD, Weber KL, Lancaster E, Mangan PA, Kulikovskaya I, Gupta M, Chen F, Tian L, Gonzalez VE, Xu J, Jung IY, Melenhorst JJ, Plesa G, Shea J, Matlawski T, Cervini A, Gaymon AL, Desjardins S, Lamontagne A, Salas-Mckee J, Fesnak A, Siegel DL, Levine BL, Jadlowsky JK, Young RM, Chew A, Hwang WT, Hexner EO, Carreno BM, Nobles CL, Bushman FD, Parker KR, Qi Y, Satpathy AT, Chang HY, Zhao Y, Lacey SF, June CH. *Co-first author; authors contributed equally. : CRISPR-engineered T cells in patients with refractory cancer. Science 367: eaba7365, Feb 2020.

Fraietta, J.A., Beckwith, K.A., Patel, P.R., Ruella, M., Zheng, Z., Barrett, D.M., Lacey, S.F., Melenhorst, J.J., McGettigan, S.E., Cook, D.R., Zhang, C., Xu, J., Do, P., Hulitt, J., Kudchodkar, S.B., Cogdill, A.P., Gill, S., Porter, D.L., Woyach, J.A., Long, M., Johnson, A.J., Maddocks, K., Muthusamy, N., Levine, B.L., June, C.H., Byrd, J.C., Maus, M.V.: Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia. Blood 127(9): 1117-27, Mar 2016.

Fraietta, J.A., Lacey, S.F., Orlando, E.J., Pruteanu-Malinici, I., Gohil, M., Lundh, S., Boesteanu, A.C., Wang, Y., O'Connor, R.S., Hwang, W.-T., Pequignot, E., Ambrose, D.E., Zhang, C., Wilcox, N., Bedoya, F., Dorfmeier, C., Chen, F., Tian, L., Parakandi, H., Gupta, M., Young, R.M., Johnson, F.B., Kulikovskaya, I., Liu, L., Xu, J., Kassim, S.H., Davis, M.M., Levine, B.L., Frey, N.V., Siegel, D.L., Huang, A.C., Wherry, E.J., Bitter, H., Brogdon, J.L., Porter, D.L., June, C.H., Melenhorst, J.J.: 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.

Fraietta, J.A., Nobles, C.L., Sammons, M.A., Lundh, S., Carty, S.A., Reich, T.J., Cogdill, A.P., Morrissette, J.J.D., DeNizio, J.E., Reddy, S., Hwang, Y., Gohil, M., Kulikovskaya, I., Nazimuddin, F., Gupta, M., Chen, F., Everett, J.K., Alexander, K.A., Lin-Shiao, E., Gee, M.H., Liu, X., Young, R.M., Ambrose, D., Wang, Y., Xu, J., Jordan, M.S., Marcucci, K.T., Levine, B.L., Garcia, K.C., Zhao, Y., Kalos, M., Porter, D,L., Kohli, R.M., Lacey, S.F., Berger, S.L., Bushman, F.D., June, C.H., Melenhorst, J.J.: Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature 558(7709): 307-312, May 2018.

Feins S, Kong W, Williams EF, Milone MC, Fraietta JA.: An introduction to chimeric antigen receptor (CAR) T-cell immunotherapy for human cancer. Am J Hematol 94: S3-S9, May 2019.

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Last updated: 01/30/2024
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