Justin Eyquem, PhD, MS
Assistant Professor
Medicine
School of Medicine
Adoptive T cell therapy, in which antigen-specific T cells are generated ex vivo and transferred back into patients, is a promising strategy to treat cancer. Although CD19-targeting chimeric antigen receptor (CAR) T cells have shown remarkable results against acute lymphoblastic leukemia (ALL), many aspects of this technology remain to be improved.
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Regarding the therapeutic challenges, relapses have been observed in a large proportion of patients, many whose tumors expressed very low levels of target antigen. Second, clinical results remain poor in solid tumors, notably due to the lack of ideal targets, inefficient homing to the tumor site, limited T cell persistence and T cell dysfunction. Third, CAR therapies have been associated with toxicities, such as cytokine release syndrome (CRS) or cerebral edema. On the manufacturing side, the wide implementation of T cell therapy is limited by the use of randomly integrating vectors in autologous patient cells, which involves high cost and unavoidably a high variability of the final product.
Our laboratory is aimed at understanding the current limitations of CAR T cell therapy using innovative tumor models and functional genomics and overcoming these challenges by reprogramming T cells with the use of genome editing and synthetic receptors.
Active projects:
1) High Throughput Tool Development for Accelerated CAR Engineering Recent studies have determined that not all CARs are created equal in terms of effector function, persistence, and antigen sensitivity. Our laboratory has developed powerful T cell editing tools which allow for high throughput screening of CAR constructs, as well as discovery of new CAR architectures with augmented effector functions, persistence and sensitivity to antigen density
2) Immunobiology of CAR T Cells in Solid Tumors CAR T cells have shown poor therapeutic efficacy in solid tumors. To understand the challenges CAR T cells are facing in solid tumors we need mouse models that effectively recapitulate the complexities of the tumor microenvironment. Our lab is developing improved mouse models to investigate the interaction of CAR T cells with the different components of the solid tumor microenvironment and to identify mechanisms by which solid tumors induce dysfunction in CAR T cells.
3) Improvement of Gene-Edited Immune Cell Manufacturing for Clinical Trials As immunotherapeutic strategies move toward more complex engineering and multiplexed editing, there is a growing need to optimize the manufacturing of CAR-engineered cells for the clinic. Our laboratory is focused on bolstering the efficiency of CAR T cell enrichment, improving the precision of T cell editing using novel tools developed in the lab. Finally, we are expanding our technologies to other immune cells and are optimizing gene editing protocols and CAR designs for NK cells.
Education & Training
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- Postdoc in T cell engineering MSKCC 01/2019
- PhD Immunology University Paris Diderot 02/2014
- MS BioEngineering AgroParisTech 06/2010
- MS Genetics University Paris Diderot 06/2010
- BS Biology University Bordeaux 06/2006
Websites
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- Eyquem Lab website (eyquemlab.org)
Publications (29)
Top publication keywords:
ImmunotherapyAntigens, NeoplasmReceptors, Antigen, T-CellPrecursor Cell Lymphoblastic Leukemia-LymphomaGenetic EngineeringLeukemia, Myeloid, AcuteAntigens, CD19DependovirusT-LymphocytesCRISPR-Cas SystemsGene TargetingImmunotherapy, AdoptiveTransgenesGene EditingMutagenesis, Insertional
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RASA2 ablation in T cells boosts antigen sensitivity and long-term function.
Nature 2022 Carnevale J, Shifrut E, Kale N, Nyberg WA, Blaeschke F, Chen YY, Li Z, Bapat SP, Diolaiti ME, O'Leary P, Vedova S, Belk J, Daniel B, Roth TL, Bachl S, Anido AA, Prinzing B, Ibañez-Vega J, Lange S, … -
Calibration of CAR activation potential directs alternative T cell fates and therapeutic potency.
Nature medicine 2018 Feucht J, Sun J, Eyquem J, Ho YJ, Zhao Z, Leibold J, Dobrin A, Cabriolu A, Hamieh M, Sadelain M -
Characterization of three loci for homologous gene targeting and transgene expression.
Biotechnology and bioengineering 2013 Eyquem J, Poirot L, Galetto R, Scharenberg AM, Smith J -
Author Correction: Generation of T-cell-receptor-negative CD8αβ-positive CAR T cells from T-cell-derived induced pluripotent stem cells.
Nature biomedical engineering 2024 van der Stegen SJC, Lindenbergh PL, Petrovic RM, Xie H, Diop MP, Alexeeva V, Shi Y, Mansilla-Soto J, Hamieh M, Eyquem J, Cabriolu A, Wang X, Abujarour R, Lee T, Clarke R, Valamehr B, Themeli M, … -
Ultra-high efficiency T cell reprogramming at multiple loci with SEED-Selection.
bioRxiv : the preprint server for biology 2024 Chang CR, Vykunta VS, Goodman DB, Muldoon JJ, Nyberg WA, Liu C, Allain V, Rothrock A, Wang CH, Marson A, Shy BR, Eyquem J
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Base-editing mutagenesis maps alleles to tune human T cell functions.
Nature 2023 Schmidt R, Ward CC, Dajani R, Armour-Garb Z, Ota M, Allain V, Hernandez R, Layeghi M, Xing G, Goudy L, Dorovskyi D, Wang C, Chen YY, Ye CJ, Shy BR, Gilbert LA, Eyquem J, Pritchard JK, Dodgson SE, … -
Structural surfaceomics reveals an AML-specific conformation of integrin β2 as a CAR T cellular therapy target.
Nature cancer 2023 Mandal K, Wicaksono G, Yu C, Adams JJ, Hoopmann MR, Temple WC, Izgutdina A, Escobar BP, Gorelik M, Ihling CH, Nix MA, Naik A, Xie WH, Hübner J, Rollins LA, Reid SM, Ramos E, Kasap C, Steri V, Serrano … -
Mitigation of chromosome loss in clinical CRISPR-Cas9-engineered T cells.
Cell 2023 Tsuchida CA, Brandes N, Bueno R, Trinidad M, Mazumder T, Yu B, Hwang B, Chang C, Liu J, Sun Y, Hopkins CR, Parker KR, Qi Y, Hofman L, Satpathy AT, Stadtmauer EA, Cate JHD, Eyquem J, Fraietta JA, June … -
Modular pooled discovery of synthetic knockin sequences to program durable cell therapies.
Cell 2023 Blaeschke F, Chen YY, Apathy R, Daniel B, Chen AY, Chen PA, Sandor K, Zhang W, Li Z, Mowery CT, Yamamoto TN, Nyberg WA, To A, Yu R, Bueno R, Kim MC, Schmidt R, Goodman DB, Feuchtinger T, Eyquem J, … -
Novel extragenic genomic safe harbors for precise therapeutic T-cell engineering.
Blood 2023 Odak A, Yuan H, Feucht J, Cantu VA, Mansilla-Soto J, Kogel F, Eyquem J, Everett J, Bushman FD, Leslie CS, Sadelain M -
Peptide-mediated delivery of CRISPR enzymes for the efficient editing of primary human lymphocytes.
Nature biomedical engineering 2023 Foss DV, Muldoon JJ, Nguyen DN, Carr D, Sahu SU, Hunsinger JM, Wyman SK, Krishnappa N, Mendonsa R, Schanzer EV, Shy BR, Vykunta VS, Allain V, Li Z, Marson A, Eyquem J, Wilson RC -
Mitigation of chromosome loss in clinical CRISPR-Cas9-engineered T cells.
bioRxiv : the preprint server for biology 2023 Tsuchida CA, Brandes N, Bueno R, Trinidad M, Mazumder T, Yu B, Hwang B, Chang C, Liu J, Sun Y, Hopkins CR, Parker KR, Qi Y, Satpathy AT, Stadtmauer EA, Cate JHD, Eyquem J, Fraietta JA, June CH, Chang … -
An evolved AAV variant enables efficient genetic engineering of murine T cells.
Cell 2023 Nyberg WA, Ark J, To A, Clouden S, Reeder G, Muldoon JJ, Chung JY, Xie WH, Allain V, Steinhart Z, Chang C, Talbot A, Kim S, Rosales A, Havlik LP, Pimentel H, Asokan A, Eyquem J -
Pooled screening of CAR T cells identifies diverse immune signaling domains for next-generation immunotherapies.
Science translational medicine 2022 Goodman DB, Azimi CS, Kearns K, Talbot A, Garakani K, Garcia J, Patel N, Hwang B, Lee D, Park E, Vykunta VS, Shy BR, Ye CJ, Eyquem J, Marson A, Bluestone JA, Roybal KT -
NUDT21 limits CD19 levels through alternative mRNA polyadenylation in B cell acute lymphoblastic leukemia.
Nature immunology 2022 Witkowski MT, Lee S, Wang E, Lee AK, Talbot A, Ma C, Tsopoulidis N, Brumbaugh J, Zhao Y, Roberts KG, Hogg SJ, Nomikou S, Ghebrechristos YE, Thandapani P, Mullighan CG, Hochedlinger K, Chen W, Abdel-… -
High-yield genome engineering in primary cells using a hybrid ssDNA repair template and small-molecule cocktails.
Nature biotechnology 2022 Shy BR, Vykunta VS, Ha A, Talbot A, Roth TL, Nguyen DN, Pfeifer WG, Chen YY, Blaeschke F, Shifrut E, Vedova S, Mamedov MR, Chung JJ, Li H, Yu R, Wu D, Wolf J, Martin TG, Castro CE, Ye L, Esensten JH, … -
Generation of T-cell-receptor-negative CD8αβ-positive CAR T cells from T-cell-derived induced pluripotent stem cells.
Nature biomedical engineering 2022 van der Stegen SJC, Lindenbergh PL, Petrovic RM, Xie H, Diop MP, Alexeeva V, Shi Y, Mansilla-Soto J, Hamieh M, Eyquem J, Cabriolu A, Wang X, Abujarour R, Lee T, Clarke R, Valamehr B, Themeli M, … -
The surfaceome of multiple myeloma cells suggests potential immunotherapeutic strategies and protein markers of drug resistance.
Nature communications 2022 Ferguson ID, Patiño-Escobar B, Tuomivaara ST, Lin YT, Nix MA, Leung KK, Kasap C, Ramos E, Nieves Vasquez W, Talbot A, Hale M, Naik A, Kishishita A, Choudhry P, Lopez-Girona A, Miao W, Wong SW, Wolf JL… -
HLA-independent T cell receptors for targeting tumors with low antigen density.
Nature medicine 2022 Mansilla-Soto J, Eyquem J, Haubner S, Hamieh M, Feucht J, Paillon N, Zucchetti AE, Li Z, Sjöstrand M, Lindenbergh PL, Saetersmoen M, Dobrin A, Maurin M, Iyer A, Garcia Angus A, Miele MM, Zhao Z, … -
The CD28-Transmembrane Domain Mediates Chimeric Antigen Receptor Heterodimerization With CD28.
Frontiers in immunology 2021 Muller YD, Nguyen DP, Ferreira LMR, Ho P, Raffin C, Valencia RVB, Congrave-Wilson Z, Roth TL, Eyquem J, Van Gool F, Marson A, Perez L, Wells JA, Bluestone JA, Tang Q -
CAR T cell trogocytosis and cooperative killing regulate tumour antigen escape.
Nature 2019 Hamieh M, Dobrin A, Cabriolu A, van der Stegen SJC, Giavridis T, Mansilla-Soto J, Eyquem J, Zhao Z, Whitlock BM, Miele MM, Li Z, Cunanan KM, Huse M, Hendrickson RC, Wang X, Rivière I, Sadelain M -
Publisher Correction: Calibration of CAR activation potential directs alternative T cell fates and therapeutic potency.
Nature medicine 2019 Feucht J, Sun J, Eyquem J, Ho YJ, Zhao Z, Leibold J, Dobrin A, Cabriolu A, Hamieh M, Sadelain M -
Low-Dose Radiation Conditioning Enables CAR T Cells to Mitigate Antigen Escape.
Molecular therapy : the journal of the American Society of Gene Therapy 2018 DeSelm C, Palomba ML, Yahalom J, Hamieh M, Eyquem J, Rajasekhar VK, Sadelain M -
Antibody with Infinite Affinity for In Vivo Tracking of Genetically Engineered Lymphocytes.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine 2018 Krebs S, Ahad A, Carter LM, Eyquem J, Brand C, Bell M, Ponomarev V, Reiner T, Meares CF, Gottschalk S, Sadelain M, Larson SM, Weber WA -
CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade.
Nature medicine 2018 Giavridis T, van der Stegen SJC, Eyquem J, Hamieh M, Piersigilli A, Sadelain M -
Integrating Proteomics and Transcriptomics for Systematic Combinatorial Chimeric Antigen Receptor Therapy of AML.
Cancer cell 2017 Perna F, Berman SH, Soni RK, Mansilla-Soto J, Eyquem J, Hamieh M, Hendrickson RC, Brennan CW, Sadelain M -
Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection.
Nature 2017 Eyquem J, Mansilla-Soto J, Giavridis T, van der Stegen SJ, Hamieh M, Cunanan KM, Odak A, Gönen M, Sadelain M -
Multiplex Genome-Edited T-cell Manufacturing Platform for "Off-the-Shelf" Adoptive T-cell Immunotherapies.
Cancer research 2015 Poirot L, Philip B, Schiffer-Mannioui C, Le Clerre D, Chion-Sotinel I, Derniame S, Potrel P, Bas C, Lemaire L, Galetto R, Lebuhotel C, Eyquem J, Cheung GW, Duclert A, Gouble A, Arnould S, Peggs K, … -
A platform for rapid prototyping of synthetic gene networks in mammalian cells.
Nucleic acids research 2014 Duportet X, Wroblewska L, Guye P, Li Y, Eyquem J, Rieders J, Rimchala T, Batt G, Weiss R