Abstract
Chimeric antigen receptor (CAR) T cell therapies are ex vivo manufactured cellular products that have been useful in the treatment of blood cancers and solid tumors. The quality of the final cellular product is influenced by several amenable factors during the manufacturing process. This review discusses several of the influences on cell product phenotype, including the raw starting material, methods of activation and transduction, and culture supplementation.
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References
Hinrichs CS, Borman ZA, Gattinoni L et al (2011) Human effector CD8+ T cells derived from naive rather than memory subsets possess superior traits for adoptive immunotherapy. Blood 117(3):808–814. https://doi.org/10.1182/blood-2010-05-286286
Berger C, Jensen MC, Lansdorp PM et al (2008) Adoptive transfer of effector CD8+ T cells derived from central memory cells establishes persistent T cell memory in primates. J Clin Invest 118(1):294–305. https://doi.org/10.1172/JCI32103
Gattinoni L, Lugli E, Ji Y et al (2011) A human memory T cell subset with stem cell-like properties. Nat Med 17(10):1290–1297. https://doi.org/10.1038/nm.2446
Hoffmann JM, Schubert ML, Wang L et al (2017) Differences in expansion potential of naive chimeric antigen receptor T cells from healthy donors and untreated chronic lymphocytic leukemia patients. Front Immunol 8:1956. https://doi.org/10.3389/fimmu.2017.01956
Kotani H, Li G, Yao J et al (2018) Aged CAR T cells exhibit enhanced cytotoxicity and effector function but shorter persistence and less memory-like phenotypes. Blood 132:2047. https://doi.org/10.1182/blood-2018-99-115351
Fraietta JA, Lacey SF, Orlando EJ et al (2018) Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat Med 24(5):563–571. https://doi.org/10.1038/s41591-018-0010-1
Wang X, Naranjo A, Brown CE, Bautista C, Wong CW, Chang WC, Aguilar B, Ostberg JR, Riddell SR, Forman SJ, Jensen MC (2012) Phenotypic and functional attributes of lentivirus-modified CD19-specific human CD8+ central memory T cells manufactured at clinical scale. J Immunother 35(9):689–701. https://doi.org/10.1097/CJI0b013e318270dec7
Wang X, Popplewell LL, Wagner JR et al (2016) Phase 1 studies of central memory-derived CD19 CAR T-cell therapy following autologous HSCT in patients with B-cell NHL. Blood 127(24):2980–2990. https://doi.org/10.1182/blood-2015-12-686725
Ruella M, Xu J, Barrett DM et al (2018) Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell. Nat Med 24(10):1499–1503. https://doi.org/10.1038/s41591-018-0201-9
Koksal H, Dillard P, Josefsson SE et al (2019) Preclinical development of CD37CAR T-cell therapy for treatment of B-cell lymphoma. Blood Adv 3(8):1230–1243. https://doi.org/10.1182/bloodadvances.2018029678
Long AH, Highfill SL, Cui Y et al (2016) Reduction of MDSCs with all-trans retinoic acid improves CAR therapy efficacy for sarcomas. Cancer Immunol Res 4(10):869–880. https://doi.org/10.1158/2326-6066.CIR-15-0230
Burga RA, Thorn M, Point GR et al (2015) Liver myeloid-derived suppressor cells expand in response to liver metastases in mice and inhibit the anti-tumor efficacy of anti-CEA CAR-T. Cancer Immunol Immunother 64(7):817–829. https://doi.org/10.1007/s00262-015-1692-6
Kunkele A, Brown C, Beebe A et al (2019) Manufacture of chimeric antigen receptor T cells from mobilized Cyropreserved peripheral blood stem cell units depends on monocyte depletion. Biol Blood Marrow Transplant 25(2):223–232. https://doi.org/10.1016/j.bbmt.2018.10.004
Stroncek DF, Lee DW, Ren J et al (2017) Elutriated lymphocytes for manufacturing chimeric antigen receptor T cells. J Transl Med 15(1):59. https://doi.org/10.1186/s12967-017-1160-5
Sommermeyer D, Hudecek M, Kosasih PL et al (2016) Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo. Leukemia 30(2):492–500. https://doi.org/10.1038/leu.2015.247
Smith-Garvin JE, Koretzky GA, Jordan MS (2009) T cell activation. Annu Rev Immunol 27:591–619. https://doi.org/10.1146/annurev.immunol.021908.132706
Acuto O, Michel F (2003) CD28-mediated co-stimulation: a quantitative support for TCR signalling. Nat Rev Immunol 3(12):939–951. https://doi.org/10.1038/nri1248
Paulos CM, Carpenito C, Plesa G et al (2010) The inducible costimulator (ICOS) is critical for the development of human T(H)17 cells. Sci Transl med 2(55):55ra78. https://doi.org/10.1126/scitranslmed.3000448
McKinney EF, Lee JC, Jayne DR et al (2015) T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection. Nature 523(7562):612–616. https://doi.org/10.1038/nature14468
Kalamasz D, Long SA, Taniguchi R et al (2004) Optimization of human T-cell expansion ex vivo using magnetic beads conjugated with anti-CD3 and anti-CD28 antibodies. J Immunother 27(5):405–418
Amirache F, Levy C, Costa C et al (2014) Mystery solved: VSV-G-LVs do not allow efficient gene transfer into unstimulated T cells, B cells, and HSCs because they lack the LDL receptor. Blood 123(9):1422–1424. https://doi.org/10.1182/blood-2013-11-540641
Gabriel R, Schmidt M, von Kalle C (2012) Integration of retroviral vectors. Curr Opin Immunol 24(5):592–597. https://doi.org/10.1016/j.coi.2012.08.006
Schambach A, Zychlinski D, Ehrnstroem B, Baum C (2013) Biosafety features of lentiviral vectors. Hum Gene Ther 24(2):132–142. https://doi.org/10.1089/hum.2012.229
Fraietta JA, Nobles CL, Sammons MA et al (2018) Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature 558(7709):307–312. https://doi.org/10.1038/s41586-018-0178-z
Long AH, Haso WM, Shern JF et al (2015) 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med 21(6):581–590. https://doi.org/10.1038/nm.3838
Gomes-Silva D, Mukherjee M, Srinivasan M et al (2017) Tonic 4-1BB Costimulation in chimeric antigen receptors impedes T cell survival and is vector-dependent. Cell Rep 21(1):17–26. https://doi.org/10.1016/j.celrep.2017.09.015
Mamonkin M, Mukherjee M, Srinivasan M et al (2018) Reversible transgene expression reduces fratricide and permits 4-1BB costimulation of CAR T cells directed to T-cell malignancies. Cancer Immunol Res 6(1):47–58. https://doi.org/10.1158/2326-6066.CIR-17-0126
Kawalekar OU, O'Connor RS, Fraietta JA et al (2016) Distinct signaling of Coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity 44(3):712. https://doi.org/10.1016/j.immuni.2016.02.023
Wilkie S, Burbridge SE, Chiapero-Stanke L et al (2010) Selective expansion of chimeric antigen receptor-targeted T-cells with potent effector function using interleukin-4. J Biol Chem 285(33):25538–25544. https://doi.org/10.1074/jbc.M110.127951
Mohammed S, Sukumaran S, Bajgain P et al (2017) Improving chimeric antigen receptor-modified T cell function by reversing the immunosuppressive tumor microenvironment of pancreatic cancer. Mol Ther 25(1):249–258. https://doi.org/10.1016/j.ymthe.2016.10.016
Tschumi BO, Dumauthioz N, Marti B et al (2018) CART cells are prone to Fas- and DR5-mediated cell death. J Immunother Cancer 6(1):71. https://doi.org/10.1186/s40425-018-0385-z
Yamamoto TN, Lee PH, Vodnala SK, Gurusamy D, Kishton RJ, Yu Z, Eidizadeh A, Eil R, Fioravanti J, Gattinoni L, Kochenderfer JN, Fry TJ, Aksoy BA, Hammerbacher JE, Cruz AC, Siegel RM, Restifo NP, Klebanoff CA (2019) T cells genetically engineered to overcome death signaling enhance adoptive cancer immunotherapy. J Clin Invest 129(4):1551–1565. https://doi.org/10.1172/JCI121491
Fowler DH, Breglio J, Nagel G et al (1996) Allospecific CD8+ Tc1 and Tc2 populations in graft-versus-leukemia effect and graft-versus-host disease. J Immunol 157(11):4811–4821
van der Windt GJ, Pearce EL (2012) Metabolic switching and fuel choice during T-cell differentiation and memory development. Immunol Rev 249(1):27–42. https://doi.org/10.1111/j.1600-065X.2012.01150.x
Kaartinen T, Luostarinen A, Maliniemi P et al (2017) Low interleukin-2 concentration favors generation of early memory T cells over effector phenotypes during chimeric antigen receptor T-cell expansion. Cytotherapy 19(6):689–702. https://doi.org/10.1016/j.jcyt.2017.03.067
Zhang X, Lv X, Song Y (2018) Short-term culture with IL-2 is beneficial for potent memory chimeric antigen receptor T cell production. Biochem Biophys Res Commun 495(2):1833–1838. https://doi.org/10.1016/j.bbrc.2017.12.041
Schluns KS, Kieper WC, Jameson SC, Lefrancois L (2000) Interleukin-7 mediates the homeostasis of naive and memory CD8 T cells in vivo. Nat Immunol 1(5):426–432. https://doi.org/10.1038/80868
van der Windt GJ, Everts B, Chang CH et al (2012) Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 36(1):68–78. https://doi.org/10.1016/j.immuni.2011.12.007
Gargett T, Brown MP (2015) Different cytokine and stimulation conditions influence the expansion and immune phenotype of third-generation chimeric antigen receptor T cells specific for tumor antigen GD2. Cytotherapy 17(4):487–495. https://doi.org/10.1016/j.jcyt.2014.12.002
Gattinoni L, Zhong XS, Palmer DC et al (2009) Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nat Med 15(7):808–813. https://doi.org/10.1038/nm.1982
Gattinoni L, Ji Y, Restifo NP (2010) Wnt/beta-catenin signaling in T-cell immunity and cancer immunotherapy. Clin Cancer Res 16(19):4695–4701. https://doi.org/10.1158/1078-0432.CCR-10-0356
Kim EH, Suresh M (2013) Role of PI3K/Akt signaling in memory CD8 T cell differentiation. Front Immunol 4:20. https://doi.org/10.3389/fimmu.2013.00020
Zheng W, O'Hear CE, Alli R, Basham JH, Abdelsamed HA, Palmer LE, Jones LL, Youngblood B, Geiger TL (2018) PI3K orchestration of the in vivo persistence of chimeric antigen receptor-modified T cells. Leukemia 32(5):1157–1167. https://doi.org/10.1038/s41375-017-0008-6
Rao RR, Li Q, Odunsi K, Shrikant PA (2010) The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T-bet and Eomesodermin. Immunity 32(1):67–78. https://doi.org/10.1016/j.immuni.2009.10.010
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Schwab, R.D., Bedoya, D.M., King, T.R., Levine, B.L., Posey, A.D. (2020). Approaches of T Cell Activation and Differentiation for CAR-T Cell Therapies. In: Swiech, K., Malmegrim, K., Picanço-Castro, V. (eds) Chimeric Antigen Receptor T Cells. Methods in Molecular Biology, vol 2086. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-0146-4_15
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DOI: https://doi.org/10.1007/978-1-0716-0146-4_15
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