Abstract
The survival of patients with hematological malignancies has been significantly improved due to the development of new therapeutic agents. However, relapse remains a major matter for concern. Recently, T cells engineered with chimeric antigen receptor (CAR) were reported to show unprecedented responses in a range of hematological malignancies. The persistence of the CAR-T cell can last for years and tends toward long-term antitumor memory by which relapses can be effectively prevented. The primary side effects that appear in most clinical trials are cytokine release syndrome and neurotoxicity. However, these symptoms can be treated and reversed. In this review, we describe CAR structure and function and summarize recent advances in CAR-T cell therapy in hematological malignancies.
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Brentjens, R., Yeh, R., Bernal, Y., Riviere, I., and Sadelain, M. (2010). Treatment of chronic lymphocytic leukemia with genetically targeted autologous T cells: case report of an unforeseen adverse event in a phase I clinical trial. Mol Ther 18, 666–668.
Brentjens, R.J., Davila, M.L., Riviere, I., Park, J., Wang, X., Cowell, L.G., Bartido, S., Stefanski, J., Taylor, C., Olszewska, M., Borquez-Ojeda, O., Qu, J., Wasielewska, T., He, Q., Bernal, Y., Rijo, I.V., Hedvat, C., Kobos, R., Curran, K., Steinherz, P., Jurcic, J., Rosenblat, T., Maslak, P., Frattini, M., and Sadelain, M. (2013). CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med 5, 177ra138.
Brentjens, R.J., Riviere, I., Park, J.H., Davila, M.L., Wang, X., Stefanski, J., Taylor, C., Yeh, R., Bartido, S., Borquez-Ojeda, O., Olszewska, M., Bernal, Y., Pegram, H., Przybylowski, M., Hollyman, D., Usachenko, Y., Pirraglia, D., Hosey, J., Santos, E., Halton, E., Maslak, P., Scheinberg, D., Jurcic, J., Heaney, M., Heller, G., Frattini, M., and Sadelain, M. (2011). Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood 118, 4817–4828.
Brentjens, R.J., Santos, E., Nikhamin, Y., Yeh, R., Matsushita, M., La Perle, K., Quintas-Cardama, A., Larson, S.M., and Sadelain, M. (2007). Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts. Clin Cancer Res 13, 5426–5435.
Carpenito, C., Milone, M.C., Hassan, R., Simonet, J.C., Lakhal, M., Suhoski, M.M., Varela-Rohena, A., Haines, K.M., Heitjan, D.F., Albelda, S.M., Carroll, R.G., Riley, J.L., Pastan, I., and June, C.H. (2009). Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proc Natl Acad Sci USA 106, 3360–3365.
Caserta, S., Alessi, P., Basso, V., and Mondino, A. (2010). IL-7 is superior to IL-2 for ex vivo expansion of tumour-specific CD4+ T cells. Eur J Immunol 40, 470–479.
Cruz, C.R., Micklethwaite, K.P., Savoldo, B., Ramos, C.A., Lam, S., Ku, S., Diouf, O., Liu, E., Barrett, A.J., Ito, S., Shpall, E.J., Krance, R.A., Kamble, R.T., Carrum, G., Hosing, C.M., Gee, A.P., Mei, Z., Grilley, B.J., Heslop, H.E., Rooney, C.M., Brenner, M.K., Bollard, C.M., and Dotti, G. (2013). Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study. Blood 122, 2965–2973.
Cui, Y., Zhang, H., Meadors, J., Poon, R., Guimond, M., and Mackall, C.L. (2009). Harnessing the physiology of lymphopenia to support adoptive immunotherapy in lymphoreplete hosts. Blood 114, 3831–3840.
Curran, K.J., Seinstra, B.A., Nikhamin, Y., Yeh, R., Usachenko, Y., van Leeuwen, D.G., Purdon, T., Pegram, H.J., and Brentjens, R.J. (2015). Enhancing antitumor efficacy of chimeric antigen receptor T cells through constitutive CD40L expression. Mol Ther 23, 769–778.
Davila, M.L., Riviere, I., Wang, X., Bartido, S., Park, J., Curran, K., Chung, S.S., Stefanski, J., Borquez-Ojeda, O., Olszewska, M., Qu, J., Wasielewska, T., He, Q., Fink, M., Shinglot, H., Youssif, M., Satter, M., Wang, Y., Hosey, J., Quintanilla, H., Halton, E., Bernal, Y., Bouhassira, D.C., Arcila, M.E., Gonen, M., Roboz, G.J., Maslak, P., Douer, D., Frattini, M.G., Giralt, S., Sadelain, M., and Brentjens, R. (2014). Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med 6, 224ra225.
Dohner, H., Fischer, K., Bentz, M., Hansen, K., Benner, A., Cabot, G., Diehl, D., Schlenk, R., Coy, J., Stilgenbauer, S., Volkmann, M., Galle, P.R., Poustka, A., Hunstein, W., and Lichter, P. (1995). p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias. Blood 85, 1580–1589.
Foon, K.A., Sherwin, S.A., Abrams, P.G., Stevenson, H.C., Holmes, P., Maluish, A.E., Oldham, R.K., and Herberman, R.B. (1985). A phase I trial of recombinant gamma interferon in patients with cancer. Cancer Immunol Immunother 20, 193–197.
Gross, G., Waks, T., and Eshhar, Z. (1989). Expression of immunoglobulin- T-cell receptor chimeric molecules as functional receptors with antibody- type specificity. Proc Natl Acad Sci USA 86, 10024–10028.
Grupp, S.A., Kalos, M., Barrett, D., Aplenc, R., Porter, D.L., Rheingold, S.R., Teachey, D.T., Chew, A., Hauck, B., Wright, J.F., Milone, M.C., Levine, B.L., and June, C.H. (2013). Chimeric antigen receptor- modified T cells for acute lymphoid leukemia. N Engl J Med 368, 1509–1518.
Hombach, A.A., Heiders, J., Foppe, M., Chmielewski, M., and Abken, H. (2012). OX40 costimulation by a chimeric antigen receptor abrogates CD28 and IL-2 induced IL-10 secretion by redirected CD4+ T cells. Oncoimmunology 1, 458–466.
Hoyos, V., Savoldo, B., Quintarelli, C., Mahendravada, A., Zhang, M., Vera, J., Heslop, H.E., Rooney, C.M., Brenner, M.K., and Dotti, G. (2010). Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety. Leukemia 24, 1160–1170.
Kalos, M., Levine, B.L., Porter, D.L., Katz, S., Grupp, S.A., Bagg, A., and June, C.H. (2011). T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 3, 95ra73.
Kochenderfer, J.N., Dudley, M.E., Carpenter, R.O., Kassim, S.H., Rose, J.J., Telford, W.G., Hakim, F.T., Halverson, D.C., Fowler, D.H., Hardy, N.M., Mato, A.R., Hickstein, D.D., Gea-Banacloche, J.C., Pavletic, S.Z., Sportes, C., Maric, I., Feldman, S.A., Hansen, B.G., Wilder, J.S., Blacklock-Schuver, B., Jena, B., Bishop, M.R., Gress, R.E., and Rosenberg, S.A. (2013). Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood 122, 4129–4139.
Kochenderfer, J.N., Dudley, M.E., Feldman, S.A., Wilson, W.H., Spaner, D.E., Maric, I., Stetler-Stevenson, M., Phan, G.Q., Hughes, M.S., Sherry, R.M., Yang, J.C., Kammula, U.S., Devillier, L., Carpenter, R., Nathan, D.A., Morgan, R.A., Laurencot, C., and Rosenberg, S.A. (2012). B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric- antigen-receptor-transduced T cells. Blood 119, 2709–2720.
Kochenderfer, J.N., Dudley, M.E., Kassim, S.H., Somerville, R.P., Carpenter, R.O., Stetler-Stevenson, M., Yang, J.C., Phan, G.Q., Hughes, M.S., Sherry, R.M., Raffeld, M., Feldman, S., Lu, L., Li, Y.F., Ngo, L.T., Goy, A., Feldman, T., Spaner, D.E., Wang, M.L., Chen, C.C., Kranick, S.M., Nath, A., Nathan, D.A., Morton, K.E., Toomey, M.A., and Rosenberg, S.A. (2015). Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol 33, 540–549.
Kohn, D.B., Dotti, G., Brentjens, R., Savoldo, B., Jensen, M., Cooper, L.J.N., June, C.H., Rosenberg, S., Sadelain, M., and Heslop, H.E. (2011). CARs on track in the clinic. Mol Ther 19, 432–438.
Lee, D.W., Gardner, R., Porter, D.L., Louis, C.U., Ahmed, N., Jensen, M., Grupp, S.A., and Mackall, C.L. (2014). Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124, 188–195.
Lee, D.W., Kochenderfer, J.N., Stetler-Stevenson, M., Cui, Y.K., Delbrook, C., Feldman, S.A., Fry, T.J., Orentas, R., Sabatino, M., Shah, N.N., Steinberg, S.M., Stroncek, D., Tschernia, N., Yuan, C., Zhang, H., Zhang, L., Rosenberg, S.A., Wayne, A.S., and Mackall, C.L. (2015). T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385, 517–528.
Maude, S.L., Barrett, D., Teachey, D.T., and Grupp, S.A. (2014a). Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J 20, 119–122.
Maude, S.L., Frey, N., Shaw, P.A., Aplenc, R., Barrett, D.M., Bunin, N.J., Chew, A., Gonzalez, V.E., Zheng, Z., Lacey, S.F., Mahnke, Y.D., Melenhorst, J.J., Rheingold, S.R., Shen, A., Teachey, D.T., Levine, B.L., June, C.H., Porter, D.L., and Grupp, S.A. (2014b). Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371, 1507–1517.
Milone, M.C., Fish, J.D., Carpenito, C., Carroll, R.G., Binder, G.K., Teachey, D., Samanta, M., Lakhal, M., Gloss, B., Danet-Desnoyers, G., Campana, D., Riley, J.L., Grupp, S.A., and June, C.H. (2009). Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther 17, 1453–1464.
Morgan, R.A., Yang, J.C., Kitano, M., Dudley, M.E., Laurencot, C.M., and Rosenberg, S.A. (2010). Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther 18, 843–851.
Overwijk, W.W., Theoret, M.R., Finkelstein, S.E., Surman, D.R., de Jong, L.A., Vyth-Dreese, F.A., Dellemijn, T.A., Antony, P.A., Spiess, P.J., Palmer, D.C., Heimann, D.M., Klebanoff, C.A., Yu, Z., Hwang, L.N., Feigenbaum, L., Kruisbeek, A.M., Rosenberg, S.A., and Restifo, N.P. (2003). Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells. J Exp Med 198, 569–580.
Pegram, H.J., Lee, J.C., Hayman, E.G., Imperato, G.H., Tedder, T.F., Sadelain, M., and Brentjens, R.J. (2012). Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning. Blood 119, 4133–4141.
Porter, D.L., Hwang, W.T., Frey, N.V., Lacey, S.F., Shaw, P.A., Loren, A.W., Bagg, A., Marcucci, K.T., Shen, A., Gonzalez, V., Ambrose, D., Grupp, S.A., Chew, A., Zheng, Z., Milone, M.C., Levine, B.L., Melenhorst, J.J., and June, C.H. (2015). Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med 7, 303ra139.
Porter, D.L., Levine, B.L., Kalos, M., Bagg, A., and June, C.H. (2011). Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 365, 725–733.
Ritchie, D.S., Neeson, P.J., Khot, A., Peinert, S., Tai, T., Tainton, K., Chen, K., Shin, M., Wall, D.M., Honemann, D., Gambell, P., Westerman, D.A., Haurat, J., Westwood, J.A., Scott, A.M., Kravets, L., Dickinson, M., Trapani, J.A., Smyth, M.J., Darcy, P.K., Kershaw, M.H., and Prince, H.M. (2013). Persistence and efficacy of second generation CAR T cell against the LeY antigen in acute myeloid leukemia. Mol Ther 21, 2122-2129.
Savoldo, B., Ramos, C.A., Liu, E., Mims, M.P., Keating, M.J., Carrum, G., Kamble, R.T., Bollard, C.M., Gee, A.P., Mei, Z., Liu, H., Grilley, B., Rooney, C.M., Heslop, H.E., Brenner, M.K., and Dotti, G. (2011). CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Invest 121, 1822–1826.
Schiller, J.H., Storer, B.E., Witt, P.L., Alberti, D., Tombes, M.B., Arzoomanian, R., Proctor, R.A., McCarthy, D., Brown, R.R., Voss, S.D., Remick, S.C., Grem, J.L., Borden, E.C., and Trump, D.L. (1991). Biological and clinical effects of intravenous tumor necrosis factor-alpha administered three times weekly. Cancer Res 51, 1651–1658.
Stancovski, I., Schindler, D.G., Waks, T., Yarden, Y., Sela, M., and Eshhar, Z. (1993). Targeting of T lymphocytes to Neu/HER2- expressing cells using chimeric single chain Fv receptors. J Immunol 151, 6577–6582.
Till, B.G., Jensen, M.C., Wang, J., Qian, X., Gopal, A.K., Maloney, D.G., Lindgren, C.G., Lin, Y., Pagel, J.M., Budde, L.E., Raubitschek, A., Forman, S.J., Greenberg, P.D., Riddell, S.R., and Press, O.W. (2012). CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: pilot clinical trial results. Blood 119, 3940–3950.
Vadhan-Raj, S., Al-Katib, A., Bhalla, R., Pelus, L., Nathan, C.F., Sherwin, S.A., Oettgen, H.F., and Krown, S.E. (1986). Phase I trial of recombinant interferon gamma in cancer patients. J Clin Oncol 4, 137–146.
Wang, Q.S., Wang, Y., Lv, H.Y., Han, Q.W., Fan, H., Guo, B., Wang, L.L., and Han, W.D. (2015). Treatment of CD33-directed chimeric antigen receptor-modified T cells in one patient with relapsed and refractory acute myeloid leukemia. Mol Ther 23, 184–191.
Wang, Y., Zhang, W.Y., Han, Q.W., Liu, Y., Dai, H.R., Guo, Y.L., Bo, J., Fan, H., Zhang, Y., Zhang, Y.J., Chen, M.X., Feng, K.C., Wang, Q.S., Fu, X.B., and Han, W.D. (2014). Effective response and delayed toxicities of refractory advanced diffuse large B-cell lymphoma treated by CD20-directed chimeric antigen receptor-modified T cells. Clin Immunol 155, 160–175.
Wrzesinski, C., Paulos, C.M., Kaiser, A., Muranski, P., Palmer, D.C., Gattinoni, L., Yu, Z., Rosenberg, S.A., and Restifo, N.P. (2010). Increased intensity lymphodepletion enhances tumor treatment efficacy of adoptively transferred tumor-specific T cells. J Immunother 33, 1–7.
Xu, X.J., Zhao, H.Z., and Tang, Y.M. (2013). Efficacy and safety of adoptive immunotherapy using anti-CD19 chimeric antigen receptor transduced T-cells: a systematic review of phase I clinical trials. Leuk Lymphoma 54, 255–260.
Zhong, X.S., Matsushita, M., Plotkin, J., Riviere, I., and Sadelain, M. (2010). Chimeric antigen receptors combining 4-1BB and CD28 signaling domains augment PI3kinase/AKT/Bcl-XL activation and CD8+ T cell-mediated tumor eradication. Mol Ther 18, 413–420.
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Li, S., Yang, Z., Shen, J. et al. Adoptive therapy with CAR redirected T cells for hematological malignancies. Sci. China Life Sci. 59, 370–378 (2016). https://doi.org/10.1007/s11427-016-5036-3
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DOI: https://doi.org/10.1007/s11427-016-5036-3