Abstract
Anti-CD19 chimeric antigen receptor-modified T (CAR-T-19) cells have emerged as a powerful targeted immunotherapy for B-cell lineage acute lymphoblastic leukemia with a remarkable clinical response in recent trials. Nonetheless, few data are available on the subsequent clinical monitoring and treatment of the patients, especially those with disease recurrence after CAR-T-19 cell infusion. Here, we analyzed three patients who survived after our phase I clinical trial and who were studied by means of biomarkers reflecting persistence of CAR-T-19 cells in vivo and predictive factors directing further treatment. One patient achieved 9-week sustained complete remission and subsequently received an allogeneic hematopoietic stem cell transplant. Another patient who showed relapse after 20 weeks without detectable leukemia in the cerebrospinal fluid after CAR-T-19 cell treatment was able to achieve a morphological remission under the influence of stand-alone low-dose chemotherapeutic agents. The third patient gradually developed extensive extramedullary involvement in tissues with scarce immune- cell infiltration during a long period of hematopoietic remission after CAR-T-19 cell therapy. Long-term and discontinuous increases in serum cytokines (mainly interleukin 6 and C-reactive protein) were identified in two patients (Nos. 1 and 6) even though only a low copy number of CAR molecules could be detected in their peripheral blood. This finding was suggestive of persistent functional activity of CAR-T-19 cells. Combined analyses of laboratory biomarkers with their clinical manifestations before and after salvage treatment showed that the persistent immunosurveillance mediated by CAR-T-19 cells would inevitably potentiate the leukemia-killing effectiveness of subsequent chemotherapy in patients who showed relapse after CAR-T-19-induced remission.
Article PDF
Similar content being viewed by others
References
Arkader, R., Troster, E.J., Lopes, M.R., Jú nior, R.R., Carcillo, J.A., Leone, C., and Okay, T.S. (2006). Procalcitonin does discriminate between sepsis and systemic inflammatory response syndrome. Arch Dis Child 91, 117–120.
Bakker, E., Qattan, M., Mutti, L., Demonacos, C., and Krstic-Demonacos, M. (2016). The role of microenvironment and immunity in drug response in leukemia. Biochim Biophys Acta 1863, 414–426.
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, 177ra38.
Butterfield, L.H., Palucka, A.K., Britten, C.M., Dhodapkar, M.V., Hå kansson, L., Janetzki, S., Kawakami, Y., Kleen, T.O., Lee, P.P., Maccalli, C., Maecker, H.T., Maino, V.C., Maio, M., Malyguine, A., Masucci, G., Pawelec, G., Potter, D.M., Rivoltini, L., Salazar, L.G., Schendel, D.J., Slingluff, C.L, Song, W., Stroncek, D.F., Tahara, H., Thurin, M., Trinchieri, G., van Der Burg, S.H., Whiteside, T.L., Wigginton, J.M., Marincola, F., Khleif, S., Fox, B.A., and Disis, M.L. (2011). Recommendations from the iSBTc-SITC/FDA/NCI workshop on immunotherapy biomarkers. Clin Cancer Res 17, 3064–3076.
Burger, J.A., and Gribben, J.G. (2014). The microenvironment in chronic lymphocytic leukemia (CLL) and other B cell malignancies: insight into disease biology and new targeted therapies. Semin Cancer Biol 24, 71–81.
Cairo, M.S., and Bishop, M. (2004). Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol 127, 3–11.
Christopoulos, P., Pfeifer, D., Bartholomé, K., Follo, M., Timmer, J., Fisch, P., and Veelken, H. (2011). Definition and characterization of the systemic T-cell dysregulation in untreated indolent B-cell lymphoma and very early CLL. Blood 117, 3836–3846.
Dai, H., Zhang, W., Li, X., Han, Q., Guo, Y., Zhang, Y., Wang, Y., Wang, C., Shi, F., Zhang, Y., Chen, M., Feng, K., Wang, Q., Zhu, H., Fu, X., Li, S., and Han, W. (2015). Tolerance and efficacy of autologous or donor-derived T cells expressing CD19 chimeric antigen receptors in adult B-ALL with extramedullary leukemia. OncoImmunology 4, e1027469.
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, 224ra25.
Fox, B.A,, Schendel, D.J., Butterfield, L.H., Aamdal, S., Allison, J.P., Ascierto, P.A., Atkins, M.B., Bartunkova, J., Bergmann, L., Berinstein, N., Bonorino, C.C., Borden, E., Bramson, J.L., Britten, C.M., Cao, X., Carson, W.E., Chang, A.E., Characiejus, D., Choudhury, A.R., Coukos, G., de Gruijl, T., Dillman, R.O., Dolstra, H., Dranoff, G., Durrant, L.G., Finke, J.H., Galon, J., Gollob, J.A., Gouttefangeas, C., Grizzi, F., Guida, M., Håkansson, L., Hege, K., Herberman, R.B., Hodi, F.S., Hoos, A., Huber, C., Hwu, P., Imai, K., Jaffee, E.M., Janetzki, S., June, C.H., Kalinski, P., Kaufman, H.L., Kawakami, K., Kawakami, Y., Keilholtz, U., Khleif, S.N., Kiessling, R., Kotlan, B., Kroemer, G., Lapointe, R., Levitsky, H.I., Lotze, M.T., Maccalli, C., Maio, M., Marschner, J.P., Mastrangelo, M.J., Masucci, G., Melero, I., Melief, C., Murphy, W.J., Nelson, B., Nicolini, A., Nishimura, M.I., Odunsi, K., Ohashi, P.S., O’Donnell-Tormey, J., Old, L.J., Ottensmeier, C., Papamichail, M., Parmiani, G., Pawelec, G., Proietti, E., Qin, S., Rees, R., Ribas, A., Ridolfi, R., Ritter, G., Rivoltini, L., Romero, P.J., Salem, M.L., Scheper, R.J., Seliger, B., Sharma, P., Shiku, H., Singh-Jasuja, H., Song, W., Straten, P.T., Tahara, H., Tian, Z., van Der Burg, S.H., von Hoegen, P., Wang, E., Welters, M.J., Winter, H., Withington, T., Wolchok, J.D., Xiao, W., Zitvogel, L., Zwierzina, H., Marincola, F.M., Gajewski, T.F., Wigginton, J.M., and Disis, M.L. (2011). Defining the critical hurdles in cancer immunotherapy. J Transl Med 9, 214.
Garcia-Manero, G., and Thomas, D.A. (2001). Salvage therapy for refractory or relapsed acute lymphocytic leukemia. Hematol Oncol Clin North Am 15, 163–205.
Ghorashian, S., Pule, M., and Amrolia, P. (2015). CD19 chimeric antigen receptor T cell therapy for haematological malignancies. Br J Haematol 169, 463–478.
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.
Kalos, M. (2011) Biomarkers in T cell therapy clinical trials. J Transl Med 9, 138.
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.
Lacey, S.F., and Kalos, M. (2013). Biomarkers in T-cell therapy clinical trials. Cytotherapy 15, 632–640.
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.
Lorentzen, C.L, and Straten, P.T. (2015). CD19-chimeric antigen receptor T cells for treatment of chronic lymphocytic leukemia and acute lymphoblastic leukemia. Scand J Immunol 82, 307–319.
Marr, L.A., Gilham, D.E., Campbell, J.D., and Fraser, A.R. Immunology in the clinic review series; focus on cancer: double trouble for tumours: bi-functional and redirected T cells as effective cancer immunotherapies. (2012). Clin Exp Immunol 167, 216–225.
Maude, S.L., Barrett, D., Teachey, D.T., and Grupp, S.A. (2014). 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. (2014). Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371, 1507–1517.
Pepys, M.B., and Hirschfield, G.M. (2003). C-reactive protein: a critical update. J Clin Invest 111, 1805–1812.
Rasool, M., Malik, A., Qureshi, M.S., Ahmad, R., Manan, A., Asif, M., Naseer, M.I., and Pushparaj, P.N. (2014). Development of tumor lysis syndrome (TLS): a potential risk factor in cancer patients receiving anticancer therapy. Bioinformation 10, 703–707.
Saha, B., Jyothi, P.S., Chandrasekar, B., and Nandi, D. (2010). Gene modulation and immunoregulatory roles of interferon gamma. Cytokine 50, 1–14.
Schultz, D.R., and Arnold, P.I. (1990). Properties of four acute phase proteins: C-reactive protein, serum amyloid A protein, alpha 1-acid glycoprotein, and fibrinogen. Semin Arthritis Rheum 20, 129–147.
Schreiber, R.D., Old, L.J., and Smyth, M.J. (2011). Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331, 1565–1570.
Howard, S.C., Jones, D.P., and Pui, C.-H. (2011). The tumor lysis syndrome. N Engl J Med 364, 1844–1854.
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.
Will, A., and Tholouli, E. (2011). The clinical management of tumour lysis syndrome in haematological malignancies. Br J Haematol 154, 3–13.
Yang, Z.Z., and Ansell, S.M. (2012). The tumor microenvironment in follicular lymphoma. Clin Adv Hematol Oncol 10, 810–818.
Zhu, Y., Tan, Y., Ou, R., Zhong, Q., Zheng, L., Du, Y., Zhang, Q., and Huang, J. (2015). Anti-CD19 chimeric antigen receptor-modified T cells for B-cell malignancies: a systematic review of efficacy and safety in clinical trials. Eur J Haematol doi: 10.1111/ejh.12602.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0), which permits use, duplication, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
About this article
Cite this article
Zhang, Y., Zhang, W., Dai, H. et al. An analytical biomarker for treatment of patients with recurrent B-ALL after remission induced by infusion of anti-CD19 chimeric antigen receptor T (CAR-T) cells. Sci. China Life Sci. 59, 379–385 (2016). https://doi.org/10.1007/s11427-016-5035-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11427-016-5035-4