The addition of the btk inhibitor ibrutinib to anti-cd19 chimeric antigen receptor T Cells (CART19) improves responses against mantle cell lymphoma

Marco Ruella, Saad Kenderian, Olga Shestova, Joseph A. Fraietta, Sohail Qayyum, Qian Zhang, Marcela V. Maus, Xiaobin Liu, Selene Nunez-Cruz, Michael Klichinsky, Omkar U. Kawalekar, Michael Milone, Simon F. Lacey, Anthony Mato, Stephen J. Schuster, Michael Kalos, Carl H. June, Saar Gill, Mariusz A. Wasik

Research output: Contribution to journalArticle

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Abstract

Purpose: Responses to therapy with chimeric antigen receptor T cells recognizing CD19 (CART19, CTL019) may vary by histology. Mantle cell lymphoma (MCL) represents a B-cell malignancy that remains incurable despite novel therapies such as the BTK inhibitor ibrutinib, and where data from CTL019 therapy are scant. Using MCL as a model, we sought to build upon the outcomes from CTL019 and from ibrutinib therapy by combining these in a rational manner. Experimental Design: MCL cell lines and primary MCL samples were combined with autologous or normal donor-derived anti-CD19 CAR T cells along with ibrutinib. The effect of the combination was studied in vitro and in mouse xenograft models. Results: MCL cells strongly activated multiple CTL019 effector functions, and MCL killing by CTL019 was further enhanced in the presence of ibrutinib. In a xenograft MCL model, we showed superior disease control in the CTL019- as compared with ibrutinib-treated mice (median survival not reached vs. 95 days, P < 0.005) but most mice receiving CTL019 monotherapy eventually relapsed. Therefore, we added ibrutinib to CTL019 and showed that 80% to 100% of mice in the CTL019 + ibrutinib armand 0%to 20%ofmice in the CTL019 arm, respectively, remained in long-term remission (P < 0.05). Conclusions: Combining CTL019 with ibrutinib represents a rational way to incorporate two of the most recent therapies in MCL. Our findings pave the way to a two-pronged therapeutic strategy in patients withMCLand other types of B-cell lymphoma.

Original languageEnglish (US)
Pages (from-to)2684-2696
Number of pages13
JournalClinical Cancer Research
Volume22
Issue number11
DOIs
StatePublished - Jun 1 2016

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CD19 Antigens
Mantle-Cell Lymphoma
Antigen Receptors
T-Lymphocytes
Heterografts
Therapeutics
PCI 32765
B-Cell Lymphoma
T-Cell Antigen Receptor
Histology
Arm
B-Lymphocytes
Research Design
Tissue Donors

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

The addition of the btk inhibitor ibrutinib to anti-cd19 chimeric antigen receptor T Cells (CART19) improves responses against mantle cell lymphoma. / Ruella, Marco; Kenderian, Saad; Shestova, Olga; Fraietta, Joseph A.; Qayyum, Sohail; Zhang, Qian; Maus, Marcela V.; Liu, Xiaobin; Nunez-Cruz, Selene; Klichinsky, Michael; Kawalekar, Omkar U.; Milone, Michael; Lacey, Simon F.; Mato, Anthony; Schuster, Stephen J.; Kalos, Michael; June, Carl H.; Gill, Saar; Wasik, Mariusz A.

In: Clinical Cancer Research, Vol. 22, No. 11, 01.06.2016, p. 2684-2696.

Research output: Contribution to journalArticle

Ruella, M, Kenderian, S, Shestova, O, Fraietta, JA, Qayyum, S, Zhang, Q, Maus, MV, Liu, X, Nunez-Cruz, S, Klichinsky, M, Kawalekar, OU, Milone, M, Lacey, SF, Mato, A, Schuster, SJ, Kalos, M, June, CH, Gill, S & Wasik, MA 2016, 'The addition of the btk inhibitor ibrutinib to anti-cd19 chimeric antigen receptor T Cells (CART19) improves responses against mantle cell lymphoma', Clinical Cancer Research, vol. 22, no. 11, pp. 2684-2696. https://doi.org/10.1158/1078-0432.CCR-15-1527
Ruella, Marco ; Kenderian, Saad ; Shestova, Olga ; Fraietta, Joseph A. ; Qayyum, Sohail ; Zhang, Qian ; Maus, Marcela V. ; Liu, Xiaobin ; Nunez-Cruz, Selene ; Klichinsky, Michael ; Kawalekar, Omkar U. ; Milone, Michael ; Lacey, Simon F. ; Mato, Anthony ; Schuster, Stephen J. ; Kalos, Michael ; June, Carl H. ; Gill, Saar ; Wasik, Mariusz A. / The addition of the btk inhibitor ibrutinib to anti-cd19 chimeric antigen receptor T Cells (CART19) improves responses against mantle cell lymphoma. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 11. pp. 2684-2696.
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abstract = "Purpose: Responses to therapy with chimeric antigen receptor T cells recognizing CD19 (CART19, CTL019) may vary by histology. Mantle cell lymphoma (MCL) represents a B-cell malignancy that remains incurable despite novel therapies such as the BTK inhibitor ibrutinib, and where data from CTL019 therapy are scant. Using MCL as a model, we sought to build upon the outcomes from CTL019 and from ibrutinib therapy by combining these in a rational manner. Experimental Design: MCL cell lines and primary MCL samples were combined with autologous or normal donor-derived anti-CD19 CAR T cells along with ibrutinib. The effect of the combination was studied in vitro and in mouse xenograft models. Results: MCL cells strongly activated multiple CTL019 effector functions, and MCL killing by CTL019 was further enhanced in the presence of ibrutinib. In a xenograft MCL model, we showed superior disease control in the CTL019- as compared with ibrutinib-treated mice (median survival not reached vs. 95 days, P < 0.005) but most mice receiving CTL019 monotherapy eventually relapsed. Therefore, we added ibrutinib to CTL019 and showed that 80{\%} to 100{\%} of mice in the CTL019 + ibrutinib armand 0{\%}to 20{\%}ofmice in the CTL019 arm, respectively, remained in long-term remission (P < 0.05). Conclusions: Combining CTL019 with ibrutinib represents a rational way to incorporate two of the most recent therapies in MCL. Our findings pave the way to a two-pronged therapeutic strategy in patients withMCLand other types of B-cell lymphoma.",
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T1 - The addition of the btk inhibitor ibrutinib to anti-cd19 chimeric antigen receptor T Cells (CART19) improves responses against mantle cell lymphoma

AU - Ruella, Marco

AU - Kenderian, Saad

AU - Shestova, Olga

AU - Fraietta, Joseph A.

AU - Qayyum, Sohail

AU - Zhang, Qian

AU - Maus, Marcela V.

AU - Liu, Xiaobin

AU - Nunez-Cruz, Selene

AU - Klichinsky, Michael

AU - Kawalekar, Omkar U.

AU - Milone, Michael

AU - Lacey, Simon F.

AU - Mato, Anthony

AU - Schuster, Stephen J.

AU - Kalos, Michael

AU - June, Carl H.

AU - Gill, Saar

AU - Wasik, Mariusz A.

PY - 2016/6/1

Y1 - 2016/6/1

N2 - Purpose: Responses to therapy with chimeric antigen receptor T cells recognizing CD19 (CART19, CTL019) may vary by histology. Mantle cell lymphoma (MCL) represents a B-cell malignancy that remains incurable despite novel therapies such as the BTK inhibitor ibrutinib, and where data from CTL019 therapy are scant. Using MCL as a model, we sought to build upon the outcomes from CTL019 and from ibrutinib therapy by combining these in a rational manner. Experimental Design: MCL cell lines and primary MCL samples were combined with autologous or normal donor-derived anti-CD19 CAR T cells along with ibrutinib. The effect of the combination was studied in vitro and in mouse xenograft models. Results: MCL cells strongly activated multiple CTL019 effector functions, and MCL killing by CTL019 was further enhanced in the presence of ibrutinib. In a xenograft MCL model, we showed superior disease control in the CTL019- as compared with ibrutinib-treated mice (median survival not reached vs. 95 days, P < 0.005) but most mice receiving CTL019 monotherapy eventually relapsed. Therefore, we added ibrutinib to CTL019 and showed that 80% to 100% of mice in the CTL019 + ibrutinib armand 0%to 20%ofmice in the CTL019 arm, respectively, remained in long-term remission (P < 0.05). Conclusions: Combining CTL019 with ibrutinib represents a rational way to incorporate two of the most recent therapies in MCL. Our findings pave the way to a two-pronged therapeutic strategy in patients withMCLand other types of B-cell lymphoma.

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