T-cell receptor stimulation enhances the expansion and function of CD19 chimeric antigen receptor–expressing T cells

Natalia Lapteva, Margaret Gilbert, Iulia Diaconu, Lisa A. Rollins, Mina Al-Sabbagh, Swati Naik, Robert A. Krance, Tamara Tripic, Manasa Hiregange, Darshana Raghavan, Olga Dakhova, Rayne H. Rouce, Hao Liu, Bilal Omer, Barbara Savoldo, Gianpietro Dotti, Conrad Russel Cruz, Keli Sharpe, Melissa Gates, Aaron OrozcoApril Durett, Elizabeth Pacheco, Adrian P. Gee, Carlos A. Ramos, Helen E. Heslop, Malcolm K. Brenner, Cliona M. Rooney

Research output: Contribution to journalArticle

Abstract

Purpose: Current protocols for CD19 chimeric antigen receptor–expressing T cells (CD19.CAR-T cells) require recipients to tolerate preinfusion cytoreductive chemotherapy, and the presence of sufficient target antigen on normal or malignant B cells. Patients and Methods: We investigated whether additional stimulation of CD19.CAR-T cells through their native receptors can substitute for cytoreductive chemotherapy, inducing expansion and functional persistence of CD19.CAR-T even in patients in remission of B-cell acute lymphocytic leukemia. We infused a low dose of CD19.CAR-modified virus-specific T cells (CD19.CAR-VST) without prior cytoreductive chemotherapy into 8 patients after allogeneic stem cell transplant. Results: Absent virus reactivation, we saw no CD19. CAR-VST expansion. In contrast, in patients with viral reactivation, up to 30,000-fold expansion of CD19.CAR-VSTs was observed, with depletion of CD19þ B cells. Five patients remain in remission at 42–60þ months. Conclusions: Dual T-cell receptor and CAR stimulation can thus potentiate effector cell expansion and CAR-target cell killing, even when infusing low numbers of effector cells without cytoreduction.

Original languageEnglish (US)
Pages (from-to)7340-7350
Number of pages11
JournalClinical Cancer Research
Volume25
Issue number24
DOIs
StatePublished - Dec 15 2019
Externally publishedYes

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CD19 Antigens
T-Cell Antigen Receptor
T-Lymphocytes
Drug Therapy
B-Lymphocytes
B-Cell Leukemia
Viruses
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Stem Cells
Cell Count
Transplants
Antigens

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Lapteva, N., Gilbert, M., Diaconu, I., Rollins, L. A., Al-Sabbagh, M., Naik, S., ... Rooney, C. M. (2019). T-cell receptor stimulation enhances the expansion and function of CD19 chimeric antigen receptor–expressing T cells. Clinical Cancer Research, 25(24), 7340-7350. https://doi.org/10.1158/1078-0432.CCR-18-3199

T-cell receptor stimulation enhances the expansion and function of CD19 chimeric antigen receptor–expressing T cells. / Lapteva, Natalia; Gilbert, Margaret; Diaconu, Iulia; Rollins, Lisa A.; Al-Sabbagh, Mina; Naik, Swati; Krance, Robert A.; Tripic, Tamara; Hiregange, Manasa; Raghavan, Darshana; Dakhova, Olga; Rouce, Rayne H.; Liu, Hao; Omer, Bilal; Savoldo, Barbara; Dotti, Gianpietro; Cruz, Conrad Russel; Sharpe, Keli; Gates, Melissa; Orozco, Aaron; Durett, April; Pacheco, Elizabeth; Gee, Adrian P.; Ramos, Carlos A.; Heslop, Helen E.; Brenner, Malcolm K.; Rooney, Cliona M.

In: Clinical Cancer Research, Vol. 25, No. 24, 15.12.2019, p. 7340-7350.

Research output: Contribution to journalArticle

Lapteva, N, Gilbert, M, Diaconu, I, Rollins, LA, Al-Sabbagh, M, Naik, S, Krance, RA, Tripic, T, Hiregange, M, Raghavan, D, Dakhova, O, Rouce, RH, Liu, H, Omer, B, Savoldo, B, Dotti, G, Cruz, CR, Sharpe, K, Gates, M, Orozco, A, Durett, A, Pacheco, E, Gee, AP, Ramos, CA, Heslop, HE, Brenner, MK & Rooney, CM 2019, 'T-cell receptor stimulation enhances the expansion and function of CD19 chimeric antigen receptor–expressing T cells', Clinical Cancer Research, vol. 25, no. 24, pp. 7340-7350. https://doi.org/10.1158/1078-0432.CCR-18-3199
Lapteva, Natalia ; Gilbert, Margaret ; Diaconu, Iulia ; Rollins, Lisa A. ; Al-Sabbagh, Mina ; Naik, Swati ; Krance, Robert A. ; Tripic, Tamara ; Hiregange, Manasa ; Raghavan, Darshana ; Dakhova, Olga ; Rouce, Rayne H. ; Liu, Hao ; Omer, Bilal ; Savoldo, Barbara ; Dotti, Gianpietro ; Cruz, Conrad Russel ; Sharpe, Keli ; Gates, Melissa ; Orozco, Aaron ; Durett, April ; Pacheco, Elizabeth ; Gee, Adrian P. ; Ramos, Carlos A. ; Heslop, Helen E. ; Brenner, Malcolm K. ; Rooney, Cliona M. / T-cell receptor stimulation enhances the expansion and function of CD19 chimeric antigen receptor–expressing T cells. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 24. pp. 7340-7350.
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T1 - T-cell receptor stimulation enhances the expansion and function of CD19 chimeric antigen receptor–expressing T cells

AU - Lapteva, Natalia

AU - Gilbert, Margaret

AU - Diaconu, Iulia

AU - Rollins, Lisa A.

AU - Al-Sabbagh, Mina

AU - Naik, Swati

AU - Krance, Robert A.

AU - Tripic, Tamara

AU - Hiregange, Manasa

AU - Raghavan, Darshana

AU - Dakhova, Olga

AU - Rouce, Rayne H.

AU - Liu, Hao

AU - Omer, Bilal

AU - Savoldo, Barbara

AU - Dotti, Gianpietro

AU - Cruz, Conrad Russel

AU - Sharpe, Keli

AU - Gates, Melissa

AU - Orozco, Aaron

AU - Durett, April

AU - Pacheco, Elizabeth

AU - Gee, Adrian P.

AU - Ramos, Carlos A.

AU - Heslop, Helen E.

AU - Brenner, Malcolm K.

AU - Rooney, Cliona M.

PY - 2019/12/15

Y1 - 2019/12/15

N2 - Purpose: Current protocols for CD19 chimeric antigen receptor–expressing T cells (CD19.CAR-T cells) require recipients to tolerate preinfusion cytoreductive chemotherapy, and the presence of sufficient target antigen on normal or malignant B cells. Patients and Methods: We investigated whether additional stimulation of CD19.CAR-T cells through their native receptors can substitute for cytoreductive chemotherapy, inducing expansion and functional persistence of CD19.CAR-T even in patients in remission of B-cell acute lymphocytic leukemia. We infused a low dose of CD19.CAR-modified virus-specific T cells (CD19.CAR-VST) without prior cytoreductive chemotherapy into 8 patients after allogeneic stem cell transplant. Results: Absent virus reactivation, we saw no CD19. CAR-VST expansion. In contrast, in patients with viral reactivation, up to 30,000-fold expansion of CD19.CAR-VSTs was observed, with depletion of CD19þ B cells. Five patients remain in remission at 42–60þ months. Conclusions: Dual T-cell receptor and CAR stimulation can thus potentiate effector cell expansion and CAR-target cell killing, even when infusing low numbers of effector cells without cytoreduction.

AB - Purpose: Current protocols for CD19 chimeric antigen receptor–expressing T cells (CD19.CAR-T cells) require recipients to tolerate preinfusion cytoreductive chemotherapy, and the presence of sufficient target antigen on normal or malignant B cells. Patients and Methods: We investigated whether additional stimulation of CD19.CAR-T cells through their native receptors can substitute for cytoreductive chemotherapy, inducing expansion and functional persistence of CD19.CAR-T even in patients in remission of B-cell acute lymphocytic leukemia. We infused a low dose of CD19.CAR-modified virus-specific T cells (CD19.CAR-VST) without prior cytoreductive chemotherapy into 8 patients after allogeneic stem cell transplant. Results: Absent virus reactivation, we saw no CD19. CAR-VST expansion. In contrast, in patients with viral reactivation, up to 30,000-fold expansion of CD19.CAR-VSTs was observed, with depletion of CD19þ B cells. Five patients remain in remission at 42–60þ months. Conclusions: Dual T-cell receptor and CAR stimulation can thus potentiate effector cell expansion and CAR-target cell killing, even when infusing low numbers of effector cells without cytoreduction.

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