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 Orozco; April Durett; Elizabeth Pacheco; Adrian P. Gee; Carlos A. Ramos; Helen E. Heslop; Malcolm K. Brenner; Cliona M. Rooney

doi:10.1158/1078-0432.CCR-18-3199

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 journal › Article › peer-review

26 Scopus citations

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 CD19^þ 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 language	English (US)
Pages (from-to)	7340-7350
Number of pages	11
Journal	Clinical Cancer Research
Volume	25
Issue number	24
DOIs	https://doi.org/10.1158/1078-0432.CCR-18-3199
State	Published - Dec 15 2019
Externally published	Yes

All Science Journal Classification (ASJC) codes

Oncology
Cancer Research

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10.1158/1078-0432.CCR-18-3199

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Lapteva, N., Gilbert, M., Diaconu, I., Rollins, L. A., Al-Sabbagh, M., Naik, S., Krance, R. A., Tripic, T., Hiregange, M., Raghavan, D., Dakhova, O., Rouce, R. H., Liu, H., Omer, B., Savoldo, B., Dotti, G., Cruz, C. R., Sharpe, K., Gates, M., ... 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

@article{1b1e7ecd75f24685a81676cd4abd4661,

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

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 CD19{\th} B cells. Five patients remain in remission at 42–60{\th} 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.",

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

note = "Funding Information: This work was supported by grants from V-Foundation, Alex's Lemonade Stand Foundation, NIH-NCI P50 CA126752 SPORE in lymphoma and Leukemia and lymphoma Society SCOR 7001. Publisher Copyright: {\textcopyright}2019 American Association for Cancer Research.",

year = "2019",

month = dec,

day = "15",

doi = "10.1158/1078-0432.CCR-18-3199",

language = "English (US)",

volume = "25",

pages = "7340--7350",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

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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

TY - JOUR

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.

N1 - Funding Information: This work was supported by grants from V-Foundation, Alex's Lemonade Stand Foundation, NIH-NCI P50 CA126752 SPORE in lymphoma and Leukemia and lymphoma Society SCOR 7001. Publisher Copyright: ©2019 American Association for Cancer Research.

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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U2 - 10.1158/1078-0432.CCR-18-3199

DO - 10.1158/1078-0432.CCR-18-3199

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C2 - 31558475

AN - SCOPUS:85076504541

SN - 1078-0432

VL - 25

SP - 7340

EP - 7350

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 24

ER -

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

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