Clinical and immunological responses after CD30-specific chimeric antigen receptor-redirected lymphocytes

Carlos A. Ramos, Brandon Ballard, Huimin Zhang, Olga Dakhova, Adrian P. Gee, Zhuyong Mei, Mrinalini Bilgi, Meng Fen Wu, Hao Liu, Bambi Grilley, Catherine M. Bollard, Bill H. Chang, Cliona M. Rooney, Malcolm K. Brenner, Helen E. Heslop, Gianpietro Dotti, Barbara Savoldo

Research output: Contribution to journalArticle

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Abstract

BACKGROUND. Targeting CD30 with monoclonal antibodies in Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) has had profound clinical success. However, adverse events, mainly mediated by the toxin component of the conjugated antibodies, cause treatment discontinuation in many patients. Targeting CD30 with T cells expressing a CD30- specific chimeric antigen receptor (CAR) may reduce the side effects and augment antitumor activity. METHODS. We conducted a phase I dose escalation study in which 9 patients with relapsed/refractory HL or ALCL were infused with autologous T cells that were gene-modified with a retroviral vector to express the CD30-specific CAR (CD30. CAR-Ts) encoding the CD28 costimulatory endodomain. Three dose levels, from 0.2 - 108 to 2 - 108 CD30.CAR-Ts/m2, were infused without a conditioning regimen. All other therapy for malignancy was discontinued at least 4 weeks before CD30. CAR-T infusion. Seven patients had previously experienced disease progression while being treated with brentuximab. RESULTS. No toxicities attributable to CD30.CAR-Ts were observed. Of 7 patients with relapsed HL, 1 entered complete response (CR) lasting more than 2.5 years after the second infusion of CD30.CAR-Ts, 1 remained in continued CR for almost 2 years, and 3 had transient stable disease. Of 2 patients with ALCL, 1 had a CR that persisted 9 months after the fourth infusion of CD30.CAR-Ts. CD30.CAR-T expansion in peripheral blood peaked 1 week after infusion, and CD30.CAR-Ts remained detectable for over 6 weeks. Although CD30 may also be expressed by normal activated T cells, no patients developed impaired virus-specific immunity. CONCLUSION. CD30.CAR-Ts are safe and can lead to clinical responses in patients with HL and ALCL, indicating that further assessment of this therapy is warranted.

Original languageEnglish (US)
Pages (from-to)3462-3471
Number of pages10
JournalJournal of Clinical Investigation
Volume127
Issue number9
DOIs
StatePublished - Sep 1 2017
Externally publishedYes

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Antigen Receptors
Lymphocytes
Anaplastic Large-Cell Lymphoma
Hodgkin Disease
T-Lymphocytes
CD30 Antigens
Disease Progression
Immunity
Therapeutics
Monoclonal Antibodies
Viruses

ASJC Scopus subject areas

  • Medicine(all)

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Ramos, C. A., Ballard, B., Zhang, H., Dakhova, O., Gee, A. P., Mei, Z., ... Savoldo, B. (2017). Clinical and immunological responses after CD30-specific chimeric antigen receptor-redirected lymphocytes. Journal of Clinical Investigation, 127(9), 3462-3471. https://doi.org/10.1172/JCI94306

Clinical and immunological responses after CD30-specific chimeric antigen receptor-redirected lymphocytes. / Ramos, Carlos A.; Ballard, Brandon; Zhang, Huimin; Dakhova, Olga; Gee, Adrian P.; Mei, Zhuyong; Bilgi, Mrinalini; Wu, Meng Fen; Liu, Hao; Grilley, Bambi; Bollard, Catherine M.; Chang, Bill H.; Rooney, Cliona M.; Brenner, Malcolm K.; Heslop, Helen E.; Dotti, Gianpietro; Savoldo, Barbara.

In: Journal of Clinical Investigation, Vol. 127, No. 9, 01.09.2017, p. 3462-3471.

Research output: Contribution to journalArticle

Ramos, CA, Ballard, B, Zhang, H, Dakhova, O, Gee, AP, Mei, Z, Bilgi, M, Wu, MF, Liu, H, Grilley, B, Bollard, CM, Chang, BH, Rooney, CM, Brenner, MK, Heslop, HE, Dotti, G & Savoldo, B 2017, 'Clinical and immunological responses after CD30-specific chimeric antigen receptor-redirected lymphocytes', Journal of Clinical Investigation, vol. 127, no. 9, pp. 3462-3471. https://doi.org/10.1172/JCI94306
Ramos, Carlos A. ; Ballard, Brandon ; Zhang, Huimin ; Dakhova, Olga ; Gee, Adrian P. ; Mei, Zhuyong ; Bilgi, Mrinalini ; Wu, Meng Fen ; Liu, Hao ; Grilley, Bambi ; Bollard, Catherine M. ; Chang, Bill H. ; Rooney, Cliona M. ; Brenner, Malcolm K. ; Heslop, Helen E. ; Dotti, Gianpietro ; Savoldo, Barbara. / Clinical and immunological responses after CD30-specific chimeric antigen receptor-redirected lymphocytes. In: Journal of Clinical Investigation. 2017 ; Vol. 127, No. 9. pp. 3462-3471.
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abstract = "BACKGROUND. Targeting CD30 with monoclonal antibodies in Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) has had profound clinical success. However, adverse events, mainly mediated by the toxin component of the conjugated antibodies, cause treatment discontinuation in many patients. Targeting CD30 with T cells expressing a CD30- specific chimeric antigen receptor (CAR) may reduce the side effects and augment antitumor activity. METHODS. We conducted a phase I dose escalation study in which 9 patients with relapsed/refractory HL or ALCL were infused with autologous T cells that were gene-modified with a retroviral vector to express the CD30-specific CAR (CD30. CAR-Ts) encoding the CD28 costimulatory endodomain. Three dose levels, from 0.2 - 108 to 2 - 108 CD30.CAR-Ts/m2, were infused without a conditioning regimen. All other therapy for malignancy was discontinued at least 4 weeks before CD30. CAR-T infusion. Seven patients had previously experienced disease progression while being treated with brentuximab. RESULTS. No toxicities attributable to CD30.CAR-Ts were observed. Of 7 patients with relapsed HL, 1 entered complete response (CR) lasting more than 2.5 years after the second infusion of CD30.CAR-Ts, 1 remained in continued CR for almost 2 years, and 3 had transient stable disease. Of 2 patients with ALCL, 1 had a CR that persisted 9 months after the fourth infusion of CD30.CAR-Ts. CD30.CAR-T expansion in peripheral blood peaked 1 week after infusion, and CD30.CAR-Ts remained detectable for over 6 weeks. Although CD30 may also be expressed by normal activated T cells, no patients developed impaired virus-specific immunity. CONCLUSION. CD30.CAR-Ts are safe and can lead to clinical responses in patients with HL and ALCL, indicating that further assessment of this therapy is warranted.",
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AU - Ramos, Carlos A.

AU - Ballard, Brandon

AU - Zhang, Huimin

AU - Dakhova, Olga

AU - Gee, Adrian P.

AU - Mei, Zhuyong

AU - Bilgi, Mrinalini

AU - Wu, Meng Fen

AU - Liu, Hao

AU - Grilley, Bambi

AU - Bollard, Catherine M.

AU - Chang, Bill H.

AU - Rooney, Cliona M.

AU - Brenner, Malcolm K.

AU - Heslop, Helen E.

AU - Dotti, Gianpietro

AU - Savoldo, Barbara

PY - 2017/9/1

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N2 - BACKGROUND. Targeting CD30 with monoclonal antibodies in Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) has had profound clinical success. However, adverse events, mainly mediated by the toxin component of the conjugated antibodies, cause treatment discontinuation in many patients. Targeting CD30 with T cells expressing a CD30- specific chimeric antigen receptor (CAR) may reduce the side effects and augment antitumor activity. METHODS. We conducted a phase I dose escalation study in which 9 patients with relapsed/refractory HL or ALCL were infused with autologous T cells that were gene-modified with a retroviral vector to express the CD30-specific CAR (CD30. CAR-Ts) encoding the CD28 costimulatory endodomain. Three dose levels, from 0.2 - 108 to 2 - 108 CD30.CAR-Ts/m2, were infused without a conditioning regimen. All other therapy for malignancy was discontinued at least 4 weeks before CD30. CAR-T infusion. Seven patients had previously experienced disease progression while being treated with brentuximab. RESULTS. No toxicities attributable to CD30.CAR-Ts were observed. Of 7 patients with relapsed HL, 1 entered complete response (CR) lasting more than 2.5 years after the second infusion of CD30.CAR-Ts, 1 remained in continued CR for almost 2 years, and 3 had transient stable disease. Of 2 patients with ALCL, 1 had a CR that persisted 9 months after the fourth infusion of CD30.CAR-Ts. CD30.CAR-T expansion in peripheral blood peaked 1 week after infusion, and CD30.CAR-Ts remained detectable for over 6 weeks. Although CD30 may also be expressed by normal activated T cells, no patients developed impaired virus-specific immunity. CONCLUSION. CD30.CAR-Ts are safe and can lead to clinical responses in patients with HL and ALCL, indicating that further assessment of this therapy is warranted.

AB - BACKGROUND. Targeting CD30 with monoclonal antibodies in Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) has had profound clinical success. However, adverse events, mainly mediated by the toxin component of the conjugated antibodies, cause treatment discontinuation in many patients. Targeting CD30 with T cells expressing a CD30- specific chimeric antigen receptor (CAR) may reduce the side effects and augment antitumor activity. METHODS. We conducted a phase I dose escalation study in which 9 patients with relapsed/refractory HL or ALCL were infused with autologous T cells that were gene-modified with a retroviral vector to express the CD30-specific CAR (CD30. CAR-Ts) encoding the CD28 costimulatory endodomain. Three dose levels, from 0.2 - 108 to 2 - 108 CD30.CAR-Ts/m2, were infused without a conditioning regimen. All other therapy for malignancy was discontinued at least 4 weeks before CD30. CAR-T infusion. Seven patients had previously experienced disease progression while being treated with brentuximab. RESULTS. No toxicities attributable to CD30.CAR-Ts were observed. Of 7 patients with relapsed HL, 1 entered complete response (CR) lasting more than 2.5 years after the second infusion of CD30.CAR-Ts, 1 remained in continued CR for almost 2 years, and 3 had transient stable disease. Of 2 patients with ALCL, 1 had a CR that persisted 9 months after the fourth infusion of CD30.CAR-Ts. CD30.CAR-T expansion in peripheral blood peaked 1 week after infusion, and CD30.CAR-Ts remained detectable for over 6 weeks. Although CD30 may also be expressed by normal activated T cells, no patients developed impaired virus-specific immunity. CONCLUSION. CD30.CAR-Ts are safe and can lead to clinical responses in patients with HL and ALCL, indicating that further assessment of this therapy is warranted.

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