Clinical responses with T lymphocytes targeting malignancy-associated κ light chains

Carlos A. Ramos, Barbara Savoldo, Vicky Torrano, Brandon Ballard, Huimin Zhang, Olga Dakhova, Enli Liu, George Carrum, Rammurti T. Kamble, Adrian P. Gee, Zhuyong Mei, Meng Fen Wu, Hao Liu, Bambi Grilley, Cliona M. Rooney, Malcolm K. Brenner, Helen E. Heslop, Gianpietro Dotti

Research output: Contribution to journalArticle

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Abstract

BACKGROUND. Treatment of B cell malignancies with adoptive transfer of T cells with a CD19-specific chimeric antigen receptor (CAR) shows remarkable clinical efficacy. However, long-term persistence of T cells targeting CD19, a pan-B cell marker, also depletes normal B cells and causes severe hypogammaglobulinemia. Here, we developed a strategy to target B cell malignancies more selectively by taking advantage of B cell light Ig chain restriction. We generated a CAR that is specific for the κ light chain (κ.CAR) and therefore recognizes κ-restricted cells and spares the normal B cells expressing the nontargeted λ light chain, thus potentially minimizing humoral immunity impairment. METHODS. We conducted a phase 1 clinical trial and treated 16 patients with relapsed or refractory κ + non-Hodgkin lymphoma/chronic lymphocytic leukemia (NHL/CLL) or multiple myeloma (MM) with autologous T cells genetically modified to express K.CAR (κ.CARTS). Other treatments were discontinued in 11 of the 16 patients at least 4 weeks prior to T cell infusion. Six patients without lymphopenia received 12.5 mg/kg cyclophosphamide 4 days before κ.CART infusion (0.2 %times; 10 8 to 2 × 10 8 κ.CARTs/m 2 ). No other lymphodepletion was used. RESULTS. κ.CART expansion peaked 1-2 weeks after infusion, and cells remained detectable for more than 6 weeks. Of 9 patients with relapsed NHL or CLL, 2 entered complete remission after 2 and 3 infusions of κ.CARTs, and 1 had a partial response. Of 7 patients with MM, 4 had stable disease lasting 2-17 months. No toxicities attributable to κ.CARTS were observed. CONCLUSION. κ.CART infusion is feasible and safe and can lead to complete clinical responses.

Original languageEnglish (US)
Pages (from-to)2588-2596
Number of pages9
JournalJournal of Clinical Investigation
Volume126
Issue number7
DOIs
StatePublished - Jul 1 2016
Externally publishedYes

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B-Lymphocytes
T-Lymphocytes
Light
Antigen Receptors
Neoplasms
Multiple Myeloma
Agammaglobulinemia
Clinical Trials, Phase I
Lymphopenia
Adoptive Transfer
B-Cell Chronic Lymphocytic Leukemia
Humoral Immunity
Non-Hodgkin's Lymphoma
Cyclophosphamide
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Ramos, C. A., Savoldo, B., Torrano, V., Ballard, B., Zhang, H., Dakhova, O., ... Dotti, G. (2016). Clinical responses with T lymphocytes targeting malignancy-associated κ light chains. Journal of Clinical Investigation, 126(7), 2588-2596. https://doi.org/10.1172/JCI86000

Clinical responses with T lymphocytes targeting malignancy-associated κ light chains. / Ramos, Carlos A.; Savoldo, Barbara; Torrano, Vicky; Ballard, Brandon; Zhang, Huimin; Dakhova, Olga; Liu, Enli; Carrum, George; Kamble, Rammurti T.; Gee, Adrian P.; Mei, Zhuyong; Wu, Meng Fen; Liu, Hao; Grilley, Bambi; Rooney, Cliona M.; Brenner, Malcolm K.; Heslop, Helen E.; Dotti, Gianpietro.

In: Journal of Clinical Investigation, Vol. 126, No. 7, 01.07.2016, p. 2588-2596.

Research output: Contribution to journalArticle

Ramos, CA, Savoldo, B, Torrano, V, Ballard, B, Zhang, H, Dakhova, O, Liu, E, Carrum, G, Kamble, RT, Gee, AP, Mei, Z, Wu, MF, Liu, H, Grilley, B, Rooney, CM, Brenner, MK, Heslop, HE & Dotti, G 2016, 'Clinical responses with T lymphocytes targeting malignancy-associated κ light chains', Journal of Clinical Investigation, vol. 126, no. 7, pp. 2588-2596. https://doi.org/10.1172/JCI86000
Ramos CA, Savoldo B, Torrano V, Ballard B, Zhang H, Dakhova O et al. Clinical responses with T lymphocytes targeting malignancy-associated κ light chains. Journal of Clinical Investigation. 2016 Jul 1;126(7):2588-2596. https://doi.org/10.1172/JCI86000
Ramos, Carlos A. ; Savoldo, Barbara ; Torrano, Vicky ; Ballard, Brandon ; Zhang, Huimin ; Dakhova, Olga ; Liu, Enli ; Carrum, George ; Kamble, Rammurti T. ; Gee, Adrian P. ; Mei, Zhuyong ; Wu, Meng Fen ; Liu, Hao ; Grilley, Bambi ; Rooney, Cliona M. ; Brenner, Malcolm K. ; Heslop, Helen E. ; Dotti, Gianpietro. / Clinical responses with T lymphocytes targeting malignancy-associated κ light chains. In: Journal of Clinical Investigation. 2016 ; Vol. 126, No. 7. pp. 2588-2596.
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abstract = "BACKGROUND. Treatment of B cell malignancies with adoptive transfer of T cells with a CD19-specific chimeric antigen receptor (CAR) shows remarkable clinical efficacy. However, long-term persistence of T cells targeting CD19, a pan-B cell marker, also depletes normal B cells and causes severe hypogammaglobulinemia. Here, we developed a strategy to target B cell malignancies more selectively by taking advantage of B cell light Ig chain restriction. We generated a CAR that is specific for the κ light chain (κ.CAR) and therefore recognizes κ-restricted cells and spares the normal B cells expressing the nontargeted λ light chain, thus potentially minimizing humoral immunity impairment. METHODS. We conducted a phase 1 clinical trial and treated 16 patients with relapsed or refractory κ + non-Hodgkin lymphoma/chronic lymphocytic leukemia (NHL/CLL) or multiple myeloma (MM) with autologous T cells genetically modified to express K.CAR (κ.CARTS). Other treatments were discontinued in 11 of the 16 patients at least 4 weeks prior to T cell infusion. Six patients without lymphopenia received 12.5 mg/kg cyclophosphamide 4 days before κ.CART infusion (0.2 {\%}times; 10 8 to 2 × 10 8 κ.CARTs/m 2 ). No other lymphodepletion was used. RESULTS. κ.CART expansion peaked 1-2 weeks after infusion, and cells remained detectable for more than 6 weeks. Of 9 patients with relapsed NHL or CLL, 2 entered complete remission after 2 and 3 infusions of κ.CARTs, and 1 had a partial response. Of 7 patients with MM, 4 had stable disease lasting 2-17 months. No toxicities attributable to κ.CARTS were observed. CONCLUSION. κ.CART infusion is feasible and safe and can lead to complete clinical responses.",
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AU - Ramos, Carlos A.

AU - Savoldo, Barbara

AU - Torrano, Vicky

AU - Ballard, Brandon

AU - Zhang, Huimin

AU - Dakhova, Olga

AU - Liu, Enli

AU - Carrum, George

AU - Kamble, Rammurti T.

AU - Gee, Adrian P.

AU - Mei, Zhuyong

AU - Wu, Meng Fen

AU - Liu, Hao

AU - Grilley, Bambi

AU - Rooney, Cliona M.

AU - Brenner, Malcolm K.

AU - Heslop, Helen E.

AU - Dotti, Gianpietro

PY - 2016/7/1

Y1 - 2016/7/1

N2 - BACKGROUND. Treatment of B cell malignancies with adoptive transfer of T cells with a CD19-specific chimeric antigen receptor (CAR) shows remarkable clinical efficacy. However, long-term persistence of T cells targeting CD19, a pan-B cell marker, also depletes normal B cells and causes severe hypogammaglobulinemia. Here, we developed a strategy to target B cell malignancies more selectively by taking advantage of B cell light Ig chain restriction. We generated a CAR that is specific for the κ light chain (κ.CAR) and therefore recognizes κ-restricted cells and spares the normal B cells expressing the nontargeted λ light chain, thus potentially minimizing humoral immunity impairment. METHODS. We conducted a phase 1 clinical trial and treated 16 patients with relapsed or refractory κ + non-Hodgkin lymphoma/chronic lymphocytic leukemia (NHL/CLL) or multiple myeloma (MM) with autologous T cells genetically modified to express K.CAR (κ.CARTS). Other treatments were discontinued in 11 of the 16 patients at least 4 weeks prior to T cell infusion. Six patients without lymphopenia received 12.5 mg/kg cyclophosphamide 4 days before κ.CART infusion (0.2 %times; 10 8 to 2 × 10 8 κ.CARTs/m 2 ). No other lymphodepletion was used. RESULTS. κ.CART expansion peaked 1-2 weeks after infusion, and cells remained detectable for more than 6 weeks. Of 9 patients with relapsed NHL or CLL, 2 entered complete remission after 2 and 3 infusions of κ.CARTs, and 1 had a partial response. Of 7 patients with MM, 4 had stable disease lasting 2-17 months. No toxicities attributable to κ.CARTS were observed. CONCLUSION. κ.CART infusion is feasible and safe and can lead to complete clinical responses.

AB - BACKGROUND. Treatment of B cell malignancies with adoptive transfer of T cells with a CD19-specific chimeric antigen receptor (CAR) shows remarkable clinical efficacy. However, long-term persistence of T cells targeting CD19, a pan-B cell marker, also depletes normal B cells and causes severe hypogammaglobulinemia. Here, we developed a strategy to target B cell malignancies more selectively by taking advantage of B cell light Ig chain restriction. We generated a CAR that is specific for the κ light chain (κ.CAR) and therefore recognizes κ-restricted cells and spares the normal B cells expressing the nontargeted λ light chain, thus potentially minimizing humoral immunity impairment. METHODS. We conducted a phase 1 clinical trial and treated 16 patients with relapsed or refractory κ + non-Hodgkin lymphoma/chronic lymphocytic leukemia (NHL/CLL) or multiple myeloma (MM) with autologous T cells genetically modified to express K.CAR (κ.CARTS). Other treatments were discontinued in 11 of the 16 patients at least 4 weeks prior to T cell infusion. Six patients without lymphopenia received 12.5 mg/kg cyclophosphamide 4 days before κ.CART infusion (0.2 %times; 10 8 to 2 × 10 8 κ.CARTs/m 2 ). No other lymphodepletion was used. RESULTS. κ.CART expansion peaked 1-2 weeks after infusion, and cells remained detectable for more than 6 weeks. Of 9 patients with relapsed NHL or CLL, 2 entered complete remission after 2 and 3 infusions of κ.CARTs, and 1 had a partial response. Of 7 patients with MM, 4 had stable disease lasting 2-17 months. No toxicities attributable to κ.CARTS were observed. CONCLUSION. κ.CART infusion is feasible and safe and can lead to complete clinical responses.

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