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Clinical responses with T lymphocytes targeting malignancy-associated ? light chains.

ABSTRACT: 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 ? light chain (?.CAR) and therefore recognizes ?-restricted cells and spares the normal B cells expressing the nontargeted ? light chain, thus potentially minimizing humoral immunity impairment.We conducted a phase 1 clinical trial and treated 16 patients with relapsed or refractory ?+ non-Hodgkin lymphoma/chronic lymphocytic leukemia (NHL/CLL) or multiple myeloma (MM) with autologous T cells genetically modified to express ?.CAR (?.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 ?.CART infusion (0.2 × 108 to 2 × 108 ?.CARTs/m2). No other lymphodepletion was used.?.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 ?.CARTs, and 1 had a partial response. Of 7 patients with MM, 4 had stable disease lasting 2-17 months. No toxicities attributable to ?.CARTs were observed.?.CART infusion is feasible and safe and can lead to complete clinical responses.ClinicalTrials.gov NCT00881920.National Cancer Institute (NCI) grants 3P50CA126752 and 5P30CA125123 and Leukemia and Lymphoma Society (LLS) Specialized Centers of Research (SCOR) grant 7018.

SUBMITTER: Ramos CA

PROVIDER: S-EPMC4922690 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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

Ramos Carlos A CA Savoldo Barbara B Torrano Vicky V Ballard Brandon B Zhang Huimin H Dakhova Olga O Liu Enli E Carrum George G Kamble Rammurti T RT Gee Adrian P AP Mei Zhuyong Z Wu Meng-Fen MF Liu Hao H Grilley Bambi B Rooney Cliona M CM Brenner Malcolm K MK Heslop Helen E HE Dotti Gianpietro G

The Journal of clinical investigation 20160606 7

<h4>Background</h4>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 t ...[more]

PMID: 27270177

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Project description:Background:Monoclonal overproduction of kappa and/or lambda light chains might result in renal light chain deposition disease. Light chain associated cast nephropathy and renal AL-amyloidosis represent two further pathologies going along with monoclonal gammopathy of renal significance and multiple myeloma. While cast nephropathy often manifests with acute kidney injury, AL-amyloidosis is rather accompanied with chronic kidney disease. Methods:Urine samples were collected from 17 patients with multiple myeloma or monoclonal gammopathy. The urine sediment was stained for cast morphology by H/E and light chain immunofluorescence. Following micro-selection of casts under microscope, proteomic analysis of casts was performed by mass spectrometry. Sucrose gradient sedimentation was employed and light chain architecture examined by immunoblotting. Uromodulin was measured by ELISA in sucrose gradient fractions. Results:Urinary casts were observed of about 30 µm in diameter by H/E staining and under immunofluorescence microscopy. Casts with a diameter of 20 µm were observed as a novel variant. Proteome analysis showed that in addition to the expected light chain variants produced by the malignant clone of plasma cells, also histones such as H2B and cathepsin B were contained. Uromodulin was not detectable in urinary casts of all patients. All eleven patients with lambda light chains showed predominant dimerized light chains in the urine immunoblot. Six patients with kappa light chains presented with predominantly monomeric forms of light chains in the immunoblot. The densitometric evaluated ratio of lambda dimers vs. monomers was significantly higher (2.12 ± 0.75) when compared with the ratio of kappa dimers vs. monomers (0.64 ± 0.47), p = 0.00001. Aggregates of light chains separated in part into denser sucrose fractions. Conclusion:This work on urinary casts and light chains demonstrates that hyaline tubular casts represent a complex formation of protein-protein aggregates with histones and cathepsin B identified as novel cast components. Apart from the proteomic composition of the casts, also the formation of the light chains and aggregates is of relevance. Dimerized light chains, which are typical for lambda paraproteins, might be less dialyzable than monomeric forms and may therefore identify patients less responsive to high cut-off dialysis.

Project description: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.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.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.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.ClinicalTrials.gov NCT01316146.National Cancer Institute (3P50CA126752, R01CA131027 and P30CA125123), National Heart, Lung, and Blood Institute (R01HL114564), and Leukemia and Lymphoma Society (LLSTR 6227-08).

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Clinical responses with T lymphocytes targeting malignancy-associated ? light chains.

Publications

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

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