Analysis of λ repertoire in κ-deficient mice

Pricop, Luminita; Hatakeyama, Akira; Isobe, H; Bona, Constantin A.

doi:10.1016/s0090-1229(95)90162-0

Cited by 4 publications

(3 citation statements)

References 77 publications

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“…22 Chimeric T lymphocytes targeting the light chain expressed by the tumor should spare normal B cells expressing the reciprocal light chain. Because no functional differences have been found between antibodies containing the or chains 23 and because light chain deficiency has been described in animals 24 and humans 24,25 without increased susceptibility to infection, sparing the normal population of B lymphocytes expressing the nontargeted light chain should have minimal adverse effects on patient immunity. We now demonstrate the feasibility of this approach using a light chain-specific chimeric T-cell receptor.…”

Section: Introductionmentioning

confidence: 99%

T lymphocytes redirected against the κ light chain of human immunoglobulin efficiently kill mature B lymphocyte-derived malignant cells

Vera

Savoldo

Vigouroux

et al. 2006

Blood

248

281

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IntroductionLow-grade non-Hodgkin lymphomas (B-NHLs) and B-cell chronic lymphocytic leukemia (B-CLL) are generally characterized by a smoldering clinical course. 1,2 Nonetheless, these diseases slowly progress and require intervention. Although remission can be obtained with chemotherapy and antibody directed to B-cell antigens such as CD20, most patients ultimately have relapses. [3][4][5] More aggressive treatments including allogeneic stem cell transplantation may eradicate disease, apparently in part by a T cell-mediated graft-versus-leukemia (GVL) effect. [6][7][8] Unfortunately, their high rate of morbidity and mortality limits their application to younger patients. 9,10 Because these malignancies are sensitive to both T cell-mediated and antibody-mediated cytotoxic effector functions, there has been increasing interest in combining these approaches and recruiting the host immune system to help eradicate the disease that remains after conventional treatments. Anti-idiotype vaccine or whole tumor cell-based vaccines have been used in several clinical trials, but although antitumor activity was observed, the effects were often limited and transient. [11][12][13][14] An alternative means of recruiting both the cellular and humoral arms of the immune response is to adoptively transfer T cells genetically modified to express a B cellspecific antibody incorporated in an artificial chimeric T-cell receptor (CAR). 15,16 These molecules combine the antigen-binding property of monoclonal antibodies with the lytic capacity and potential longevity of T lymphocytes to provide an enhanced antitumor effect. 16 Because B-NHL and B-CLL stably express CD19 or CD20 antigens, adoptive transfer of CD19-or CD20-specific CARs to T lymphocytes has been proposed. [17][18][19][20] However, adoptively transferred T cells, unlike monoclonal antibodies, may have almost indefinite persistence 21 so that success of this approach would likely be associated with long-term impairment of humoral immunity. We now propose an alternative target for chimeric T cells. B lymphocytes express surface monoclonal immunoglobulins with either or light chains. Because expression of / is clonally restricted, and because low-grade B-NHL and B-CLL are themselves clonal, the malignant cells in a given individual will express either or light chain. 22 Chimeric T lymphocytes targeting the light chain expressed by the tumor should spare normal B cells expressing the reciprocal light chain. Because no functional differences have been found between antibodies containing the or chains 23 and because light chain deficiency has been described in animals 24 and humans 24,25 without increased susceptibility to infection, sparing the normal population of B lymphocytes expressing the nontargeted light chain should have minimal adverse effects on patient immunity. We now demonstrate the feasibility of this approach using a light chain-specific chimeric T-cell receptor. For personal use only. on May 11, 2018. by guest www.bloodjournal.org From culture with RPMI 1640 medi...

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Section: Introductionmentioning

confidence: 99%

T lymphocytes redirected against the κ light chain of human immunoglobulin efficiently kill mature B lymphocyte-derived malignant cells

Vera

Savoldo

Vigouroux

et al. 2006

Blood

248

281

View full text Add to dashboard Cite

show abstract

“…B cells and plasma cells can express kappa or lambda chains on their surfaces. The defect of kappa light chain does not lead to a significant down-regulation of humoral immunity and up-regulation of susceptibility to pathogens (37). In MM patients, the positive detection rate of monoclonal kappa light chain antigen on the surface of MM cells expressing only kappa light chain was 70%, while no monoclonal lambda light chain antigen was detected on the surface of MM cells expressing lambda light chain (38).…”

Section: Immunoglobulin Kappa Light Chainmentioning

confidence: 96%

Novel progresses of chimeric antigen receptor (CAR) T cell therapy in multiple myeloma

Ding¹,

Hu²,

Huang³

2021

Stem Cell Investig

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Multiple myeloma (MM) is a malignant proliferative disease of plasma cells, which leads to suppressed hematopoietic and osteolytic diseases. Despite the use of traditional chemotherapy, hematopoietic stem cell transplantation (HSCT) and targeted drugs, MM still cannot be completely cured. In recent years, chimeric antigen receptor (CAR) T cells have revolutionized immunotherapy and cancer treatment. The great success of CAR-T cells in leukemia and lymphoma has promoted its development in MM. The primary requisite for developing clinically effective CAR-T cells suitable for MM is to identify the appropriate targets. In early clinical trials, CAR-T cells targeting B-cell maturation antigen (BCMA) have shown significant anti-MM activity. Currently popular targets in clinical research and preclinical research include CD138, CD38, CS1, CD19, κ light chain, CD56, CD44v6, Lewis Y, NY-ESO-1, CD229, etc.Common toxicities such as cytokine release syndrome (CRS) and neurotoxicity also occur but controllable.MM cells are mainly localized in bone marrow, therefore, the bone marrow microenvironment has a significant effect on the therapeutic effect of CAR-T cells. Targeting both MM cells and the bone marrow microenvironment is currently the most promising treatment. In this review, we provide a comprehensive overview of CAR-T cell therapy in MM, as well as outline potential targets and methods that can overcome local immunosuppression and improve the efficacy of CAR-T cells.

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“…The concept behind this approach is that B-cell malignancies are clonal disorders wherein a patient’s malignant cells express a κ or λ-restricted sIg, but not both. In those patients with a κ-restricted malignancy, the anti-κ CAR T-cells would ideally eliminate all malignant cells and, consequently, normal B-cells with κ expression; however, normal λ-restricted B cells would be left untouched providing these patients with adequate B-cell immunity [ 207 , 208 ].…”

Section: Reviewmentioning

confidence: 99%

Adoptive T-cell therapy for Leukemia

Garber¹,

Mirza²,

Mittendorf³

et al. 2014

Molecular and Cellular Therapies

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Allogeneic stem cell transplantation (alloSCT) is the most robust form of adoptive cellular therapy (ACT) and has been tremendously effective in the treatment of leukemia. It is one of the original forms of cancer immunotherapy and illustrates that lymphocytes can specifically recognize and eliminate aberrant, malignant cells. However, because of the high morbidity and mortality that is associated with alloSCT including graft-versus-host disease (GvHD), refining the anti-leukemia immunity of alloSCT to target distinct antigens that mediate the graft-versus-leukemia (GvL) effect could transform our approach to treating leukemia, and possibly other hematologic malignancies. Over the past few decades, many leukemia antigens have been discovered that can separate malignant cells from normal host cells and render them vulnerable targets. In concert, the field of T-cell engineering has matured to enable transfer of ectopic high-affinity antigen receptors into host or donor cells with greater efficiency and potency. Many preclinical studies have demonstrated that engineered and conventional T-cells can mediate lysis and eradication of leukemia via one or more leukemia antigen targets. This evidence now serves as a foundation for clinical trials that aim to cure leukemia using T-cells. The recent clinical success of anti-CD19 chimeric antigen receptor (CAR) cells for treating patients with acute lymphoblastic leukemia and chronic lymphocytic leukemia displays the potential of this new therapeutic modality. In this review, we discuss some of the most promising leukemia antigens and the novel strategies that have been implemented for adoptive cellular immunotherapy of lymphoid and myeloid leukemias. It is important to summarize the data for ACT of leukemia for physicians in-training and in practice and for investigators who work in this and related fields as there are recent discoveries already being translated to the patient setting and numerous accruing clinical trials. We primarily focus on ACT that has been used in the clinical setting or that is currently undergoing preclinical testing with a foreseeable clinical endpoint.

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Analysis of λ repertoire in κ-deficient mice

Cited by 4 publications

References 77 publications

T lymphocytes redirected against the κ light chain of human immunoglobulin efficiently kill mature B lymphocyte-derived malignant cells

T lymphocytes redirected against the κ light chain of human immunoglobulin efficiently kill mature B lymphocyte-derived malignant cells

Novel progresses of chimeric antigen receptor (CAR) T cell therapy in multiple myeloma

Adoptive T-cell therapy for Leukemia

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