Bispecific Antibodies for the Treatment of Acute Myeloid Leukemia

Guy, Daniel; Uy, Brian

doi:10.1007/s11899-018-0472-8

Cited by 69 publications

(51 citation statements)

References 72 publications

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“…There were 13/42 responders (6 stringent complete responses (sCRs), 3 complete responses (CRs), 2 very good partial responses (VGPRs), and 2 partial responses (PRs)) [72]. A number of BiTEs targeting CD33, CD123, and CLEC12A/CCL-1 (CD371) have been developed for AML [73][74][75][76]. The full-length human IgG1 bispecific antibody MCLA-117 targeting CLEC12AxCD3 is also currently being tested in AML (NCR03038230) [77].…”

Section: Recent Findings Related To Immunotherapy Against Multiple Mymentioning

confidence: 99%

“…The full-length human IgG1 bispecific antibody MCLA-117 targeting CLEC12AxCD3 is also currently being tested in AML (NCR03038230) [77]. Flotetuzumab (a bispecific antibody that targets both CD3 and CD123) demonstrated measurable anti-leukemic effects in 8/14 patients with chemotherapy-refractory AML (57%), and two of these patients achieved complete remission [75].…”

Section: Recent Findings Related To Immunotherapy Against Multiple Mymentioning

confidence: 99%

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NK and NKT Cell-Mediated Immune Surveillance against Hematological Malignancies

Shimizu

Iyoda

Yamasaki

et al. 2020

Cancers

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Recent cancer treatment modalities have been intensively focused on immunotherapy. The success of chimeric antigen receptor T cell therapy for treatment of refractory B cell acute lymphoblastic leukemia has pushed forward research on hematological malignancies. Among the effector types of innate lymphocytes, natural killer (NK) cells show great importance in immune surveillance against infectious and tumor diseases. Particularly, the role of NK cells has been argued in either elimination of target tumor cells or escape of tumor cells from immune surveillance. Therefore, an NK cell activation approach has been explored. Recent findings demonstrate that invariant natural killer T (iNKT) cells capable of producing IFN-γ when optimally activated can promptly trigger NK cells. Here, we review the role of NKT and/or NK cells and their interaction in anti-tumor responses by highlighting how innate immune cells recognize tumors, exert effector functions, and amplify adaptive immune responses. In addition, we discuss these innate lymphocytes in hematological disorders, particularly multiple myeloma and acute myeloid leukemia. The immune balance at different stages of both diseases is explored in light of disease progression. Various types of innate immunity-mediated therapeutic approaches, recent advances in clinical immunotherapies, and iNKT-mediated cancer immunotherapy as next-generation immunotherapy are then discussed.

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Section: Recent Findings Related To Immunotherapy Against Multiple Mymentioning

confidence: 99%

Section: Recent Findings Related To Immunotherapy Against Multiple Mymentioning

confidence: 99%

NK and NKT Cell-Mediated Immune Surveillance against Hematological Malignancies

Shimizu

Iyoda

Yamasaki

et al. 2020

Cancers

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“…For example, several of these bi-specific antibody-type drugs are able to recruit lymphoid killer cells onto the malignant target cells. 82,89,90 Bi-specific antibodies can also be directed against key checkpoint molecules, such as PD-L1, PD-1, or CD47. A clinically important point is that in most instances, bi-specific antibodies do not need to internalize for therapeutic efficacy as their major task is to recruit immune cells for killing LSC.…”

Section: Targeting Of Aml Lsc By Applying Bi-or Tri-specific Antibomentioning

confidence: 99%

“…A clinically important point is that in most instances, bi-specific antibodies do not need to internalize for therapeutic efficacy as their major task is to recruit immune cells for killing LSC. 89,90 There are several types of bi-specific antibodies applied in clinical hematology. In the past few years, several efforts have been made to develop effective bi-specific antibodies for the treatment of AML.…”

Section: Targeting Of Aml Lsc By Applying Bi-or Tri-specific Antibomentioning

confidence: 99%

Cell-based and antibody-mediated immunotherapies directed against leukemic stem cells in acute myeloid leukemia: Perspectives and open issues

Valent

Bauer

Sadovnik

et al. 2020

Stem Cells Translational Medicine

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Despite new insights in molecular features of leukemic cells and the availability of novel treatment approaches and drugs, acute myeloid leukemia (AML) remains a major clinical challenge. In fact, many patients with AML relapse after standard therapy and eventually die from progressive disease. The basic concept of leukemic stem cells (LSC) has been coined with the goal to decipher clonal architectures in various leukemia-models and to develop curative drug therapies by eliminating LSC. Indeed, during the past few years, various immunotherapies have been tested in AML, and several of these therapies follow the strategy to eliminate relevant leukemic subclones by introducing LSC-targeting antibodies or LSC-targeting immune cells. These therapies include, among others, new generations of LSC-eliminating antibody-constructs, checkpoint-targeting antibodies, bi-specific antibodies, and CART or CAR-NK cell-based strategies. However, responses are often limited and/or transient which may be due to LSC resistance. Indeed, AML LSC exhibit multiple forms of resistance against various drugs and immunotherapies. An additional problems are treatment-induced myelotoxicity and other side effects. The current article provides a short overview of immunological targets expressed on LSC in AML. Moreover, cell-based therapies and immunotherapies tested in AML are discussed. Finally, the article provides an overview about LSC resistance and strategies to overcome resistance.

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“…Bispecific antibodies (BsAbs) offer a promising immunotherapeutic approach for numerous malignancies including MM. Immune effector cell redirecting BsAbs commonly bind to a tumor cell antigen and CD3 on a T cell, resulting in T cell binding to the tumor cell, activation, and tumor cell lysis (11,12). Since BsAbs directly stimulate CD3 and thus bypass the T cell receptor, they activate T cells independently from antigen presentation on major histocompatibility complex (MHC) class I.…”

Section: Introductionmentioning

confidence: 99%

Bispecific Antibodies for Multiple Myeloma: A Review of Targets, Drugs, Clinical Trials, and Future Directions

et al. 2020

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Multiple myeloma (MM) is a plasma cell malignancy and the second most common hematological neoplasm in adults, comprising 1.8% of all cancers. With an annual incidence of ∼30,770 cases in the United States, MM has a high mortality rate, leading to 12,770 deaths per year. MM is a genetically complex, highly heterogeneous malignancy, with significant inter-and intra-patient clonal variability. Recent years have witnessed dramatic improvements in the diagnostics, classification, and treatment of MM. However, patients with high-risk disease have not yet benefited from therapeutic advances. Highrisk patients are often primary refractory to treatment or relapse early, ultimately resulting in progression toward aggressive end-stage MM, with associated extramedullary disease or plasma cell leukemia. Therefore, novel treatment modalities are needed to improve the outcomes of these patients. Bispecific antibodies (BsAbs) are immunotherapeutics that simultaneously target and thereby redirect effector immune cells to tumor cells. BsAbs have shown high efficacy in B cell malignancies, including refractory/relapsed acute lymphoblastic leukemia. Various BsAbs targeting MM-specific antigens such as B cell maturation antigen (BCMA), CD38, and CD138 are currently in pre-clinical and clinical development, with promising results. In this review, we outline these advances, focusing on BsAb drugs, their targets, and their potential to improve survival, especially for high-risk MM patients. In combination with current treatment strategies, BsAbs may pave the way toward a cure for MM.

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Bispecific Antibodies for the Treatment of Acute Myeloid Leukemia

Cited by 69 publications

References 72 publications

NK and NKT Cell-Mediated Immune Surveillance against Hematological Malignancies

NK and NKT Cell-Mediated Immune Surveillance against Hematological Malignancies

Cell-based and antibody-mediated immunotherapies directed against leukemic stem cells in acute myeloid leukemia: Perspectives and open issues

Bispecific Antibodies for Multiple Myeloma: A Review of Targets, Drugs, Clinical Trials, and Future Directions

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