International Journal of Molecular Sciences

Research

Jump to: Review

14 pages, 2023 KiB

Open AccessArticle

Comparison of FACS and PCR for Detection of BCMA-CAR-T Cells

by Avinoam Reichman, Alexander Kunz, Jara J. Joedicke, Uta E. Höpken, Anna Keib, Brigitte Neuber, David Sedloev, Lei Wang, Genqiao Jiang, Angela Hückelhoven-Krauss, Franziska Eberhardt, Carsten Müller-Tidow, Martin Wermke, Armin Rehm, Michael Schmitt and Anita Schmitt

Int. J. Mol. Sci. 2022, 23(2), 903; https://doi.org/10.3390/ijms23020903 - 14 Jan 2022

Cited by 7 | Viewed by 3558

Abstract

Chimeric-antigen-receptor (CAR)-T-cell therapy is already widely used to treat patients who are relapsed or refractory to chemotherapy, antibodies, or stem-cell transplantation. Multiple myeloma still constitutes an incurable disease. CAR-T-cell therapy that targets BCMA (B-cell maturation antigen) is currently revolutionizing the treatment of those [...] Read more.

Chimeric-antigen-receptor (CAR)-T-cell therapy is already widely used to treat patients who are relapsed or refractory to chemotherapy, antibodies, or stem-cell transplantation. Multiple myeloma still constitutes an incurable disease. CAR-T-cell therapy that targets BCMA (B-cell maturation antigen) is currently revolutionizing the treatment of those patients. To monitor and improve treatment outcomes, methods to detect CAR-T cells in human peripheral blood are highly desirable. In this study, three different detection reagents for staining BCMA-CAR-T cells by flow cytometry were compared. Moreover, a quantitative polymerase chain reaction (qPCR) to detect BCMA-CAR-T cells was established. By applying a cell-titration experiment of BCMA-CAR-T cells, both methods were compared head-to-head. In flow-cytometric analysis, the detection reagents used in this study could all detect BCMA-CAR-T cells at a similar level. The results of false-positive background staining differed as follows (standard deviation): the BCMA-detection reagent used on the control revealed a background staining of 0.04% (±0.02%), for the PE-labeled human BCMA peptide it was 0.25% (±0.06%) and for the polyclonal anti-human IgG antibody it was 7.2% (±9.2%). The ability to detect BCMA-CAR-T cells down to a concentration of 0.4% was similar for qPCR and flow cytometry. The qPCR could detect even lower concentrations (0.02–0.01%). In summary, BCMA-CAR-T-cell monitoring can be reliably performed by both flow cytometry and qPCR. In flow cytometry, reagents with low background staining should be preferred. Full article

(This article belongs to the Special Issue Novel Approaches to Hematologic Malignancies by Immunotherapy)

► Show Figures

Figure 1

Review

Jump to: Research

22 pages, 784 KiB

Open AccessReview

Promising Immunotherapeutic Modalities for B-Cell Lymphoproliferative Disorders

by Jana Mihályová, Katarína Hradská, Tomáš Jelínek, Benjamin Motais, Piotr Celichowski and Roman Hájek

Int. J. Mol. Sci. 2021, 22(21), 11470; https://doi.org/10.3390/ijms222111470 - 25 Oct 2021

Cited by 6 | Viewed by 5838

Abstract

Over the last few years, treatment principles have been changed towards more targeted therapy for many B-cell lymphoma subtypes and in chronic lymphocytic leukemia (CLL). Immunotherapeutic modalities, namely monoclonal antibodies (mAbs), bispecific antibodies (bsAbs), antibody-drug conjugates (ADCs), and chimeric antigen receptor T (CAR-T) [...] Read more.

Over the last few years, treatment principles have been changed towards more targeted therapy for many B-cell lymphoma subtypes and in chronic lymphocytic leukemia (CLL). Immunotherapeutic modalities, namely monoclonal antibodies (mAbs), bispecific antibodies (bsAbs), antibody-drug conjugates (ADCs), and chimeric antigen receptor T (CAR-T) cell therapy, commonly use B-cell-associated antigens (CD19, CD20, CD22, and CD79b) as one of their targets. T-cell engagers (TCEs), a subclass of bsAbs, work on a similar mechanism as CAR-T cell therapy without the need of previous T-cell manipulation. Currently, several anti-CD20xCD3 TCEs have demonstrated promising efficacy across different lymphoma subtypes with slightly better outcomes in the indolent subset. Anti-CD19xCD3 TCEs are being developed as well but only blinatumomab has been evaluated in clinical trials yet. The results are not so impressive as those with anti-CD19 CAR-T cell therapy. Antibody-drug conjugates targeting different B-cell antigens (CD30, CD79b, CD19) seem to be effective in combination with mAbs, standard chemoimmunotherapy, or immune checkpoint inhibitors. Further investigation will show whether immunotherapy alone or in combinatory regimens has potential to replace chemotherapeutic agents from the first line treatment. Full article

(This article belongs to the Special Issue Novel Approaches to Hematologic Malignancies by Immunotherapy)

► Show Figures

Figure 1

20 pages, 960 KiB

Open AccessReview

Targeted Therapeutic Approach Based on Understanding of Aberrant Molecular Pathways Leading to Leukemic Proliferation in Patients with Acute Myeloid Leukemia

by Moo-Kon Song, Byeong-Bae Park and Ji-Eun Uhm

Int. J. Mol. Sci. 2021, 22(11), 5789; https://doi.org/10.3390/ijms22115789 - 28 May 2021

Cited by 6 | Viewed by 3453

Abstract

Acute myeloid leukemia (AML) is a heterogenous hematopoietic neoplasm with various genetic abnormalities in myeloid stem cells leading to differentiation arrest and accumulation of leukemic cells in bone marrow (BM). The multiple genetic alterations identified in leukemic cells at diagnosis are the mainstay [...] Read more.

Acute myeloid leukemia (AML) is a heterogenous hematopoietic neoplasm with various genetic abnormalities in myeloid stem cells leading to differentiation arrest and accumulation of leukemic cells in bone marrow (BM). The multiple genetic alterations identified in leukemic cells at diagnosis are the mainstay of World Health Organization classification for AML and have important prognostic implications. Recently, understanding of heterogeneous and complicated molecular abnormalities of the disease could lead to the development of novel targeted therapeutic agents. In the past years, gemtuzumab ozogamicin, BCL-2 inhibitors (venetovlax), IDH 1/2 inhibitors (ivosidenib and enasidenib) FLT3 inhibitors (midostaurin, gilteritinib, and enasidenib), and hedgehog signaling pathway inhibitors (gladegib) have received US Food and Drug Administration (FDA) approval for the treatment of AML. Especially, AML patients with elderly age and/or significant comorbidities are not currently suitable for intensive chemotherapy. Thus, novel therapeutic planning including the abovementioned target therapies could lead to improve clinical outcomes in the patients. In the review, we will present various important and frequent molecular abnormalities of AML and introduce the targeted agents of AML that received FDA approval based on the previous studies. Full article

(This article belongs to the Special Issue Novel Approaches to Hematologic Malignancies by Immunotherapy)

► Show Figures

Figure 1

20 pages, 2662 KiB

Open AccessReview

Emerging Immunotherapy for Acute Myeloid Leukemia

by Rikako Tabata, SungGi Chi, Junichiro Yuda and Yosuke Minami

Int. J. Mol. Sci. 2021, 22(4), 1944; https://doi.org/10.3390/ijms22041944 - 16 Feb 2021

Cited by 37 | Viewed by 6798

Abstract

Several immune checkpoint molecules and immune targets in leukemic cells have been investigated. Recent studies have suggested the potential clinical benefits of immuno-oncology (IO) therapy against acute myeloid leukemia (AML), especially targeting CD33, CD123, and CLL-1, as well as immune checkpoint inhibitors (e.g., [...] Read more.

Several immune checkpoint molecules and immune targets in leukemic cells have been investigated. Recent studies have suggested the potential clinical benefits of immuno-oncology (IO) therapy against acute myeloid leukemia (AML), especially targeting CD33, CD123, and CLL-1, as well as immune checkpoint inhibitors (e.g., anti-PD (programmed cell death)-1 and anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) antibodies) with or without conventional chemotherapy. Early-phase clinical trials of chimeric antigen receptor (CAR)-T or natural killer (NK) cells for relapsed/refractory AML showed complete remission (CR) or marked reduction of marrow blasts in a few enrolled patients. Bi-/tri-specific antibodies (e.g., bispecific T-cell engager (BiTE) and dual-affinity retargeting (DART)) exhibited 11–67% CR rates with 13–78% risk of cytokine-releasing syndrome (CRS). Conventional chemotherapy in combination with anti-PD-1/anti-CTLA4 antibody for relapsed/refractory AML showed 10–36% CR rates with 7–24 month-long median survival. The current advantages of IO therapy in the field of AML are summarized herein. However, although cancer vaccination should be included in the concept of IO therapy, it is not mentioned in this review because of the paucity of relevant evidence. Full article

(This article belongs to the Special Issue Novel Approaches to Hematologic Malignancies by Immunotherapy)

► Show Figures

Figure 1

21 pages, 958 KiB

Open AccessReview

Gene Modified CAR-T Cellular Therapy for Hematologic Malignancies

by Wen-Ying Lin, Hsin-Hui Wang, Yi-Wei Chen, Chun-Fu Lin, Hueng-Chuen Fan and Yi-Yen Lee

Int. J. Mol. Sci. 2020, 21(22), 8655; https://doi.org/10.3390/ijms21228655 - 17 Nov 2020

Cited by 15 | Viewed by 3968

Abstract

With advances in the understanding of characteristics of molecules, specific antigens on the surface of hematological malignant cells were identified and multiple therapies targeting these antigens as neoplasm treatments were developed. Among them, chimeric antigen receptor (CAR) T-cell therapy, which got United States [...] Read more.

With advances in the understanding of characteristics of molecules, specific antigens on the surface of hematological malignant cells were identified and multiple therapies targeting these antigens as neoplasm treatments were developed. Among them, chimeric antigen receptor (CAR) T-cell therapy, which got United States Food and Drug Administration (FDA) approval for relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) as well as for recurrent acute lymphoblastic leukemia (ALL) within the past five years, and for r/r mantle cell lymphoma (MCL) this year, represents one of the most rapidly evolving immunotherapies. Nevertheless, its applicability to other hematological malignancies, as well as its efficacy and persistence are fraught with clinical challenges. Currently, more than one thousand clinical trials in CAR T-cell therapy are ongoing and its development is changing rapidly. This review introduces the current status of CAR T-cell therapy in terms of the basic molecular aspects of CAR T-cell therapy, its application in hematological malignancies, adverse reactions during clinical use, remaining challenges, and future utilization. Full article

(This article belongs to the Special Issue Novel Approaches to Hematologic Malignancies by Immunotherapy)

► Show Figures

Figure 1

12 pages, 237 KiB

Open AccessReview

Novel Therapies for Relapsed or Refractory Diffuse Large B-Cell Lymphoma

by Leonard Jeff Harris, Kruti Patel and Michael Martin

Int. J. Mol. Sci. 2020, 21(22), 8553; https://doi.org/10.3390/ijms21228553 - 13 Nov 2020

Cited by 21 | Viewed by 5730

Abstract

The most common type of non-Hodgkin lymphoma in adults is diffuse large B-cell (DLBCL). There is a historical unmet need for more effective therapies in the 2nd and 3rd line setting. Emerging immunochemotherapies have shown activity in small studies of heavily pre-treated patients [...] Read more.

The most common type of non-Hodgkin lymphoma in adults is diffuse large B-cell (DLBCL). There is a historical unmet need for more effective therapies in the 2nd and 3rd line setting. Emerging immunochemotherapies have shown activity in small studies of heavily pre-treated patients with prolonged remissions achieved in some patients. Anti-CD19 CAR (chimeric antigen receptor) T cells are potentially curative in the 3rd line and beyond setting and are under investigation in earlier lines of therapy. Antibody-drug conjugates (ADC’s) such as polatuzumab vedotin targeting the pan-B-cell marker CD79b has proven effectiveness in multiply-relapsed DLBCL patients. Tafasitamab (MOR208) is an anti-CD19 monoclonal antibody producing prolonged remissions when combined with Lenalidomide (LEN) in patients who were not candidates for salvage chemotherapy or autologous stem cell transplant. Selinexor, an oral, small-molecule selective inhibitor of XPO1-mediated nuclear export (SINE), demonstrated prolonged activity against heavily-pretreated DLBCL without cumulative toxicity and is being investigated as part of an oral, chemotherapy-free regimen for relapsed aggressive lymphoma. This article reviews current strategies and novel therapies for relapsed/refractory DLBCL. Full article

(This article belongs to the Special Issue Novel Approaches to Hematologic Malignancies by Immunotherapy)

23 pages, 1664 KiB

Open AccessReview

Immunotherapy in Hematologic Malignancies: Emerging Therapies and Novel Approaches

by Ji-Yoon Noh, Huiyun Seo, Jungwoon Lee and Haiyoung Jung

Int. J. Mol. Sci. 2020, 21(21), 8000; https://doi.org/10.3390/ijms21218000 - 27 Oct 2020

Cited by 18 | Viewed by 7374

Abstract

Immunotherapy is extensively investigated for almost all types of hematologic tumors, from preleukemic to relapse/refractory malignancies. Due to the emergence of technologies for target cell characterization, antibody design and manufacturing, as well as genome editing, immunotherapies including gene and cell therapies are becoming [...] Read more.

Immunotherapy is extensively investigated for almost all types of hematologic tumors, from preleukemic to relapse/refractory malignancies. Due to the emergence of technologies for target cell characterization, antibody design and manufacturing, as well as genome editing, immunotherapies including gene and cell therapies are becoming increasingly elaborate and diversified. Understanding the tumor immune microenvironment of the target disease is critical, as is reducing toxicity. Although there have been many successes and newly FDA-approved immunotherapies for hematologic malignancies, we have learned that insufficient efficacy due to disease relapse following treatment is one of the key obstacles for developing successful therapeutic regimens. Thus, combination therapies are also being explored. In this review, immunotherapies for each type of hematologic malignancy will be introduced, and novel targets that are under investigation will be described. Full article

(This article belongs to the Special Issue Novel Approaches to Hematologic Malignancies by Immunotherapy)

► Show Figures

Figure 1

35 pages, 2058 KiB

Open AccessReview

Facts and Challenges in Immunotherapy for T-Cell Acute Lymphoblastic Leukemia

by Fátima Bayón-Calderón, María L. Toribio and Sara González-García

Int. J. Mol. Sci. 2020, 21(20), 7685; https://doi.org/10.3390/ijms21207685 - 16 Oct 2020

Cited by 32 | Viewed by 6567

Abstract

T-cell acute lymphoblastic leukemia (T-ALL), a T-cell malignant disease that mainly affects children, is still a medical challenge, especially for refractory patients for whom therapeutic options are scarce. Recent advances in immunotherapy for B-cell malignancies based on increasingly efficacious monoclonal antibodies (mAbs) and [...] Read more.

T-cell acute lymphoblastic leukemia (T-ALL), a T-cell malignant disease that mainly affects children, is still a medical challenge, especially for refractory patients for whom therapeutic options are scarce. Recent advances in immunotherapy for B-cell malignancies based on increasingly efficacious monoclonal antibodies (mAbs) and chimeric antigen receptors (CARs) have been encouraging for non-responding or relapsing patients suffering from other aggressive cancers like T-ALL. However, secondary life-threatening T-cell immunodeficiency due to shared expression of targeted antigens by healthy and malignant T cells is a main drawback of mAb—or CAR-based immunotherapies for T-ALL and other T-cell malignancies. This review provides a comprehensive update on the different immunotherapeutic strategies that are being currently applied to T-ALL. We highlight recent progress on the identification of new potential targets showing promising preclinical results and discuss current challenges and opportunities for developing novel safe and efficacious immunotherapies for T-ALL. Full article

(This article belongs to the Special Issue Novel Approaches to Hematologic Malignancies by Immunotherapy)

► Show Figures

Figure 1

15 pages, 274 KiB

Open AccessReview

Immune-Checkpoint Blockade Therapy in Lymphoma

by Ayumi Kuzume, SungGi Chi, Nobuhiko Yamauchi and Yosuke Minami

Int. J. Mol. Sci. 2020, 21(15), 5456; https://doi.org/10.3390/ijms21155456 - 30 Jul 2020

Cited by 23 | Viewed by 2862

Abstract

Tumor cells use immune-checkpoint pathways to evade the host immune system and suppress immune cell function. These cells express programmed cell-death protein 1 ligand 1 (PD-L1)/PD-L2, which bind to the programmed cell-death protein 1 (PD-1) present on cytotoxic T cells, trigger inhibitory signaling, [...] Read more.

Tumor cells use immune-checkpoint pathways to evade the host immune system and suppress immune cell function. These cells express programmed cell-death protein 1 ligand 1 (PD-L1)/PD-L2, which bind to the programmed cell-death protein 1 (PD-1) present on cytotoxic T cells, trigger inhibitory signaling, and reduce cytotoxicity and T-cell exhaustion. Immune-checkpoint blockade can inhibit this signal and may serve as an effective therapeutic strategy in patients with solid tumors. Several trials have been conducted on immune-checkpoint inhibitor therapy in patients with malignant lymphoma and their efficacy has been reported. For example, in Hodgkin lymphoma, immune-checkpoint blockade has resulted in response rates of 65% to 75%. However, in non-Hodgkin lymphoma, the response rate to immune-checkpoint blockade was lower. In this review, we evaluate the biology of immune-checkpoint inhibition and the current data on its efficacy in malignant lymphoma, and identify the cases in which the treatment was more effective. Full article

(This article belongs to the Special Issue Novel Approaches to Hematologic Malignancies by Immunotherapy)

Journal Menu

Journal Browser

Novel Approaches to Hematologic Malignancies by Immunotherapy

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Published Papers (9 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI