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Open AccessEditorial

Immune Therapies for Hematologic Malignancies

by Matthew J. Olnes

Cancers 2021, 13(2), 295; https://doi.org/10.3390/cancers13020295 - 15 Jan 2021

Viewed by 1690

Abstract

The era of immunotherapy for hematologic malignancies began with the first allogeneic hematopoietic stem cell transplant (HSCT) study published by E [...] Full article

(This article belongs to the Special Issue Immune Therapies for Hematologic Malignancies)

Research

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16 pages, 4842 KiB

Open AccessArticle

LAG-3 Blockade with Relatlimab (BMS-986016) Restores Anti-Leukemic Responses in Chronic Lymphocytic Leukemia

by Christian Sordo-Bahamonde, Seila Lorenzo-Herrero, Ana P. González-Rodríguez, Ángel R. Payer, Esther González-García, Alejandro López-Soto and Segundo Gonzalez

Cancers 2021, 13(9), 2112; https://doi.org/10.3390/cancers13092112 - 27 Apr 2021

Cited by 58 | Viewed by 5516

Abstract

The inclusion of monoclonal antibodies targeting immune checkpoints such PD-1/PD-L1 or CTLA-4 has revolutionized the landscape of anti-cancer therapy. However, PD-1 and CTLA-4 blockade failed to achieve clinical benefit in CLL, thus attention has been focused on emerging checkpoints in this malignancy. LAG-3 [...] Read more.

The inclusion of monoclonal antibodies targeting immune checkpoints such PD-1/PD-L1 or CTLA-4 has revolutionized the landscape of anti-cancer therapy. However, PD-1 and CTLA-4 blockade failed to achieve clinical benefit in CLL, thus attention has been focused on emerging checkpoints in this malignancy. LAG-3 is an immune checkpoint receptor that negatively regulates T cell-mediated responses by inducing an hyporesponsive state, thus promoting tumor escape. Patients with chronic lymphocytic leukemia (CLL) develop a profound immune suppression that leads to lessened immunosurveillance and increased risk of developing a secondary neoplasia. In the study herein, we report the profound dysregulation of LAG-3 on leukemic cells in CLL. Likewise, natural killer (NK) and T cells showed increased LAG-3 expression, hence suggesting a role for this checkpoint in CLL-associated immunosuppression. High LAG-3 expression, as well as high levels of soluble LAG-3 (sLAG-3), correlated with adverse cytogenetics and poor outcome in patients with CLL, highlighting the clinical relevance of this immune checkpoint. Treatment of peripheral blood mononuclear cells (PBMCs) from patients with CLL with relatlimab, a new anti-LAG-3 blocking antibody currently evaluated in numerous clinical trials, depleted leukemic cells and restored NK cell- and T cell-mediated responses. Moreover, combination of LAG-3 with the immunomodulatory drug (IMiD) lenalidomide significantly increased IL-2 production by T cells and antibody-dependent cytotoxicity (ADCC) mediated by NK cells. Altogether, these data provide new insights into the potential anti-leukemic effects of relatlimab, currently in clinical trials in CLL, and provides the rationale to further investigate its combination with IMiDs for the management of hematological malignancies. Full article

(This article belongs to the Special Issue Immune Therapies for Hematologic Malignancies)

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14 pages, 4444 KiB

Open AccessArticle

An Fc-Optimized CD133 Antibody for Induction of NK Cell Reactivity against B Cell Acute Lymphoblastic Leukemia

by Fabian Riegg, Martina S. Lutz, Bastian J. Schmied, Jonas S. Heitmann, Manon Queudeville, Peter Lang, Gundram Jung, Helmut R. Salih and Melanie Märklin

Cancers 2021, 13(7), 1632; https://doi.org/10.3390/cancers13071632 - 1 Apr 2021

Cited by 6 | Viewed by 1991

Abstract

In recent decades, antibody-dependent cellular cytotoxicity (ADCC)-inducing monoclonal antibodies (mAbs) have revolutionized cancer immunotherapy, and Fc engineering strategies have been utilized to further improve efficacy. A promising option is to enhance the affinity of an antibody’s Fc-part to the Fc-receptor CD16 by altering [...] Read more.

In recent decades, antibody-dependent cellular cytotoxicity (ADCC)-inducing monoclonal antibodies (mAbs) have revolutionized cancer immunotherapy, and Fc engineering strategies have been utilized to further improve efficacy. A promising option is to enhance the affinity of an antibody’s Fc-part to the Fc-receptor CD16 by altering the amino acid sequence. Herein, we characterized an S239D/I332E-modified CD133 mAb termed 293C3-SDIE for treatment of B cell acute lymphoblastic leukemia (B-ALL). Flow cytometric analysis revealed CD133 expression on B-ALL cell lines and leukemic cells of 50% (14 of 28) B-ALL patients. 293C3-SDIE potently induced NK cell reactivity against the B-ALL cell lines SEM and RS4;11, as well as leukemic cells of B-ALL patients in a target antigen-dependent manner, as revealed by analysis of NK cell activation, degranulation, and cytotoxicity. Of note, CD133 expression did not correlate with BCR-ABL, CD19, CD20, or CD22, which are presently used as therapeutic targets in B-ALL, which revealed CD133 as an independent target for B-ALL treatment. Increased CD133 expression was also observed in MLL-AF4-rearranged B-ALL, indicating that 293C3-SDIE may constitute a particularly suitable treatment option in this hard-to-treat subpopulation. Taken together, our results identify 293C3-SDIE as a promising therapeutic agent for the treatment of B-ALL. Full article

(This article belongs to the Special Issue Immune Therapies for Hematologic Malignancies)

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Review

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15 pages, 3170 KiB

Open AccessReview

CAR-NK Cells: A Chimeric Hope or a Promising Therapy?

by Mohamad Sabbah, Ludovic Jondreville, Claire Lacan, Francoise Norol, Vincent Vieillard, Damien Roos-Weil and Stéphanie Nguyen

Cancers 2022, 14(15), 3839; https://doi.org/10.3390/cancers14153839 - 8 Aug 2022

Cited by 15 | Viewed by 4193

Abstract

Immunotherapy with chimeric antigen receptor-engineered T cells (CAR-T) has revolutionized the treatment landscape of relapsed/refractory B-cell malignancies. Nonetheless, the use of autologous T cells has certain limitations, including the variable quality and quantity of collected effector T cells, extended time of cell processing, [...] Read more.

Immunotherapy with chimeric antigen receptor-engineered T cells (CAR-T) has revolutionized the treatment landscape of relapsed/refractory B-cell malignancies. Nonetheless, the use of autologous T cells has certain limitations, including the variable quality and quantity of collected effector T cells, extended time of cell processing, limited number of available CAR cells, toxicities, and a high cost. Thanks to their powerful cytotoxic capabilities, with proven antitumor effects in both haploidentical hematopoietic stem cell transplantation and adoptive cell therapy against solid tumors and hematological malignancies, Natural Killer cells could be a promising alternative. Different sources of NK cells can be used, including cellular lines, cord blood, peripheral blood, and induced pluripotent stem cells. Their biggest advantage is the possibility of using them in an allogeneic context without major toxic side effects. However, the majority of the reports on CAR-NK cells concern preclinical or early clinical trials. Indeed, NK cells might be more difficult to engineer, and the optimization and standardization of expansion and transfection protocols need to be defined. Furthermore, their short persistence after infusion is also a major setback. However, with recent advances in manufacturing engineered CAR-NK cells exploiting their cytolytic capacities, antibody-dependent cellular cytotoxicity (ADCC), and cytokine production, “off-the-shelf” allogeneic CAR-NK cells can provide a great potential in cancer treatments. Full article

(This article belongs to the Special Issue Immune Therapies for Hematologic Malignancies)

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26 pages, 3662 KiB

Open AccessEditor’s ChoiceReview

Emerging CAR T Cell Strategies for the Treatment of AML

by Paresh Vishwasrao, Gongbo Li, Justin C. Boucher, D. Lynne Smith and Susanta K. Hui

Cancers 2022, 14(5), 1241; https://doi.org/10.3390/cancers14051241 - 27 Feb 2022

Cited by 24 | Viewed by 6831

Abstract

Engineered T cells expressing chimeric antigen receptors (CARs) on their cell surface can redirect antigen specificity. This ability makes CARs one of the most promising cancer therapeutic agents. CAR-T cells for treating patients with B cell hematological malignancies have shown impressive results. Clinical [...] Read more.

Engineered T cells expressing chimeric antigen receptors (CARs) on their cell surface can redirect antigen specificity. This ability makes CARs one of the most promising cancer therapeutic agents. CAR-T cells for treating patients with B cell hematological malignancies have shown impressive results. Clinical manifestation has yielded several trials, so far five CAR-T cell therapies have received US Food and Drug Administration (FDA) approval. However, emerging clinical data and recent findings have identified some immune-related toxicities due to CAR-T cell therapy. Given the outcome and utilization of the same proof of concept, further investigation in other hematological malignancies, such as leukemias, is warranted. This review discusses the previous findings from the pre-clinical and human experience with CAR-T cell therapy. Additionally, we describe recent developments of novel targets for adoptive immunotherapy. Here we present some of the early findings from the pre-clinical studies of CAR-T cell modification through advances in genetic engineering, gene editing, cellular programming, and formats of synthetic biology, along with the ongoing efforts to restore the function of exhausted CAR-T cells through epigenetic remodeling. We aim to shed light on the new targets focusing on acute myeloid leukemia (AML). Full article

(This article belongs to the Special Issue Immune Therapies for Hematologic Malignancies)

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22 pages, 798 KiB

Open AccessReview

Natural Killer Cell-Mediated Immunotherapy for Leukemia

by Michaela Allison, Joel Mathews, Taylor Gilliland and Stephen O. Mathew

Cancers 2022, 14(3), 843; https://doi.org/10.3390/cancers14030843 - 8 Feb 2022

Cited by 17 | Viewed by 5360

Abstract

Leukemia is a malignancy of the bone marrow and blood resulting from the abnormal differentiation of hematopoietic stem cells (HSCs). There are four main types of leukemia including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and chronic lymphocytic [...] Read more.

Leukemia is a malignancy of the bone marrow and blood resulting from the abnormal differentiation of hematopoietic stem cells (HSCs). There are four main types of leukemia including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and chronic lymphocytic leukemia (CLL). While chemotherapy and radiation have been conventional forms of treatment for leukemia, these therapies increase infection susceptibility, adverse side effects and immune cell inactivation. Immunotherapies are becoming promising treatment options for leukemia, with natural killer (NK) cell-mediated therapy providing a specific direction of interest. The role of NK cells is critical for cancer cell elimination as these immune cells are the first line of defense against cancer proliferation and are involved in both recognition and cytolysis of rapidly dividing and abnormal cell populations. NK cells possess various activating and inhibitory receptors, which regulate NK cell function, signaling either inhibition and continued surveillance, or activation and subsequent cytotoxic activity. In this review, we describe NK cells and NK cell receptors, functional impairment of NK cells in leukemia, NK cell immunotherapies currently under investigation, including monoclonal antibodies (mAbs), adoptive transfer, chimeric antigen receptor-NKs (CAR-NKs), bi-specific/tri-specific killer engagers (BiKEs/TriKEs) and future potential targets of NK cell-based immunotherapy for leukemia. Full article

(This article belongs to the Special Issue Immune Therapies for Hematologic Malignancies)

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19 pages, 512 KiB

Open AccessReview

Immunotherapy for Diffuse Large B-Cell Lymphoma: Current Landscape and Future Directions

by Dipenkumar Modi, Bindu Potugari and Joseph Uberti

Cancers 2021, 13(22), 5827; https://doi.org/10.3390/cancers13225827 - 20 Nov 2021

Cited by 19 | Viewed by 6663

Abstract

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease. B-cell receptor (BCR) pathway is essential for malignant B-cell growth, survival, and proliferation. Various immune cells, including T-cells and macrophages in the tumor microenvironment (TME) contribute to tumor cell survival and pathogenesis of chemo-resistance. [...] Read more.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease. B-cell receptor (BCR) pathway is essential for malignant B-cell growth, survival, and proliferation. Various immune cells, including T-cells and macrophages in the tumor microenvironment (TME) contribute to tumor cell survival and pathogenesis of chemo-resistance. The presence of many targets on the malignant B-cells and in the TME has led to emergence of novel therapeutic agents. Stem cell transplant is the oldest treatment modality leveraging immune system in DLBCL. Subsequently, CD20 targeting monoclonal antibody and chimeric antigen receptor (CAR) T-cell therapy changed the treatment landscape of DLBCL. Recently, multiple novel immunotherapeutic agents have been added in the armamentarium for the management of DLBCL, and many are under development. In this review article, we will review latest updates of immunotherapeutic agents in the management of DLBCL. Full article

(This article belongs to the Special Issue Immune Therapies for Hematologic Malignancies)

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23 pages, 10438 KiB

Open AccessReview

Novel Molecular Mechanism of Lenalidomide in Myeloid Malignancies Independent of Deletion of Chromosome 5q

by Isaac Park, Tra Mi Phan and Jing Fang

Cancers 2021, 13(20), 5084; https://doi.org/10.3390/cancers13205084 - 11 Oct 2021

Cited by 5 | Viewed by 3002

Abstract

Lenalidomide as well as other immunomodulatory drugs (IMiDs) have achieved clinical efficacies in certain sub-types of hematologic malignancies, such as multiple myeloma, lower-risk myelodysplastic syndromes (MDS) with a single deletion of chromosome 5q (del(5q)) and others. Despite superior clinical response to lenalidomide in [...] Read more.

Lenalidomide as well as other immunomodulatory drugs (IMiDs) have achieved clinical efficacies in certain sub-types of hematologic malignancies, such as multiple myeloma, lower-risk myelodysplastic syndromes (MDS) with a single deletion of chromosome 5q (del(5q)) and others. Despite superior clinical response to lenalidomide in hematologic malignancies, relapse and resistance remains a problem in IMiD-based therapy. The last ten years have witnessed the discovery of novel molecular mechanism of IMiD-based anti-tumor therapy. IMiDs bind human cereblon (CRBN), the substrate receptor of the CRL4 E3 ubiquitin ligase complex. Binding of CRBN with IMiDs leads to degradation of the Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3) and casein kinase 1 alpha. We have found that lenalidomide-mediated degradation of IKZF1 leads to activation of the G protein-coupled receptor 68 (GPR68)/calcium/calpain pro-apoptotic pathway and inhibition of the regulator of calcineurin 1 (RCAN1)/calcineurin pro-survival pathway in MDS and acute myeloid leukemia (AML). Calcineurin inhibitor Cyclosporin-A potentiates the anti-leukemia activity of lenalidomide in MDS/AML with or without del(5q). These findings broaden the therapeutic potential of IMiDs. This review summarizes novel molecular mechanism of lenalidomide in myeloid malignancies, especially without del(5q), in the hope to highlight novel therapeutic targets. Full article

(This article belongs to the Special Issue Immune Therapies for Hematologic Malignancies)

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30 pages, 16667 KiB

Open AccessReview

Immune Therapies for Myelodysplastic Syndromes and Acute Myeloid Leukemia

by Sargam Kapoor, Grace Champion, Aparna Basu, Anu Mariampillai and Matthew J. Olnes

Cancers 2021, 13(19), 5026; https://doi.org/10.3390/cancers13195026 - 8 Oct 2021

Cited by 7 | Viewed by 3386

Abstract

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are hematologic malignancies arising from the bone marrow. Despite recent advances in treating these diseases, patients with higher-risk MDS and AML continue to have a poor prognosis with limited survival. It has long been recognized [...] Read more.

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are hematologic malignancies arising from the bone marrow. Despite recent advances in treating these diseases, patients with higher-risk MDS and AML continue to have a poor prognosis with limited survival. It has long been recognized that there is an immune component to the pathogenesis of MDS and AML, but until recently, immune therapies have played a limited role in treating these diseases. Immune suppressive therapy exhibits durable clinical responses in selected patients with MDS, but the question of which patients are most suitable for this treatment remains unclear. Over the past decade, there has been remarkable progress in identifying genomic features of MDS and AML, which has led to an improved discernment of the molecular pathogenesis of these diseases. An improved understanding of immune and inflammatory molecular mechanisms of MDS and AML have also recently revealed novel therapeutic targets. Emerging treatments for MDS and AML include monoclonal antibodies such as immune checkpoint inhibitors, bispecific T-cell-engaging antibodies, antibody drug conjugates, vaccine therapies, and cellular therapeutics including chimeric antigen receptor T-cells and NK cells. In this review, we provide an overview of the current understanding of immune dysregulation in MDS and AML and an update on novel immune therapies for these bone marrow malignancies. Full article

(This article belongs to the Special Issue Immune Therapies for Hematologic Malignancies)

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18 pages, 1353 KiB

Open AccessReview

Paving the Way for Immunotherapy in Pediatric Acute Myeloid Leukemia: Current Knowledge and the Way Forward

by Joost B. Koedijk, Inge van der Werf, Friso G. Calkoen, Stefan Nierkens, Gertjan J. L. Kaspers, Christian Michel Zwaan and Olaf Heidenreich

Cancers 2021, 13(17), 4364; https://doi.org/10.3390/cancers13174364 - 28 Aug 2021

Cited by 4 | Viewed by 3337

Abstract

Immunotherapeutic agents may be an attractive option to further improve outcomes and to reduce treatment-related toxicity for pediatric AML. While improvements in outcome have been observed with immunotherapy in many cancer types, immunotherapy development and implementation into patient care for both adult and [...] Read more.

Immunotherapeutic agents may be an attractive option to further improve outcomes and to reduce treatment-related toxicity for pediatric AML. While improvements in outcome have been observed with immunotherapy in many cancer types, immunotherapy development and implementation into patient care for both adult and pediatric AML has been hampered by an incomplete understanding of the bone marrow environment and a paucity of tumor-specific antigens. Since only a minority of patients respond in most immunotherapy trials across different cancer types, it will be crucial to understand which children with AML are likely to respond to or may benefit from immunotherapies. Immune cell profiling efforts hold promise to answer this question, as illustrated by the development of predictive scores in solid cancers. Such information on the number and phenotype of immune cells during current treatment regimens will be pivotal to generate hypotheses on how and when to intervene with immunotherapy in pediatric AML. In this review, we discuss the current understanding of the number and phenotype of immune cells in the bone marrow in pediatric AML, ongoing immunotherapy trials and how comprehensive immune profiling efforts may pave the way for successful clinical trials (and, ultimately, implementation into patient care). Full article

(This article belongs to the Special Issue Immune Therapies for Hematologic Malignancies)

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