Bispecific Antibodies in Clinical Practice and Clinical Trials (Literature Review)

REVIEWS bispecific antibodies, catumaxomab, clinical trial, emicizumab

ON Solopova, VA Misyurin

NN Blokhin National Medical Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Vsevolod Andreevich Misyurin, PhD in Biology, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(985)436-30-19; e-mail: vsevolod.misyurin@gmail.com

For citation: Solopova ON, Misyurin VA. Bispecific Antibodies in Clinical Practice and Clinical Trials (Literature Review). Clinical oncohematology. 2019;12(2):125–44.

DOI: 10.21320/2500-2139-2019-12-2-125-144

ABSTRACT

Therapeutic monoclonal antibodies have long been an effective tool deployed by physicians of different specialties, particularly by oncologists. Bispecific antibodies opened up new horizons in the treatment of cancer as they allow to involve a patient’s endogenous immunity in his or her fight against tumor. The present review covers all the formats and strategies used in engineering of bispecific antibodies which reached the stage of clinical trials and also focuses on the available results of these clinical trials.

Keywords: bispecific antibodies, blinatumomab, catumaxomab, emicizumab, clinical trial.

Received: August 13, 2018

Accepted: January 22, 2019

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Clinical Efficacy of Chelation Therapy in Patients with Low-Risk Myelodysplastic Syndrome

REVIEWS iron chelators, low risk, myelodysplastic syndrome, survival, transfusion dependence

SV Gritsaev, II Kostroma, AA Zhernyakova

Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

For correspondence: Sergei Vasil’evich Gritsaev, MD, PhD, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024; Tel.: +7(812)717-54-68; e-mail: gritsaevsv@mail.ru

For citation: Gritsaev SV, Kostroma II, Zhernyakova AA. Clinical Efficacy of Chelation Therapy in Patients with Low-Risk Myelodysplastic Syndrome. Clinical oncohematology. 2019;12(2):120–4.

DOI: 10.21320/2500-2139-2019-12-2-120-124

ABSTRACT

The present literature review provides evidence that in patients with low-risk myelodysplastic syndrome and transfusion dependence blood parameters and survival rates can be improved by administration of iron chelators. Dose adequacy and therapy duration underlie clinical efficacy of chelators. Toxicity can be reduced by administrating a new formula of deferasirox that does not need to be dissolved in liquid before consuming.

Keywords: myelodysplastic syndrome, low risk, transfusion dependence, iron chelators, survival.

Received: August 20, 2018

Accepted: February 2, 2019

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REFERENCES

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Achievements and Challenges in Allogeneic Hematopoietic Stem Cell Transplantation in Cytogenetically Unfavorable Acute Leukemias (Literature Review)

REVIEWS acute leukemias, additional chromosome abnormalities, allo-HSCT, cytogenetically unfavorable variants, outcomes, “graft versus leukemia” effect

NN Mamaev, TL Gindina, BV Afanas’ev

RM Gorbacheva Scientific Research Institute of Pediatric Oncology, Hematology and Transplantation; IP Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

For correspondence: Nikolai Nikolaevich Mamaev, MD, PhD, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; e-mail: nikmamaev524@gmail.com

For citation: Mamaev NN, Gindina TL, Afanas’ev BV. Achievements and Challenges in Allogeneic Hematopoietic Stem Cell Transplantation in Cytogenetically Unfavorable Acute Leukemias (Literature Review). Clinical oncohematology. 2019;12(2):111–9.

DOI: 10.21320/2500-2139-2019-12-2-111-119

ABSTRACT

Literature review provides the analysis of treatment results of implementing allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with cytogenetically unfavorable acute myeloid and lymphoblastic leukemias including monosomal, complex, and hyperdiploid karyotypes, t(3;3)/inv(3), t(v;11)(v;q23), t(4;11)(q21;q23), t(9;22)(q34;q11) translocations, 17p abnormalities, and some other disorders. The major disadvantage of allo-HSCT seems to be linked to a strong chromosome-damaging effect of cytostatic drugs used in conditioning regimens which in turn is associated with additional chromosome abnormalities occurring in tumors, increasing genomic instability, and tumor progression. On the other hand, one of the advantages of allo-HSCT can consist in its specific “graft versus leukemia” (GVL) effect whose degree has not yet been adequately studied. To minimize the risks of allo-HSCT in above mentioned patients it appears appropriate to apply new treatment approaches based on de-escalation of chromosome- and whole-genome-damaging effects and also to introduce recent methods of active stimulation and qualitative assessment of GVL effect into clinical practice.

Keywords: acute leukemias, cytogenetically unfavorable variants, allo-HSCT, outcomes, additional chromosome abnormalities, “graft versus leukemia” effect.

Received: October 22, 2018

Accepted: February 2, 2019

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Konuma T, Kondo T, Yamashita T, et al. Outocome of allogeneic hematopoietic stem cell transplantation in adult patients with acute myeloid leulkemia harboring trisomy 8. Ann Hematol. 2017;96(3):469–78. doi: 1007/s00277-016-2009-2.
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Mohr B, Schetelig J, Schafer-Eckart K, et al. Impact of allogeneic haematopoietic stem cell transplantation in patients with abnl(17p) acute myeloid leukemia. Br J Haematol. 2013;161(2):237–44. doi: 10.1111/bjh.12253.
Middeke JM, Fang M, Cornellisen JJ, et al. Outcome of patients with abnl(17p) acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation. Blood. 2014;123(19):2960–7. doi: 10.1182/blood-2013–12-544957.
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Current Issues in Carcinogenesis

REVIEWS carcinogenesis, initiation, promotion, proto-oncogenes, repair, suppressor genes, targeted therapy

IV Vysotskaya¹, VP Letyagin², MA Shabanov², VYu Kirsanov¹, EA Kim¹, NV Levkina¹

¹IM Sechenov First Moscow State Medical University, 8 bld. 2 Trubetskaya str., Moscow, Russian Federation, 119991

²NN Blokhin National Medical Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Prof. Irina Viktorovna Vysotskaya, MD, PhD, 8 bld. 2 Trubetskaya str., Moscow, Russian Federation, 119991; e-mail: vysotskaya.irina@mail.ru

For citation: Vysotskaya IV, Letyagin VP, Shabanov MA, et al. Current Issues in Carcinogenesis. Clinical oncohematology. 2019;12(1):101–6.

DOI: 10.21320/2500-2139-2019-12-1-101-106

ABSTRACT

The review presents current data on the major pathogenetic mechanisms underlying uncontrolled growth and dissemination of tumor and its resistance to conventional treatment. Cell genetic instability associated with accumulation of mutations in genes controlling cell growth and differentiation is a key factor in tumor proliferation. Due understanding and detailed analysis of carcinogenesis processes provide the basis for creation of new anticancer drugs which in turn enables optimization and individualization of cancer treatment.

Keywords: carcinogenesis, initiation, promotion, repair, proto-oncogenes, suppressor genes, Ras, TP53, targeted therapy.

Received: June 27, 2018

Accepted: December 20, 2018

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Clinical and Prognostic Value of Molecular Markers of Diffuse Large B-Cell Lymphoma

REVIEWS B-cells, DLBCL, epigenomics, gene expression, genomics, lymphoma, transcriptomics

SM Rastorguev¹, DA Koroleva², ES Boulygina¹, SV Tsygankova¹, NG Goncharov¹, OS Naraikin¹, NG Gabeeva², EE Zvonkov², AV Nedoluzhko¹

¹National Research Center “Kurchatov Institute”, 1 Akademika Kurchatova sq., Moscow, Russian Federation, 123182

² National Medical Hematology Research Center, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

For correspondence: Artem Valer’evich Nedoluzhko, PhD in Biology, 1 Akademika Kurchatova sq., Moscow, Russian Federation, 123182; Tel.: +7(916)670-55-95; e-mail: nedoluzhko@gmail.com

For citation: Rastorguev SM, Koroleva DA, Bulygina ES, et al. Clinical and Prognostic Value of Molecular Markers of Diffuse Large B-Cell Lymphoma. Clinical oncohematology. 2019:12(1):95–100.

DOI: 10.21320/2500-2139-2019-12-1-95-100

ABSTRACT

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid tumor in adults which is associated with approximately 30–40 % of all non-Hodgkin’s lymphomas. Diagnostic criteria include diffuse growth of large anaplastic tumor cells, expression of В-cell markers, and a high proliferative index. Due to the development of molecular genetic technologies it became obvious that underlying cause of clinical diversity is a huge amount of genetic failures which determine epigenetic modification of gene expression, activation variability of certain signaling pathways, and immunological properties of tumor cells. The study and systemization of molecular markers present a significant trend in DLBCL diagnosis and treatment. This review discusses most important molecular markers and current view on their clinical value.

Keywords: lymphoma, DLBCL, B-cells, transcriptomics, gene expression, epigenomics, genomics.

Received: July 3, 2018

Accepted: December 10, 2018

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Immunological Synapse in the Biology of Chronic Lymphocytic Leukemia

REVIEWS chronic lymphocytic leukemia, immune system, immunological synapse

DS Badmazhapova, IV Gal’tseva, EE Zvonkov

National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

For correspondence: Darima Semunkoevna Badmazhapova, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(929)562-93-41; e-mail: badmazhapova-darima@mail.ru

For citation: Badmazhapova DS, Gal’tseva IV, Zvonkov EE. Immunological Synapse in the Biology of Chronic Lymphocytic Leukemia. Clinical oncohematology. 2018;11(4):313–8.

DOI: 10.21320/2500-2139-2018-11-4-313-318

ABSTRACT

Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disease manifested by accumulation of tumor B-cells with characteristic immunophenotype (CD19+CD5+CD23+) in bone marrow, peripheral blood and secondary lymphoid organs. The clinical course of CLL is heterogeneous. This is the most prevalent leukemia among older-aged patients. Despite the use of novel drugs refractory forms of disease remain. The latest discoveries in immunology enabled understanding of some mechanisms of tumor evasion from immune surveillance. The interaction of immune system cells occurs due to the development of immunological synapse that predominantly depends on the family of CD28/В7 molecules, the so-called immune checkpoints able to control the activating and inhibiting mechanisms of cells. The acquisition of tumor phenotype is a multistage process, in which cells obtain unique biological properties including the ability of being invisible to the immune system. As opposed to solid tumors in lymphoproliferative diseases tumor B-cells are able to express major histocompatibility complex class II and CD80 and CD86 co-stimulatory molecules. It proves their ability to present antigens to T-cells. Co-inhibitory molecules on the surface of tumor cells is a factor contributing to the inhibition of immune response. The present paper reviews current conceptions of biological properties and immunological interactions of CLL cells with the microenvironmental cells.

Keywords: chronic lymphocytic leukemia, immunological synapse, immune system.

Received: March 15, 2018

Accepted: June 29, 2018

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Immune Checkpoint Inhibitors in the Treatment of Lymphomas

REVIEWS classical Hodgkin’s lymphoma, ICP inhibitors, immune checkpoints (ICP), non-Hodgkin’s lymphoma

KV Lepik

For correspondence: Kirill Viktorovich Lepik, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; e-mail: lepikkv@gmail.com

For citation: Lepik KV. Immune Checkpoint Inhibitors in the Treatment of Lymphomas. Clinical oncohematology. 2018;11(4):303–12.

DOI: 10.21320/2500-2139-2018-11-4-303-312

ABSTRACT

Programmed death receptors and ligands (PD-1 and PD-L1) are the best studied immune checkpoints (ICP) and are considered to be key factors of immune response control. The ability of tumor cells to affect the ICP receptors is one of the principal mechanisms of suppressing antitumor immunity. The development of ICP inhibitors creates an opportunity to control and activate immune response and opens new perspectives for immunotherapy of cancers, including lymphomas. The paper reviews the biological background for the use of ICP inhibitors in the treatment of classical Hodgkin’s and non-Hodgkin’s lymphomas and summarizes the clinical experience of their use. The new approaches for the creation of combination regimens with ICP are also highlighted.

Keywords: immune checkpoints (ICP), PD-1, PD-L1, classical Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, ICP inhibitors.

Received: March 25, 2018

Accepted: July 23, 2018

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Theory and Practice of Immunotherapy Directed against the PRAME Antigen

REVIEWS dendritic cell vaccines, immunotherapy, peptide vaccines, PRAME, T-cell vaccines, therapeutic antibodies

VA Misyurin

NN Blokhin National Medical Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Vsevolod Andreevich Misyurin, PhD in Biology, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(985)4363019; e-mail: vsevolod.misyurin@gmail.com

For citation: Misyurin VA. Theory and Practice of Immunotherapy Directed against the PRAME Antigen. Clinical oncohematology. 2018;11(2):138–49.

DOI: 10.21320/2500-2139-2018-11-2-138-149

ABSTRACT

The preferentially expressed antigen of melanoma (PRAME) is a significant target for monoclonal antibodies and an oncospecific marker known for its activity on all the tumor cell differentiation stages and its eliciting of a spontaneous T-cell response. Since PRAME protein is active in approximately every second patient with solid tumors and oncohematological diseases, anti-PRAME immunotherapy is very promising. In current review the mechanism of spontaneous immune response against PRAME is discussed as well as the role of this antigen in immunosurveillance. The review deals with the PRAME-specific T-cell genesis and risk assessment of immunotherapy directed against PRAME-positive cells. The risks and benefits of various immunotherapy approaches including the use of dendritic cell vaccines, PRAME vaccination, development of specific T-cells, and development of specific monoclonal antibodies were analysed. Possible causes of treatment failure are analysed, and methods of overcoming them are suggested. The literature search in the Pubmed, Scopus, and eLibrary databases, with the use of “PRAME” as a keyword was performed. Only publications related to various aspects of immunotherapy and anti-PRAME-specific agents were included in the review.

Keywords: PRAME, immunotherapy, dendritic cell vaccines, peptide vaccines, T-cell vaccines, therapeutic antibodies.

Received: December 19, 2017

Accepted: February 5, 2018

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Clinical Significance of the PRAME Gene Expression in Oncohematological Diseases

REVIEWS leukemia, lymphoma, PRAME, prognosis

VA Misyurin

NN Blokhin National Medical Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Vsevolod Andreevich Misyurin, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(985)436-30-19; e-mail: vsevolod.misyurin@gmail.com

For citation: Misyurin AV. Clinical Significance of the PRAME Gene Expression in Oncohematological Diseases. Clinical oncohematology. 2018;11(1):26–33.

DOI: 10.21320/2500-2139-2018-11-1-26-33

ABSTRACT

Although the PRAME activity was first discovered in solid tumors, this gene is very frequently expressed in oncohematological diseases. PRAME can be regarded as a reliable biomarker of tumor cells. Determination of PRAME transcripts is used in residual disease monitoring and molecular relapse diagnostics. Experimentation with PRAME expressing lines of leukemia cells yielded controversial results. Therefore, it is hardly possible to estimate the prognostic value of PRAME activity in oncohematological diseases. In chronic myeloproliferative disease and chronic myeloid leukemia, however, PRAME activity proves to be a predictor of negative prognosis, and on the contrary, it can be regarded as a positive prognostic factor in acute myeloid or lymphoid leukemia. Despite many clinical studies prognostic value of PRAME expression in some diseases requires further investigation. The present literature review contains the data concerning PRAME expression in oncohematological diseases.

Keywords: PRAME, leukemia, lymphoma, prognosis.

Received: September 14, 2017

Accepted: December 2, 2017

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New Possibilities of Treatment for Relapsed/Refractory Multiple Myeloma: A Literature Review

REVIEWS immunomodulatory, monoclonal antibodies, multiple myeloma, proteasome inhibitors

OM Votyakova

NN Blokhin National Medical Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Ol’ga Mikhailovna Votyakova, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: 8(499)324-92-09; e-mail: omvtk@yandex.ru 24

For citation: Votyakova OM. New Possibilities of Treatment for Relapsed/Refractory Multiple Myeloma: A Literature Review. Clinical oncohematology. 2017;10(4):425–34 (In Russ).

DOI: 10.21320/2500-2139-2017-10-4-425-434

ABSTRACT

Despite improvements in the treatment of patients with newly diagnosed multiple myeloma (MM) through the introduction of new drugs and high-dose chemotherapy with autologous hematopoietic stem cell transplantation, relapses are still inevitable in all patients. The use of immunomodulatory agents (thalidomide, lenalidomide) and proteasome inhibitor bortezomib has improved the treatment of relapses. However, the disease progression lead to repeated relapses and eventually refractory MM. For these patients new therapeutic strategies are needed, including the development of more effective drugs within the existing classes and the study of new combinations, as well as searching new targets for the treatment of MM. We present the key clinical data on the efficacy and safety of the most promising proteasome inhibitors (carfilzomib, ixazomib), new generation immunomodulatory drug pomalidomide, and monoclonal antibodies (daratumumab and elotuzumab).

Keywords: proteasome inhibitors, immunomodulatory medication, monoclonal antibodies, multiple myeloma.

Received: March 14, 2017

Accepted: June 20, 2017

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