ISSN 1866-8836
Клеточная терапия и трансплантация

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Volume 9, Number 4
12/30/2020
Volume 9, Number 4
Editor-in-Chief
Kulagin A. D. (St. Petersburg, Russia)
Co-Editors-in-Chief
Wagemaker G. (Rotterdam, Netherlands)
Zander A. R. (Hamburg, Germany)
Deputy Editor
Fehse B. (Hamburg, Germany)
Managing Editor
Chukhlovin A. B. (St. Petersburg, Russia)
Editorial Board
Aleynikova O. V. (Minsk, Republic of Belarus)
Borset M. (Trondheim, Norway)
Chechetkin A. V. (St. Petersburg, Russia)
Fibbe W. (Leiden, Netherlands)
Galibin O. V. (St. Petersburg, Russia)
Hölzer D. (Frankfurt a.M., Germany)
Klimko N. N. (St. Petersburg, Russia)
Kolb H.-J. (München, Germany)
Kröger N. (Hamburg, Germany)
Lange C. (Hamburg, Germany)
Mamaev N. N. (St. Petersburg, Russia)
Mikhailova N. B. (St. Petersburg, Russia)
Moiseev I. S. (St. Petersburg, Russia)
Nagler A. (Tel-Aviv, Israel)
Nemkov A. S. (St. Petersburg, Russia)
Paramonov I. V. (Kirov, Russia)
Roumiantsev A. G. (Moscow, Russia)
Savchenko V. G. (Moscow, Russia)
Smirnov A. V. (St. Petersburg, Russia)
Uss A. L. (Minsk, Republic of Belarus)
Zubarovskaya L. S. (St. Petersburg, Russia)
In this Issue

Dear CTT authors and readers,

Despite great advances made in targeted treatments of blood cancer, we are still facing a lot of cases, in which these methods are not efficient or safe enough. Аllogeneic hematopoietic stem cell transplantation (allo-HSCT), an old method with proven efficacy, is still required to change the course of the disease. For this, chronic myeloid leukemia (CML) may be the most obvious showcase.

For the last 150 years CML has been among most studied hematological malignancies. It was the first hematological disorder with marker chromosomal aberration, later a bcr/abl fusion gene, was identified as the main mechanism of disease development. Imatinib, the first clinically used tyrosine kinase inhibitor (TKI), proved to be remarkably effective for long-term CML control, and now TKIs have largely replaced HSCT, which was the only curative treatment method prior to their introduction into clinical practice. Presently, the survival of most patients with CML is the same as in general population. However, there are still some cases, in which common TKI therapy is ineffective. In some of them, 2nd and 3rd generation TKIs may be a solution. However, in acceleration phase (AP) and blast crisis (BC), HSCT still remain the method of choice.

An evolution of therapeutic approaches to CML is well illustrated by a review of current European LeukemiaNet (ELN) recommendations presented in this issue of CTT by the head of ELN, Prof. Dr. R. Hehlmann, who is one of the persons defining general strategy of CML treatment. This review specifically concerns second and higher-line TKI therapy in CML based on detection of additional chromosomal aberrations, minimal residual disease levels, previous therapies, and age-dependent comorbidities. These factors are also assessed to determine an individual risk for potential allo-HSCT recipients, when this treatment option is considered.

Also, this issue contains a description of single-center experience of HSCT and targeted therapies in patients with advanced-stage CML presented by Dr. Morozova E. et al. In this extensive cohort containing mainly patients with very unfavorable disease allo-HSCT still has an evident advantage over conservative approaches. Thus, it appears to be a positive answer to the key question posed by Prof. Gale: "Is there a future for hematopoietic cell transplantation?"

Transplantation aspects of blood malignancies are in focus of Cellular Therapy and Transplantation. Our potential authors from different clinics worldwide are invited to present their experience in novel treatments in hematological disorders, including immune and targeted therapy, role of HSCT (including genetically modified stem cells) in malignant and nonmalignant disorders.

Professor Alexander D. Kulagin, Editor-in-Chief, Cellular Therapy and Transplantation Journal

Keynote

Is there a Future for Haematopoietic Cell Transplants?

Robert P. Gale            

Review articles

Clinical studies

Long-term goals in the treatment of chronic graft-versus-host disease after matched allogeneic hematopoietic stem cell transplantation

Ivan S. Moiseev, Anna A. Dotsenko, Anna G. Smirnova, Yulia Yu. Vlasova, Elena V. Morozova, Sergey N. Bondarenko, Boris V. Afanasyev

Fanconi Anemia in the Czech Republic: role of HSCT and long-term follow-up

Petr Sedlacek, Petra Keslova, Petr Smisek, Martina Sukova, Marcela Malikova, Spiros Tavandzis, Jaroslav Cermak, Jan Stary

Donor-specific anti-HLA antibodies detection by de facto crossmatch method in pediatric recipients before haploidentical hematopoetic stem cell transplantation

Olesya V. Paina1, Irina E. Pavlova1,2, Natalia E. Ivanova1, Alexander L. Alyanskiy1, Tatiana A. Bykova1, Ludmila S. Zubarovskaya1, Alexander D. Kulagin1, Boris V. Afanasyev1

Risk factors for graft failure in allogeneic hematopoietic stem cell transplantation: a single-center study

Igor Novitzky-Basso1, Eshrak Al-Shaibani1, Mats Remberger2, Carol Chen1, Wilson Lam1, Arjun D. Law1, Ivan Pasic1, Fotios V. Michelis1, Auro Viswabandya1, Dennis D. Kim1, Jeffrey H. Lipton1, Armin Gerbitz1, Jonas Mattsson1, Rajat Kumar1, Zeyad Al-Shaibani1

The outcome of patients with advanced phase chronic myeloid leukemia with and without allogeneic hematopoietic stem cell transplantation

Elena V. Morozova, Yulia Yu. Vlasova, Maria V. Barabanshikova, Ksenia S. Jurovskaya, Tatyana V. Shneider, Tatyana L. Gindina, Ildar M. Barkhatov, Evgenij A. Bakin, Ivan S. Moiseev, Alexander D. Kulagin, Ludmila S. Zubarovskaya, Boris V. Afanasyev

Experimental studies

Biomimetics for treatment of endometrial pathologies: an overview

Maria V. Konovalova1, Daria S. Tsaregorodtseva1,2, Rimma A. Poltavtseva3, Elena V. Svirshchevskaya1,3

Morphology of target drug delivery systems (CaCO3 vaterites covered with dextran sulfate) in rat muscular tissue

Pavel V. Popryadukhin1, Natalia N. Sudareva1,2, Оlga М. Suvorova1, Galina Yu. Yukina2, Еlena G. Sukhorukova2, Natalia N. Saprykina1, Ilya A. Barsuk3, Oleg V. Galibin2, Aleksandr D. Vilesov1,2

Letter to the Editor

Not all T cells are created alike!

Manuel Abecasis                                                                               

Keynote

Is there a Future for Haematopoietic Cell Transplants?

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Robert P. Gale            

Haematology Research Centre, Department of Immunology and Inflammation Imperial College, London, UK


Correspondence

Robert Peter Gale MD, PhD, DSc (hc), FACP, FRCPI (hon), FRSM, Haematology Research Centre, Department of Immunology and Inflammation Imperial College, London, UK
Phone: +1-908-656-0484
Fax: +1-310-388-1320
E-mail: robertpetergale@alumni.ucla.edu

Recent advances in anti-cancer chemotherapy and in targeted and immune therapies raise the question whether there is a future for haematopoietic cell transplants. I discuss their importance but in the end the magnitude of these improvements is modest. I point out the efficacy of immune therapy is predominately restricted to B-cell cancers and that many if not most successful immune therapy recipients eventually receive an allogeneic haematopoietic cell transplant, especially those with acute lymphoblastic leukaemia (ALL).

I also discuss most allotransplants are done for cancers not treated with current immune therapy. Randomized trials show an autotransplant is better than new drugs in young persons with plasma cell myeloma. Considerable data indicate much of the efficacy of allotransplants results from a non-cancer-specific allogeneic effect not expected to operate with current immune therapies. Lastly, I discuss a role for donor-derived chimeric antigen receptor (CAR)-T-cells in persons relapsing after an allotransplant for B-cell cancers. The sum of these considerations suggest an ongoing role for haematopoietic cell transplants in diverse settings.

Keywords

Hematopoietic stem cell transplantation, targeted drugs, immune therapy, (CAR)-T cells, efficiency.

Review articles

The new ELN Recommendations for treating CML. Early transplantation in patients with high-risk ACA

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Rüdiger Hehlmann                        

Medical Faculty Mannheim, Heidelberg University; ELN Foundation Weinheim, Germany


Correspondence
Prof. Dr. Rüdiger Hehlmann, Medical Faculty Mannheim, Heidelberg University; ELN Foundation Weinheim, Germany
E-mail: Hehlmann.eln@gmail.com

After 150 years of mostly palliative CML therapy, treatment advances with BCR-ABL1 tyrosine kinase inhibitors (TKI) have resulted in normal survival for most patients with CML. The new treatment goal is treatment-free remission (TFR) with survival at good quality of life without life-long treatment. The European LeukemiaNet (ELN) has accounted for this development with its most recent recommendations. Hematopoietic stem cell transplantation has retained an important role in patients who have become resistant or intolerant to all TKI or progress to advanced phases. This review focuses on the ELN 2020 recommendations for treating CML and on early transplantation in high-risk patients.

Keywords

Chronic myeloid leukemia, high-risk group, tyrosine kinase inhibitors, hematopoietic stem cell transplantation, ELN recommendations.

Clinical studies

Long-term goals in the treatment of chronic graft-versus-host disease after matched allogeneic hematopoietic stem cell transplantation

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Ivan S. Moiseev, Anna A. Dotsenko, Anna G. Smirnova, Yulia Yu. Vlasova, Elena V. Morozova, Sergey N. Bondarenko, Boris V. Afanasyev

RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, St. Petersburg, Russia


Correspondence
Ivan S. Moiseev, PhD, MD. RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, L.Tolstoy St. 6-8, 197022, St. Petersburg, Russia
Phone: +7(812) 338 6259, +7 (921) 796 1951
Fax: +7(812) 338 6263
E-mail: moisiv@mail.ru

Chronic graft-versus-host disease (cGvHD) is a common complication of allogeneic hematopoietic stem cell transplantation. Its incidence varies from 10% to 80% according to the type of prophylaxis, type of the donor and other risk factors. Although cGvHD is associated with reduced risk of relapse, the persistence of clinical signs is associated with long-term mortality, morbidity and disability. Despite there are clear endpoints for the clinical trials of novel agents, the choices in clinical practice should involve long-term goals like in all autoimmune disease. So far, there is no consensus on these goals. Analyzing the results of cGvHD therapy in the large single-center cohort of patients we tried to focus on predictors of long-term prognosis and their association with therapy.

Patients and methods

The study included 182 patients with moderate and severe cGvHD. The majority of patients were allografted for malignant diseases and 49% had severe cGvHD, 51% – moderate disease. Median follow up time was 52 months. Beyond the first line 39.56% of patients required additional treatment.

Results

At five years the cumulative incidence of complete responses was 16.9% (95% CI 10.5-24.7%) and immunosuppressive therapy (IST) discontinuation without GvHD flare was 51.2% (95% CI 40.0-61.2%). The major predictors of IST discontinuation were overall severity of cGvHD (HR 0.45, 95%CI 0.25-0.84, p=0.0049) and female donor for male recipient (HR 0.33, 95%CI 0.25-0.81, p= 0.0370). The analysis of non-relapse mortality (NRM) demonstrated that discontinuation of IST was the major predictor (2% vs 42%, HR 0.03, 95%CI 0.01-0.15, p=0.0005). At the end of the follow up patients with complete response discontinued IST in 91% of cases, with mild cGvHD in 53% of cases, with moderate in 24% of cases and with severe in 2% of cases. The other significant factors for NRM were steroid-free starting therapy (HR 0.25, 95%CI 0.08-0.58, p=0.0035) and early use of second-line therapy (HR 0.49, 95%CI 0.25-0.96, p=0.0322). In conclusion, the study demonstrated that discontinuation of systemic IST therapy without the flare of cGvHD should be the goal of therapy. Also the study creates a rationale for randomized studies of novel second-line options not with but against steroids in the first line.

Keywords

Chronic graft-versus-host disease, therapy, long-term outcomes, goals of therapy.

Clinical studies

Fanconi Anemia in the Czech Republic: role of HSCT and long-term follow-up

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Petr Sedlacek, Petra Keslova, Petr Smisek, Martina Sukova, Marcela Malikova, Spiros Tavandzis, Jaroslav Cermak, Jan Stary

Department of Pediatric Hematology and Oncology, 2nd Medical School at Charles University, University Hospital Motol, Prague, Czech Republic


Correspondence
Prof. Dr. Petr Sedlacek, Department of Pediatric Hematology and Oncology, 2nd Medical School at Charles University, University Hospital Motol, V Uvalu 84, 150 06 Prague, Czech Republic
Phone: +420 22443 6552
Fax: +420 22443 6519
E-mail: petr.sedlacek@lfmotol.cuni.cz

Fanconi anemia (FA) is a rare and heterogeneous syndrome associated with bone marrow failure and increased risk of cancer. While FA is often characterized by the presence of congenital malformations, in some patients cytopenia may be the only sign. In our cohort diagnosis was based on evidence of increased chromosome fragility with subsequent confirmation by gene mutation detection.

Methods

Our cohort includes 35 probands diagnosed with FA aged 0-24.3 (median 6) years between January 1986 and August 2020. Congenital anomalies at diagnosis were seen in 5 and cytopenia in 22 patients, 8 patients had family history of FA. Genetic test confirmed FANCA gene mutations in 24, FANCG in 3, FANCD1 in 4, and FANCB in 2 siblings.

Results

During follow-up 7 patients developed malignancy (among them all 4 patients with FANCD1 mutation). Seventeen patients developed marrow failure, for which 15 patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) at the median age of 9.3 (4.6-24.3) years. All transplanted patients achieved stable hematopoietic engraftment. However, in 2 patients due to inadequate immune reconstitution developed fatal CMV pneumonia and invasive aspergillosis 12 and 14 months post HSCT, accordingly. In one patient we have diagnosed adenocarcinoma of the gut 10 years and squamous cell carcinoma of tongue 13 years after HSCT. Thirteen patients are alive with a median follow-up of 10.6 (0.3 – 15.1 years) years after HSCT. With a median follow-up till the last visit of 12.6 (0.2-34.4) years 28/35 (80%) patients are alive, 4 died of malignancy, 2 died due to HSCT-related complications, and one due to severe congenital somatic defects.

Conclusions

HSCT is effective in FA patients with bone marrow failure and prevents further development of hematological malignancies. A lifelong and careful multidisciplinary follow-up of patients with FA is essential for early detection of bone marrow failure or any malignant disease.

Keywords

Fanconi anemia, somatic anomalies, gene mutations, bone marrow failure, solid tumors, hematopoietic stem cell transplantation, long-term outpatient observation.

Clinical studies

Donor-specific anti-HLA antibodies detection by de facto crossmatch method in pediatric recipients before haploidentical hematopoetic stem cell transplantation

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Olesya V. Paina1, Irina E. Pavlova1,2, Natalia E. Ivanova1, Alexander L. Alyanskiy1, Tatiana A. Bykova1, Ludmila S. Zubarovskaya1, Alexander D. Kulagin1, Boris V. Afanasyev1

1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, St. Petersburg, Russia
2 Russian Research Institute of Hematology and Transfusiology, St. Petersburg, Russia


Correspondence
Dr. Irina E. Pavlova, Russian Research Institute of Hematology and Transfusiology, 2nd Sovetskaya St 16, 191024, St. Petersburg, Russia
Phone: +7 (921) 983 6664
E-mail: dr_pavlova_irina@mail.ru

Donor-specific antibodies (DSA) have been recently recognized as an important risk factor for the failing engraftment of HLA-haploidentical donor cells. In this study, we aimed to determine the frequency of anti-HLA DSA detection in recipients before haplo-HSCT using the enzyme-linked immunosorbent assay and establishing an association between the DSA presence and primary graft failure and/or graft hypofunction in children after haplo-HSCT. 40 patients have been tested (22-M, 18-F): 27 ALL, 8 AML, 1 MDS, 1 AA, 3 JMML. The median age of the patients was 8.5 years (1-17 years). Medians of the number of transplanted nucleated and CD34+ cells were 8.5×108/kg (2.3-17.9×108/kg) and 7.6×106/kg (2.3-8.2×106/kg) respectively. The donor bone marrow was the source of stem cells in all cases. Detection of DSA has been performed by using the commercial kit (XMatch®, Protrans) that allows determining antibodies against donor's HLA class I and class II separately in the ELISA de facto crossmatching. Among all the examined children, 3 patients (7.5%) were found to be positive for DSA, while the vast majority (n=37; 92.5%) had no detectable DSA. It was also found that in all cases DSA were directed against HLA class II antigens.

Comparative analysis of the results shows that patients with DSA before haplo-HSCT are more likely to develop primary graft failure or hypofunction compared to the group of recipients without DSA. All 3 patients with detected antibodies were diagnosed with either primary graft failure (n=1, 33%) or graft hypofunction (n=2, 67%). In the control group of patients without DSA primary graft failure or graft hypofunction were observed in 5 (13.5%) and 1 (2.7%) cases respectively, with a total of 6 cases (16.2%). Implementation of DSA-testing into routine practice in recipients before haplo-HSCT will optimize the choice of a donor, as well as select a group of potential recipients who need to be treated in the pre-transplant period for desensitization.

Keywords

Donor-specific antibodies, hematopoietic stem cell transplantation, HLA-haplocompatible donors, HLA-haploidentical donors.

Clinical studies

Risk factors for graft failure in allogeneic hematopoietic stem cell transplantation: a single-center study

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Igor Novitzky-Basso1, Eshrak Al-Shaibani1, Mats Remberger2, Carol Chen1, Wilson Lam1, Arjun D. Law1, Ivan Pasic1, Fotios V. Michelis1, Auro Viswabandya1, Dennis D. Kim1, Jeffrey H. Lipton1, Armin Gerbitz1, Jonas Mattsson1, Rajat Kumar1, Zeyad Al-Shaibani1

1 Hans Messner Allogeneic Transplant Program, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada
2 Department of Medical Sciences, Uppsala University and KFUE, Uppsala University Hospital, Uppsala, Sweden


Correspondence
Igor Novitzky-Basso MD PhD, Hans Messner Allogeneic Transplant Program, Princess Margaret Cancer Centre, University Health Network, University of Toronto, 610 University Avenue, Toronto, ON, M5G 2M9, Canada
Phone: +1 647 927 8700
Fax: +1 416 946 4407
E-mail: igor.novitzkybasso@uhn.ca

Objectives

Graft failure (GF) following allogeneic hematopoietic stem cell transplantation (allo-HCT) has a dismal prognosis. This study assessed incidence, risk factors (RF) and outcome of GF in a single-center population.

Patients and methods

Between 2015-2018, 557 patients underwent allo-HCT. Primary GF (PGF) was defined as failure to achieve absolute neutrophil count (ANC) of >0.5×109/L by 28 days after allo-HCT. Secondary GF (SGF) was characterized by loss of donor cells after initial engraftment with recurrence of ANC <0.5×109/L without relapse or other causes of cytopenia. Endpoints of the study were cumulative incidence of GF and overall survival (OS). Risk factors for GF were assessed in multivariate analysis.

Results

Nine patients had PGF, and 34 had SGF. The cumulative incidence of GF overall (primary and secondary) is 1.6% (CI95%; 0.8-3.0%) at day 100 and 6.5% (CI95%; 4.5-8.8%) at day 800 respectively. Multivariate analysis showed diagnosis (myelodysplastic syndrome [MDS], myelofibrosis [MF], lymphoma or non-malignant diseases) and donor type (HLA-mismatched-unrelated or haploidentical) were significantly associated with GF. For the absence of any of the risk factors (n=279), the incidence of GF was 3.6%. For the presence of one risk factor (n=229), the incidence of GF was 9.9%, while for 2 concurrent risk factors (n=49), the incidence of GF was 24.5% (p=0.002). Median OS of patients following PGF was 41 days, SGF – 144 days. The D100 OS in PGF was 22%, SGF – 64%; 2-year overall survival for SGF was 28%.

Conclusions

This study showed increased risk of GF following mismatched-unrelated or haploidentical donor allo-HCT or for non-leukemia diagnosis, for which we suggest close monitoring for early diagnostic and therapeutic interventions, in order to improve clinical outcomes.

Keywords

Allogeneic hematopoietic stem cell transplantation, graft failure, incidence, risk factors.

Clinical studies

The outcome of patients with advanced phase chronic myeloid leukemia with and without allogeneic hematopoietic stem cell transplantation

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Elena V. Morozova, Yulia Yu. Vlasova, Maria V. Barabanshikova, Ksenia S. Jurovskaya, Tatyana V. Shneider, Tatyana L. Gindina, Ildar M. Barkhatov, Evgenij A. Bakin, Ivan S. Moiseev, Alexander D. Kulagin, Ludmila S. Zubarovskaya, Boris V. Afanasyev

RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, St. Petersburg, Russia


Correspondence
Dr. Elena V. Morozova, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, L.Tolstoy St. 6-8, 197022, St. Petersburg, Russia
Phone: +7(911) 927 8229
E-mail: dr_morozova@mail.ru

Prognosis of patients with advanced stage CML (accelerated phase, AP, or blast crisis, BC) is still dismal in the era of tyrosine kinase inhibitors (TKIs). This study is aimed to evaluate whether allogeneic hemopoietic stem cell transplantation (allo-HSCT) improves their prognosis.

A total of 162 patients with AP/BC CML were divided into two homogeneous cohorts. The first one consisted of reduced-intensity conditioning allo-HSTC (n=82) recipients. The second (n=80) consisted of patients receiving only TKI-based therapy (in 85% of cases 2nd and 3rd generation TKIs) while not being referred to transplant center or refusing allo-HSCT. The response to therapy was defined according to ELN and NCCN recommendations.

The median follow-up for entire cohort was 44 (1-344) months. Among the patients with BC, 36 (59%) did not respond to therapy, in 22 cases (34%) CHR was documented, in one case (2%) complete cytogenetic response (CCR) was revealed, and a complete molecular response (CMR) was achieved in two cases (3%). Among allo-HST recipients 86% engrafted, the D+100 and 1-year cumulative non-relapse mortality were 10% and 18%, respectively. Twenty eight patients with post-transplant relapse received additional therapy achieving CMR in 9 cases. The 4-year OS and EFS were better in allo-HSCT compared to TKIs group: 58% vs 33% (p=0.032) and 35% vs 17% (p=0.5), accordingly. Patients in BC at the moment of allo-HSCT had significantly worse 4-year OS compared to responders: 23% vs 63% (p=0.007), accordingly. While allo-HSCT has an advantage for many advanced-stage CML patients, in BC its results are comparable to TKIs treatment. Therefore, these patients should be referred to transplant center as soon as the second chronic phase is achieved.

Keywords

Chronic myelogenous leukemia, BCR/ABL, allo-HSCT, tyrosine kinase inhibitors, blast crisis, outcomes.

Experimental studies

Biomimetics for treatment of endometrial pathologies: an overview

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Maria V. Konovalova1, Daria S. Tsaregorodtseva1,2, Rimma A. Poltavtseva3, Elena V. Svirshchevskaya1,3

1 Shemyakin-Ovchinnikov Institute of Bioorganic Сhemistry RAS, Moscow, Russia
2 Sechenov’s First Moscow State Medical University, Moscow, Russia
3 V. I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow, Russia


Correspondence
Elena Svirshchevskaya, PhD, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 16/10 Miklukho-Maklaya St, Moscow, 117997, Russia
Phone: +7 (910) 464 8760
Fax: +7 (495) 330 4011
E-mail: esvir@mail.ibch.ru

Secondary infertility among women in their childbearing age is one of sufficient problems in Russia. It is often caused by damage to the basal layer of endometrium when performing gynecological procedures, e.g., dilatation of uterine cavity, diagnostic curettage, cesarean section, uterine surgey, as well as consequences of complicated pregnancies. As a result, hypo- or hypermetriosis may develop, along with intrauterine adhesions (synechiae), leading to the development of Asherman’s syndrome. Despite large amounts of medical data, there are no quite effective ways to treat secondary infertility. Currently, various biological polymers and composite materials based on biopolymers with incorporated active molecules, genetic substances, platelet-rich plasma, stem cells or microvesicles/exosomes of stem cells are used with some success for treatment of hypometriosis and Asherman’s syndrome. Gel substances based on sodium hyaluronate, carboxymethylcellulose, polyethylene oxide, collagen and others are certified for clinical use. Biopolymer gels serve, on the one hand, as the materials separating the uterine walls (barrier function), and, on the other hand, they work as carriers of biologically active molecules and cells. Biomimetics can stimulate the regeneration and normalization of endometrium at different efficiency rates, thus promoting restoration of reproductive capacity. Biomimetic-based therapies are under investigation. The present review provides data on treatment efficiency of endometrial disorders by means of biotherapeutic approaches.

Keywords

Infertility, hypometriosis, Asherman's syndrome, barrier materials, biogels, biomimetics.

Experimental studies

Morphology of target drug delivery systems (CaCO3 vaterites covered with dextran sulfate) in rat muscular tissue

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Pavel V. Popryadukhin1, Natalia N. Sudareva1,2, Оlga М. Suvorova1, Galina Yu. Yukina2, Еlena G. Sukhorukova2, Natalia N. Saprykina1, Ilya A. Barsuk3, Oleg V. Galibin2, Aleksandr D. Vilesov1,2

1 Institute of Macromolecular Compounds RAS, St. Petersburg, Russia
2 Pavlov University, St. Petersburg, Russia
3 S.M.Kirov Military Medical Academy, St. Petersburg, Russia


Correspondence
Dr. Pavel V. Popryadukhin, Institute of Macromolecular Compounds, St. Petersburg, Russia
E-mail: pavelpnru@gmail.com

The present work is focused on the study of target drug delivery systems comprised of porous spherical calcium carbonate vaterites (СаСО3) covered with the dextran sulfate protective shell. Behavior of the objects was investigated in vivo. The samples were implanted into rat muscular tissue and removed after different periods of exposure (3 days, 1, 2, 4, and 12 weeks after operation). It was shown that certain transformations in structure of the implanted carriers occurred over time, after which they underwent bioresorption. In 3 days after implantation, spherical vaterites degraded, and needle-like calcium carbonate objects were formed; during the following two weeks, these objects were completely resorbed in living tissues. Since no pathogenic influence of the samples on the surrounding tissues was revealed, we believe that СаСО3 vaterites covered with protective shells are safe for potential medicinal applications and can be recommended for further studies as target drug delivery systems.

Keywords

Target drug delivery, calcium carbonate, dextran sulfate, bioresorption, muscular tissue, in vivo experiment.

Experimental studies

Endothelial differentiation of Wharton’s Jelly-derived mesenchymal stem cells seeded on chitosan/hyaluronan multilayer films

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Hana Dennaoui1, Eliane Chouery2, Chaza Harmoush1

1 Laboratory of Applied Biotechnology: Biomolecules, Biotherapies and Bioprocesses, AZM Centre for Biotechnology Research and its Applications, Doctoral School of Science and Technology, Lebanese University, Tripoli, Lebanon
2 Medical Genetics Unit, Faculty of Medicine, Saint Joseph University (USJ), Mar Mikhaël, Beirut, Lebanon


Correspondence
Dr. Hana Dennaoui, Laboratory of Applied Biotechnology: Biomolecules, Biotherapies and Bioprocesses, AZM Centre for Biotechnology Research and its Applications, Doctoral School of Science and Technology, Lebanese University, El Mitein St, Tripoli, Lebanon
E-mail: hana.dennaoui@hotmail.com

The ease of harvesting of mesenchymal stem cells from Wharton’s jelly (WJ-MSCs), their great differentiation plasticity and low immunogenicity make them a suitable tool for allogeneic cell therapy. The aim of present study was to explore the potential of WJ-MSCs seeded on chitosan/hyaluronic acid (HA/CHI) multilayers to differentiate into endothelial-like cells.

Methods

In this study, we differentiate WJ-MSCs into an angiogenic lineage using polyelectrolyte multilayer film as a substrate. WJ-MSCs were cultivated on HA/CHI multilayer film and stimulated (or not) with EGM-2® culture medium. Type I collagen was used as control. mRNA and protein expression of CD31, vascular endothelial growth factor-receptor 2 (VEGF2) and vascular endothelial (VE)-cadherin, along with Dil-acetylated low-density lipoprotein-uptake and von Willebrand Factor protein expression were performed.

Results

The isolated MSCs showed typical fibroblast-like morphology. We have shown that WJ-MSCs express endothelial markers after 15 days of culture in EGM-2® medium. The mRNA levels were higher on CHI/HA than on collagen for CD31 and KDR, with only KDR increase being statistically significant. At the protein level, a trend for increase in KDR and CDH5 levels was also shown on CHI/HA relative to collagen. Moreover, the WJ-MSCs seeded on CHI/HA showed a high fluorescence specific to von Willebrand factor after endothelial differentiation for 15 days.

Conclusion

We report here a new biocompatible coating allowing differentiation of WJ-MSCs into endothelial-like cells. This substrate opens new routes in tissue engineering to design allogeneic vascular grafts.

Keywords

Mesenchymal stem cells, Wharton’s jelly, differentiation, endothelial lineage, chitosan, hyaluronic acid, multilayer substrate, tissue engineering.

Letter to the Editor

Not all T cells are created alike!

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Manuel Abecasis                                                                               

Lisboa, Portugal


Correspondence
Prof. Manuel Abecasis, MD PhD, Director, Hematology Department, Instituto Português Oncologia, Lisboa, Portugal
E-mail: mabecasis@ipolisboa.min-saude.pt

The comment concerns discussion of results reported by K. Beider on the clinical response rates in patients with resistant/refractory lymphomas treated with CAR-T cells, and the factors predicting therapeutic success, in particular, distinct role of T cell ageing and their exhaustion phenotype as a reason for decreased response after adoptive cellular therapy. The patients who responded to treatment, had low levels of exhausted cells in blood and final CAR T cell product. Additional studies are needed to establish desirable attributes of CAR T cells, but the optimal characteristics might differ depending on the CAR construct and the malignancy being targeted.

Keywords

CAR-T cells, exhaustion phenotype, lymphoma, treatment.