AUTOIMMUNE THROMBOCYTOPENIA

Safety and Efficacy of BeEAC as a Conditioning Regimen Prior to Autologous Hematopoietic Stem Cell Transplantation in Relapsed/Refractory Lymphomas

AUTOIMMUNE THROMBOCYTOPENIA , , ,

VO Sarzhevskii, AA Samoilova, VYa Melnichenko, YuN Dubinina, NE Mochkin, DS Kolesnikova, DA Fedorenko, EG Smirnova, AE Bannikova, VS Bogatyrev

NI Pirogov Russian National Medical Center of Surgery, 70 Nizhnyaya Pervomaiskaya str., Moscow, Russian Federation, 105203

For correspondence: Anastasiya Aleksandrovna Samoilova, 70 Nizhnyaya Pervomaiskaya str., Moscow, Russian Federation, 105203; Tel.: +7(495)603-72-17; e-mail: samoylove03@gmail.com

For citation: Sarzhevskii VO, Samoilova AA, Melnichenko VYa, et al. Safety and Efficacy of BeEAC as a Conditioning Regimen Prior to Autologous Hematopoietic Stem Cell Transplantation in Relapsed/Refractory Lymphomas. Clinical oncohematology. 2020;13(2):185–92 (In Russ).

DOI: 10.21320/2500-2139-2020-13-2-185-192

ABSTRACT

Aim. To assess the safety and efficacy of BeEAC as a conditioning regimen prior to autologous hematopoietic stem cell transplantation (auto-HSCT) in relapsed and primary resistant lymphomas (ClinicalTrials.gov NCT03315520).

Materials & Methods. The trial included 113 patients with Hodgkin’s (HL) and non-Hodgkin’s lymphomas (NHL). The patients were included into the protocol during the period from February 2016 to June 2018. Median follow-up was 26 months. Among the patients there were 58 men and 55 women. Median age was 33 years (range 18–65 years). In 72 patients HL and in 41 patients NHL (in 15 diffuse large B-cell lymphoma, in 8 primary mediastinal (thymic) large B-cell lymphoma, in 10 mantle cell lymphoma, in 4 peripheral T-cell lymphoma unspecified, and in 4 patients follicular lymphoma) were diagnosed. BeEAC conditioning regimen consisted of administering 160–200 mg/m2 bendamustine in increasing doses on Day –6 and Day –5 combined with fixed doses of 200 mg/m2 cytarabine every 12 hours, 200 mg/m2 etoposide, and 140 mg/kg cyclophosphamide from Day –4 to Day –1.

Results. In phase 1, when bendamustine dose was increased from 160 mg/m2 to 200 mg/m2, no dose-limiting toxicity was observed. Afterwards patients received 200 mg/m2 of bendamustine. The assessment of tumor status in 2–3 months after auto-HSCT showed that complete remission was achieved in 62.9 % (n = 71) of patients, partial remission in 16.8 % (n = 19) of patients, stabilization in 0.9 % (n = 1) of patients and progression in 15 % (n = 17) of patients. In 5 patients the treatment effect was not assessed. Early post-transplant mortality (up to Day +30) was 3.6 % (n = 4) and overall mortality within the follow-up period (median 26 months) was 23 % (n = 26). Overall survival in the whole cohort of patients for 12, 18, 24, and 36 months was 88 %, 82 %, 78 %, and 64 %, respectively, and progression-free survival was 61 %, 57 %, 54 %, and 40 %, respectively.

Conclusion. BeEAC proved to be relatively safe when applied as a conditioning regimen prior to auto-HSCT in HL and NHL patients. Further data need to be collected to finally assess the efficacy of this regimen and to conduct a retrospective comparative analysis of it and other conditioning regimens in lymphomas.

Keywords: high-dose chemotherapy, autologous hematopoietic stem cell transplantation, conditioning regimens, bendamustine, toxicity.

Received: September 6, 2019

Accepted: March 3, 2020

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Development and Validation Results of the Russian MPN10 Form for Symptom Assessment in Patients with Myeloproliferative Neoplasms Compliant with International Recommendations

AUTOIMMUNE THROMBOCYTOPENIA

TI Ionova1,2, OYu Vinogradova3,4,5, EV Efremova6, AE Kersilova6, TP Nikitina1,2, MM Pankrashkina3, NM Porfir’eva2, A-PA Poshivai6, MS Fominykh6,7, DI Shikhbabaeva3, VA Shuvaev6

1 NI Pirogov Clinic for High Medical Technology, Saint Petersburg State University, 7-9 Universitetskaya nab., Saint Petersburg, Russian Federation, 199034

2 Multinational Research Center for Quality of Life, 1 Artilleriiskaya str., Saint Petersburg, Russian Federation, 191014

3 SP Botkin Municipal Clinical Hospital, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284

4 Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology, 1 Samory Mashela str., Moscow, Russian Federation, 117997

5 NI Pirogov Russian National Research Medical University, 1 Ostrovityanova str., Moscow, Russian Federation, 117997

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

7 Saint Petersburg State University, 7-9 Universitetskaya nab., Saint Petersburg, Russian Federation, 199034

For correspondence: Tat’yana Pavlovna Nikitina, MD, PhD, 1 Artilleriiskaya str., Saint Petersburg, Russian Federation, 191014; Tel.: +7(962)710-17-12; e-mail: qolife@mail.ru

For citation: Ionova TI, Vinogradova OYu, Efremova EV, et al. Development and Validation Results of the Russian MPN10 Form for Symptom Assessment in Patients with Myeloproliferative Neoplasms Compliant with International Recommendations. Clinical oncohematology. 2020;13(2):176–84 (In Russ).

DOI: 10.21320/2500-2139-2020-13-2-176-184

ABSTRACT

Aim. To develop a Russian version of MPN10 form for patients with myeloproliferative neoplasms (MPN) compliant with international recommendations.

Materials & Methods. The trial included 57 patients treated in 2019 at the Moscow Municipal Center for Hematology of the SP Botkin Clinical Hospital (n = 30) and the Russian Research Institute of Hematology and Transfusiology (n = 27). Among them there were 36 myelofibrosis, 9 polycythemia vera, and 12 essential thrombocythemia patients. Mean age of the patients was 54.6 years (standard deviation 15.9 years; age range 20–79 years). The male/female ratio was 23/34 (40.4 %/59.6 %). Underlying disease duration was from 1 month to 33 years (mean duration 7 years; standard deviation 8.6 years).

Results. A stable structure and a high inner consistency of the form as well as its reproducibility as a tool were demonstrated. The trial also confirmed its convergent and discriminant validity and satisfactory sensitivity to changes in a patient’s status.

Conclusion. The Russian MPN10 version can be used for symptom assessment in MPN patients in clinical practice and scientific research.

Keywords: symptom assessment form, myeloproliferative neoplasms, psychometric properties of the form, validation.

Received: January 15, 2020

Accepted: March 29, 2020

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REFERENCES

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Prognostic Value of Next-Generation Sequencing Data in Patients with Myelodysplastic Syndrome

AUTOIMMUNE THROMBOCYTOPENIA

NYu Tsvetkov1, EV Morozova1, IM Barkhatov1, IS Moiseev1, MV Barabanshchikova1, AV Tishkov2, DS Bug2, NV Petukhova2, EA Izmailova1, SN Bondarenko1, BV Afanasyev1

1 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

2 Research Center for Bioinformatics, Academic Institute of Biomedicine, IP Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

For correspondence: Nikolai Yur’evich Tsvetkov, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; Tel.: +7(911)233-48-77, +7(812)338-62-27; e-mail: nikolai.tcvetkov@yandex.ru

For citation: Tsvetkov NYu, Morozova EV, Barkhatov IM, et al. Prognostic Value of Next-Generation Sequencing Data in Patients with Myelodysplastic Syndrome. Clinical oncohematology. 2020;13(2):170–5 (In Russ).

DOI: 10.21320/2500-2139-2020-13-2-170-175

ABSTRACT

Aim. To assess the prognostic value of the mutation of DNA methylation genes, SF3B1, and TP53 in patients with myelodysplastic syndrome (MDS).

Materials & Methods. Out of 35 MDS patients included into the trial 2 had multilineage dysplasia, 13 with excess blasts-I, 19 with excess blasts-II, and 1 had 5q-syndrome (criteria WHO 2016). In 30 patients primary MDS was identified, in 5 patients it was detected after prior chemo- or radiotherapy. 25 patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT). According to IPSS-R there were 1 low-risk, 5 intermediate risk, 17 high-risk, and 12 very high-risk patients. Hypomethylating agents were administered to 28 patients. Median age of patients was 49 years (range 18–80 years). Next-generation sequencing was applied for identifying somatic mutations in DNA methylation genes (TET2, IDH1/2, ASXL1, and DNMT3A) as well as in SF3B1, TP53, IDH, and RUNX1. Time to progression (TTP) was defined as the time from the initial diagnosis to the date of acute leukemia diagnosis. Allo-HSCT- or antitumor therapy-associated death was considered as competing risk.

Results. Methylation gene analysis showed no mutation in 37 % of patients, in 40 % mutation was detected only in one of the genes, in 23 % mutation was identified in ≥ 2 genes. SF3B1 mutations were reported in 23 % and TP53 in 11 % of patients. Median follow-up was 25 months (range 5–116 months). Univariate analysis showed no considerable differences in overall survival depending on mutation status. Median TTP in the group with allo-HSCT was not achieved, in the group without allo-HSCT it was 6 months (p = 0.0001). In patients with no SF3B1 mutation median TTP was 35 months, in patients with this mutation it was not achieved (p = 0.043). With ≥ 2 mutations in methylation genes median TTP was 12 months, in other cases it was not achieved (p = 0.024). In cases of TP53 mutation median TTP was 6 months, in cases without this mutation it was 43 months (p = 0.023). Multivariate analysis confirmed unfavorable prognostic value of TP53 mutation or ≥ 2 mutations in methylation genes in terms of TTP regardless of the drug treatment or allo-HSCT performed (hazard ratio 7.1; 95% confidence interval 2.6–19.6; p = 0.0001).

Conclusion. The analysis of molecular markers yields additional data concerning the MDS prognosis. Further research is required to determine the prognostic value of molecular markers in clinical practice which will enable to individualize approaches to MDS treatment.

Keywords: myelodysplastic syndrome, molecular markers, mutations, next-generation sequencing, prognosis.

Received: December 27, 2019

Accepted: March 25, 2020

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Diagnosis and Treatment of Clonal Myeloproliferative Neoplasms with Eosinophilia

AUTOIMMUNE THROMBOCYTOPENIA

IS Nemchenko, NN Tsyba, AG Turkina, EYu Chelysheva, OA Shukhov, AM Kovrigina, TN Obukhova

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

For correspondence: Irina Semenovna Nemchenko, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; e-mail: isn1965@mail.ru

For citation: Nemchenko IS, Tsyba NN, Turkina AG, et al. Diagnosis and Treatment of Clonal Myeloproliferative Neoplasms with Eosinophilia. Clinical oncohematology. 2020;13(2):161–9 (In Russ).

DOI: 10.21320/2500-2139-2020-13-2-161-169

ABSTRACT

Aim. Based on our own materials to characterize the clinical manifestations of hypereosinophilic states distinguishing between reactive eosinophilia (RE), clonal myeloproliferative neoplasms with eosinophilia (MPN-eo), and myeloproliferative variant of hypereosinophilic syndrome (MP-HES); to evaluate treatment results.

Materials & Methods. The trial included 188 patients with primary HES (132 men and 56 women, aged 19–72 years) having been followed-up at the National Research Center for Hematology since 2001. The main entry criteria were blood eosinophilia ≥ 1.5 × 109/L and clinical symptoms resulting sometimes from hypereosinophilia. All patients received complete physical examination, immunomorphological, standard cytogenetic, and molecular genetic testing. Treatment was provided to 73 patients (63 men and 10 women) including those with MPN-eo PDGFRA+ (n = 39), PDGFRB+ (n = 2), FGFR1+ (n = 1), chronic eosinophilic leukemia not otherwise specified (n = 8), systemic mastocytosis (n = 1), and MP-HES (n = 22). Complete hematological response (CHR) was the criterion for treatment efficacy. In the MPN-eo PDGFRA+ and PDGFRB+ groups molecular response (MR) rate was also estimated in cases of imatinib treatment. MR was considered as no expression of the FIP1L1-PDGFRA and ETV6-PDGFRB transcripts in RT-PCR.

Results. The trial yielded the cause of eosinophilia in 117 (62.2 %) out of 188 patients. RE was diagnosed in 60 (32 %) out of 117 patients, various types of clonal MPNs were reported in 57 (30 %) patients. In 71 (38 %) out of 188 patients HES was still present at the first trial stages. Later within this group MP-HES was identified in 22 (30.9 %) out of 71 patients. Among imatinib recipients CHR was achieved in 37 (90 %) out of 41 patients within 1–3 months: in 36 patients with MPN-eo FIP1L1-PDGFRA+ and in 1 patient with MPN-eo ETV6-PDGFRB+. MR was achieved in 88 % of cases. In the absence of molecular markers characteristic of MPN-eo CHR was achieved in 26 % of cases. Among the recipients of treatments other than imatinib nobody achieved CHR.

Conclusion. The diagnosis approach in patients with HES should be complex and individualized. Development and enhancement of molecular genetic diagnostic techniques are regarded as ones of the highest priority areas in modern hematology. The use of imatinib mesylate in MPN-eo therapy commonly results in long-term hematological and molecular remissions. On achieving CHR to imatinib treatment of patients without molecular markers characteristic of MPN-eo early use of this drug (or other tyrosine kinase inhibitors) can be recommended in acute forms of HES.

Keywords: eosinophilia, hypereosinophilic syndrome, myeloproliferative neoplasm, PDGFRA, PDGFRВ, FGFR1, imatinib.

Received: November 15, 2019

Accepted: February 28, 2020

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Molecular Diagnosis of FLT3 Mutations in Acute Myeloid Leukemia Patients

AUTOIMMUNE THROMBOCYTOPENIA

EK Zaikova1,2, EV Belotserkovskaya1,2, DV Zaytsev1, AV Petukhov1,2, OA Fedorova2, DV Motorin1, VV Ivanov1, AYu Zaritskey1, LL Girshova1

1 VA Almazov National Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341

2 Institute of Citology, 4 Tikhoretskii pr-t, Saint Petersburg, Russian Federation, 194064

For correspondence: Ekaterina Vasil’evna Belotserkovskaya, PhD in Biology, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; e-mail: belotserkovskaya.ev@gmail.com

For citation: Zaikova EK, Belotserkovskaya EV, Zaytsev DV, et al. Molecular Diagnosis of FLT3 Mutations in Acute Myeloid Leukemia Patients. Clinical oncohematology. 2020;13(2):150–60 (In Russ).

DOI: 10.21320/2500-2139-2020-13-2-150-160

ABSTRACT

Background. FLT3 gene is an important prognostic molecular marker in acute myeloid leukemia (AML). However, the detection of FLT3 mutations presents a challenge.

Aim. To compare techniques used for the detection of FLT3 mutations, and to develop a test-system based on polymerase chain reaction (PCR) for quick and reliable determination of FLT3 mutation status.

Materials & Methods. Bone marrow samples obtained from AML patients were subjected to examination. To detect FLT3-ITD и FLT3-TKD mutations PCR was performed with subsequent agarose gel electrophoresis visualization. The results were verified by Sanger sequencing. The data obtained using our test-system were compared with widely applied commercial kit ‘FLT3 Mutation Assay for Gel Detection’ by Invivoscribe.

Results. To determine the FLT3 mutation status a PCR test was developed. This technique was validated on 22 bone marrow samples obtained from AML patients. FLT3-ITD mutation was detected in 4 patients, 3 patients showed FLT3-TKD mutation. In 1 patient both mutations were identified. These results fully corresponded to the molecular genetic analysis of FLT3, performed by ‘FLT3 Mutation Assay for Gel Detection’. The chosen technique was validated using Sanger sequencing data analysis.

Conclusion. The article offers the review of all existing FLT3 mutation screening techniques and describes the experience of developing the PCR test for FLT3-ITD and FLT3-TKD mutation detection. The chosen technique is affordable and easy to use compared with the others. The present study with its applied nature can provide guidance for both doctors and researchers.

Keywords: acute myeloid leukemia, FLT3-ITD and FLT3-TKD mutations.

Received: January 10, 2020

Accepted: March 27, 2020

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Bendamustine in the Treatment of Relapsed/Refractory Hodgkin’s Lymphoma: Literature Review and Clinical Experience

AUTOIMMUNE THROMBOCYTOPENIA ,

SS Shklyaev, NA Falaleeva, TI Bogatyreva, AYu Terekhova, MA Danilova

AF Tsyb Medical Radiological Research Centre, branch of the NMRC of Radiology, 4 Koroleva str., Kaluga Region, Obninsk, Russian Federation, 249036

For correspondence: Stanislav Sergeevich Shklyaev, MD, PhD, 4 Koroleva str., Kaluga Region, Obninsk, Russian Federation, 249036; Tel.: +7(484)399-30-31; e-mail: staniss1@yahoo.com

For citation: Shklyaev SS, Falaleeva NA, Bogatyreva TI, et al. Bendamustine in the Treatment of Relapsed/Refractory Hodgkin’s Lymphoma: Literature Review and Clinical Experience. Clinical oncohematology. 2020;13(2):136–49 (In Russ).

DOI: 10.21320/2500-2139-2020-13-2-136-149

ABSTRACT

Aim. To assess the efficacy of bendamustine combined with dexamethasone in the treatment of relapsed/refractory Hodgkin’s lymphoma (HL).

Materials & Methods. The article provides an updated review of literature as well as the data of prospective observational clinical trial in 47 HL patients (17 men and 30 women aged 20–65 years, median age 36 years) with relapses after standard and high-dose chemotherapy with autologous hematopoietic stem cell transplantation. The therapy regimen included 120 mg/m2 of bendamustine IV on Days 1 and 2 and 20 mg of oral dexamethasone from Day 1 to Day 4. Retreatment was administered 21 days after the start of the previous one. Radiotherapy was applied only to the regions of massive relapsed lesions and bone destructions with pain syndrome.

Results. From April 2011 to September 2017 all 47 patients received 149 bendamustine + dexamethasone therapy regimens with the overall response of 57 % (complete response 27 %, partial response 30 %). Disease progression on therapy was reported in 20 (43 %) patients, its incidence was the highest after the first (n = 8) or the second cycle (n = 4). In the group of 27 patients with overall response 19 (70 %) patients showed new relapses. In these cases the treatment-free period was from 8 to 31 months (median 11 months). The repeated administration of 57 bendamustine + dexamethasone therapy regimens in 12 out of 47 patients achieved clinical effect for 4–36 months (median 6 months). After the first failure of bendamustine-based therapy 13 patients were treated with brentuximab vedotin and nivolumab, the new salvage therapy drugs. With median follow-up of 22 months (range 1–69 months) median overall survival (OS) and time to the next progression were 35 and 10 months, respectively, in all patients. Multivariate analysis showed that OS was unfavorably affected only by B-symptoms on bendamustine + dexamethasone administration (p = 0.046), and the time to the next progression was shorter in the presence of B-symptoms (p = 0.017) and in histological variant “nodular sclerosis type II” (p = 0.006).

Conclusion. Bendamustine + dexamethasone therapy is a relatively low-toxic and effective method of life prolongation in HL patients with chemotherapy-refractory tumors and recurrent relapses, provided no B-symptoms occur by the start of antitumor therapy.

Keywords: Hodgkin’s lymphoma, bendamustine, chemotherapy-refractory disease, relapses.

Received: December 15, 2019

Accepted: March 20, 2020

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Pyroptosis as Inflammatory Cell Death

AUTOIMMUNE THROMBOCYTOPENIA

AA Vartanyan, VS Kosorukov

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

For correspondence: Amaliya Artashevna Vartanyan, PhD in Biology, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(499)324-10-65; e-mail: zhivotov57@mail.ru

For citation: Vartanyan AA, Kosorukov VS. Pyroptosis as Inflammatory Cell Death. Clinical oncohematology. 2020;13(2):129–35 (In Russ).

DOI: 10.21320/2500-2139-2020-13-2-129-135

ABSTRACT

Pyroptosis, caspase-1-dependent inflammatory cell death, is induced by intracellular pathogens or tissue lesions. Procaspase-1 activation, which is essential for the processing of proinflammatory cytokines pro-IL-1β and pro-IL-18, occurs in macromolecular protein complexes, also referred to as inflammasomes. In the gram-negative bacilli-induced infections inflammasome assembly incorporates caspase-4 and caspase-5. Originally identified as a protective mechanism of innate immunity, at present pyroptosis is not limited to the inhibition of intracellular pathogen multiplication. The current review discusses molecular mechanisms of pyroptosis-like cell death and possible pyroptosis involvement in tumor cell death.

Keywords: cell death, pyroptosis, caspases, inflammation, innate immunity.

Received: December 24, 2019

Accepted: March 17, 2020

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Aldehyde Dehydrogenase as a Marker of Early Mesenchymal Progenitor Cells in Donor Bone Marrow Stroma

AUTOIMMUNE THROMBOCYTOPENIA

KA Vetoshkin, NV Isaeva, MA Butolina, NV Minaeva, NA Zorina, MN Khorobrykh, YuS Zmeeva

Kirov Research Institute of Hematology and Transfusiology, 72 Krasnoarmeiskaya str., Kirov, Russian Federation, 610027

For correspondence: Konstantin Aleksandrovich Vetoshkin, MD, PhD, 72 Krasnoarmeiskaya str., Kirov, Russian Federation, 610027; Tel.: +7(905)870-06-92; e-mail: kostyavetoshkin@yandex.ru

For citation: Vetoshkin KA, Isaeva NV, Butolina MA, et al. Aldehyde Dehydrogenase as a Marker of Early Mesenchymal Progenitor Cells in Donor Bone Marrow Stroma. Clinical oncohematology. 2020;13(2):123–8 (In Russ).

DOI: 10.21320/2500-2139-2020-13-2-123-128

ABSTRACT

Aim. To analyze the growth rate of mesenchymal stromal cell (MSC) culture depending on the aldehyde dehydrogenase-positive (ALDH+) cell count.

Materials & Methods. The study involved bone marrow mesenchymal cell cultures of 10 donors (5 men and 5 women) with median age of 34.5 years (range 14–38 years). Nucleated cells were obtained by density gradient centrifugation. MSCs were cultivated according to the conventional protocol using platelet-rich donor plasma. Stromal cell identification and ALDH+ cell counting were performed by laser flow cytometry according to the criteria of the International Society for Cell Therapy.

Results. The growth rate of MSC cultures and ALDH+ cell counts are maximum at primary and passage No. 1, becoming significantly lower by passage No. 3. The relationship between MSC culture growth rate and ALDH+ cell count was revealed. The older the donor, the lower MSC culture growth rate and ALDH+ cell count in bone marrow stroma.

Conclusion. The data obtained indicate the relationship between bone marrow MSC culture growth rate, donor’s age, and ALDH+ cell count. ALDH-expressing cells proved to confer MSC population renewal. Based on the results acquired, we assume that the studied ALDH marker can serve as an objective criterion for placing mesenchymal cell elements into the category of early progenitor cells.

Keywords: cell culture, mesenchymal cells, aldehyde dehydrogenase, culture growth rate.

Received: November 28, 2019

Accepted: March 1, 2020

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Granulocyte-Macrophage Colony-Stimulating Factor and CAR-T Technology for Solid Tumors in Experiment

AUTOIMMUNE THROMBOCYTOPENIA

DV Zaytsev1, EK Zaikova1,2, AS Golovkin1, ER Bulatov3, AKh Valiullina3, RM Mirgayazova3, AA Daks2, AYu Zaritskey1, AV Petukhov1,2

1 VA Almazov National Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341

2 Institute of Citology, 4 Tikhoretskii pr-t, Saint Petersburg, Russian Federation, 194064

3 Kazan (Privolzhskii) Federal University, 18 Kremlevskaya str., Kazan, Russian Federation, 420008

For correspondence: Daniil Vladislavovich Zaytsev, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; Tel.: +7(981)727-16-74; e-mail: zaicev_daniil@mail.ru

For citation: Zaytsev DV, Zaikova EK, Golovkin AS, et al. Granulocyte-Macrophage Colony-Stimulating Factor and CAR-T Technology for Solid Tumors in Experiment. Clinical oncohematology. 2020;13(2):115–22 (In Russ).

DOI: 10.21320/2500-2139-2020-13-2-115-122

ABSTRACT

Background. Cytokines are considered as important factors that enhance the efficacy of CAR-T cell therapy. Besides, they are key elements of the pathogenesis of cytokine release syndrome and neurotoxicity in applying the CAR-T technology. However, cytokine effects in the context of CAR-T therapy have not yet been properly studied.

Aim. To quantitatively assess cytokine secretion using multiplex assay with co-incubation of anti-CD19 CAR-T lymphocytes with epithelial HeLa and A431 cell lines expressing CD19 on their surface.

Materials & Methods. T-lymphocytes were transduced with the lentiviral vector containing anti-СD19-CAR gene. CAR expression was tested based on GFP reporter using flow cytometry. To confirm a specific CAR-T cell activation response to tumor antigen, the levels of interleukin-2, interferon-γ, and tumor necrosis factor-α were measured by means of immunoassay. Cytotoxic activity of CAR-T lymphocytes obtained was examined with their direct co-culturing with target cells. The levels of cytokines isolated prior to and after incubation of targets with CAR-T cells were compared using multiplex assay.

Results. The level of some proinflammatory cytokines (interleukin-6, interleukin-1β, interferon-γ) (p < 0.01) increased. The difference in the levels of anti-inflammatory cytokines (interleukin-4, interleukin-10) was inconsiderable, and in the HeLa cell line experiment it was insignificant (p > 0.05). The concentration of granulocyte-macrophage colony-stimulating factor (GM-CSF) was many times higher after incubation with CAR-T lymphocytes (p < 0.01).

Conclusion. The trial revealed multiple enhancement of GM-CSF, one of the key elements of the pathogenesis of cytokine release syndrome and CAR-T-associated neurotoxicity. The results of further studies of GM-CSF can contribute to improving the efficacy of CAR-T therapy with considerably lower toxicity.

Keywords: CAR-T cells, GM-CSF, cytokines, immunotherapy.

Received: January 10, 2020

Accepted: March 28, 2020

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Multiple Myeloma

AUTOIMMUNE THROMBOCYTOPENIA

SV Semochkin

NI Pirogov Russian National Research Medical University, 1 Ostrovityanova str., Moscow, Russian Federation, 117997; Municipal Clinical Hospital No. 52, 3 Pekhotnaya str., Moscow, Russian Federation, 123182

For correspondence: Prof. Sergei Vyacheslavovich Semochkin, MD, PhD, 3 Pekhotnaya str., Moscow, Russian Federation, 123182; Tel./fax: +7(495)369-00-36; e-mail: semochkin_sv@rsmu.ru

The interview was conducted by Prof. E.A. Osmanov, MD, PhD.

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