XIII R. Gorbacheva Memorial Symposium Hematopoietic Stem Cell Transplantation. Gene and Cellular Therapy: an Overview
Boris V. Afanasyev
Editor-in Chief, Cellular Therapy and Transplantation
Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Chair of Hematology, Transfusiology and Transplantology, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russia
Phone: +7 (812) 338 6265
Accepted 11 October 2019
XIII R. Gorbacheva Memorial Symposium proceeded in St. Petersburg (September 19-21, 2019) at the Sokos Olimpia Garden Hotel, being attended by numerous well-known experts in hematopoietic stem cell transplantation, chemo- and immune therapy, mostly from European countries. The meeting has attracted over 300 participants from different regions of Russia, as well as Republic of Belarus, Kazakhstan.
After official welcome word by Prof. Boris Afanasyev, the XIII Symposium started with R. Gorbacheva memorial lecture Can Immune Therapy Cure acute myeloid leukemia? presented by Prof. Robert P. Gale (Los Angeles, USA), a known expert in leukemia, bone marrow transplantation and related fields of molecular biology. Previous trials of different immunotherapies in AML were mostly unsuccessful, and cytostatic drugs remain the main treatment option in this disorder. Therapy with MAbs is used, mainly, in lymphoid malignancies. Search for molecular targets in AML is underway. Graft-versus-leukemia effects in allo-HSCT are considered. Some MAbs to early myeloid antigens, especially, gemtuzumab, CAR-T cells, and immune control point inhibitors are now under trials.
Professor Axel Zander (Hamburg, Germany) has presented a lecture Development of MSC Therapy concerning the modern studies of mesenchymal stem cells (MSC). Immunomodulatory properties of this heterogenous population are of sufficient clinical importance. Antiinflammatory, antiapoptotic, angiogenic, and mitogenic mechanisms are considered. E.g., MSC therapy alleviates experimental acute kidney injury, as well as acute radiation syndrome. Some authors treat GVHD with MSC infusions. However, wide unproven indications for MSC therapy should be avoided.
Professor Nicolaus KrÖger (Hamburg, Germany) reported about Haplo-identical Stem Cell Transplantation which is recently a quite popular type of HSCT, despite of high GVHD rates due to partial HLA-mismatch. However, ex vivo α/β T cell depletion, CD34+ cell enrichment, and usage of posttransplant cyclophosphamide may reduce these complications, while increasing the infection incidence.
Professor Gerard Wagemaker (Rotterdam, The Netherlands) continued the session with a lecture Current clinical implementation of gene therapy in rare, inherited diseases. Among thousands genetic disorders, the main success was achieved with inborn immune deficiencies treated by allo-HSCT. Recent advances in gene therapy allow usage of the SIN lentiviral vectors with good safety profile in order to deliver normal genes to the target cells. At the present time, several clinical trials are performed with gene therapy for lysosomal enzyme deficiencies, hemophilia, and some other rare disorders by means of gene transfer to autologous stem cells using lentiviral and AAV-based vectors.
Professor Hans-Jochem Kolb (München, Germany) presented a lecture Late effects after allogeneic stem cell transplantation where he summarized clinical observations for the patients transplanted from 1975 to 2002. Chronic GVHD, infections and secondary cancers were the most remarkable complications, especially, in children who survived anticancer treatment. A sufficient role of radiation therapy was also shown to be an important risk factor of late carcinogenic effects.
Professor Michael Maschan (Moscow, Russia) held a report dedicated to Evolution of approach to HSCT for pediatric leukemia: from haploidentical donors to CAR-T therapy presenting different approaches to ex vivo graft manipulations, mainly, when treating lymphoblastic leukemia. He concluded that creative graft engineering (e.g., αβ T cell depletion) is able to solve key historic problems of HSCT, and successful CAR-T therapy can be delivered effectively by local manufacturing.
A report by Dr. Sergey Bondarenko (St. Petersburg, Russia) concerned the Choice of optimal time for allo-HSCT in AML: CR1 or CR2 based on clinical results of EBMT center CIC 725 of allo-HSCT performed in AML since 2005 to 2018. The main result showed that the patients with adverse-risk AML, as based on clinical and molecular signs, should receive allo-HSCT in the 1st complete remission, and the patients with favourable risk have been transplanted in 2nd remission.
Prof. Rüdiger Hehlmann (Heidelberg, Germany) presented a report Recognition and management perspectives of refractory end-phase CML focused on the so-called high-risk additional chromosomal aberrations and some specific gene mutations as important prognostic factors for clinical outcomes in refractory CML cases.
A lecture by Prof. Pierre Fenaux (Paris, France) When should MDS/CMML be transplanted? Should transplant be preceded by cytoreductive treatment? argued for proper timing and risk stratification of myelodysplastic syndrome (MDS) for allo-HSCT. Severe pre-treatment and some gene mutations (e.g., p53) cause low survival post-transplant. Relative life-prolonging effects are compared for allo-HSCT and hypomethylating drugs.
Prof. Crzegorz Basak (Warsaw, Poland) presented a review Transplantation in elderly – sky is the limit? Based on current improvements in reduced-conditioning regimens, a strong rationale to perform allo-HSCT exists for elderly patients, even >75 years old, despite risk for GVHD and infections. One should recommend allo-HSCT in elderly taking into account early, well-controled disease; absence of heavy pre-treatment, low cytogenetic risk, with good physical performance and mental status.
Dr. Ivan Moiseev (St. Petersburg, Russia) presented an assay entitled: Evolution of graft-versus-host disease prophylaxis and treatment regimens: leaving the Seattle nest. He briefly described history of GVHD prevention with metylprednisolone and calcineurin inhibitors, and later schedules including posttransplant cyclophosphamide, as well as novel immunosuppressors (monoclonal antibodies, JAK2 inhibitors etc.).
Dr. Mikhail Drokov (Moscow, Russia) continued this topic in their report Reconstitution of immune system after different regimens of GVHD prophylaxis. E.g., they showed comparable immunoablative effects of PT-CY and T cell αβ-depletion which seems to be based on Tnv+scm depletion. The use of prophylactic infusion of selected lymphocytes (CMV-specific T-lymphocytes, CD45RA- fraction) can improve the reconstitution of antiviral immunity. Donor T-regulatory cells may provide a more effective GVHD protection.
Dr. Dmitry Motorin (St. Petersburg, Russia) told about Allogeneic Stem Cell Transplantation in patients with blast crisis in chronic myeloid leukemia. Their general approach includes combination of chemotherapy and TKIs; change of previous TKI to the 2nd-3rd –generation drug; НSCT from allogeneic donor after achieving 1st-2nd chronic phase. Type of donor seemed not to influence clinical outcomes.
Dr. Elena Morozova (St. Petersburg, Russia) presented the data from R. Gorbacheva Institute concerning The results of allogeneic hematopoietic stem cells transplant in patients with CML. She concluded that allo-HSCT is a feasible option for treatment of advanced CML. The TKI drugs may be used as a bridge before allo-HSCT. TKIs are safe and effective in post-transplant settings, and donor lymphocyte infusions may provide additional control in high-risk cases.
Prof. Tapani Ruutu (Helsinki, Finland) continued the discussion on GVHD in his report Is there any role for corticosteroids in GVHD prophylaxis? He based on previous controversial results obtained with corticosteroids added to cyclosporin and methotrexate-containing schedules. Most recent works, however, confirm preventive effect of methylprednisolone addition to the GVHD prophylaxis protocols.
Prof. Belinda Pinto-Simoes (Sao Paulo, Brazil) concerned the topic of auto-HSCT in non-malignant diseases. In her report SCT in multiple sclerosis, a number of studies worldwide is summarized, with long-term progression-free survival rates of 60-80% among the transplanted patients. Critical questions in treatment of this disorder are: when should be HSCT optimally used, and what conditioning regimen is used. Comparative data with other innovative therapies are required in future.
Prof. Laurant Garderet (Paris, France) presented a lecture: Will autologous stem cell transplantation remain a treatment for multiple myeloma? Effective myeloma therapy, following induction treatment, is based on auto-HSCT, but now competes with new drugs, specific monocloical antibodies and CAR-T cells. Auto-HSCT remains, however, the most efficient approach with respect to clinical response in standard-risk disease.
Prof. Dietger Niederwieser (Leipzig, Germany) discussed a quite actual topic in his report: The role of stem cell transplantation in the treatment of acute myeloid leukemia. HSCT is typical in high-risk AML, however, gene and chromosome mutations should be made to choose HSCT in the intermediate-risk cases. In older patients, an option of demethylating therapy is considered.
Several short presentations were presented by young specialists in the field. Dr. Anastasia Beynarovich dealt with local experience of haploidentical transplantation at the R. Gorbacheva Institute. The study confirmed haplo-HSCT to be a feasible option for high-risk hematological malignancies. However, haplo-HSCT is still associated with higher non-relapse mortality due to graft failure and GVHD.
Dr. Kirill Kirgizov (Moscow, Russia) told about Hematopoietic stem cell transplantation for children with multiple sclerosis based on their own studies at D. Rogachev Pediatric Research Center in Moscow. Auto-HSCT seems to be rather effective for children with severe disorder, by stopping progression of the disease. ASCT should be performed earlier, using less toxic conditioning regimens. Dr. Maria Dovydenko (Moscow, Russia) presented data on Haploidentical stem cell transplantation with previous TCR α/β and CD19 Depletion in adults. The study confirmed high efficiency of haplo-HSCT. Severe GVHD is prevented by depletion of TCRαβ/CD19 cells from the graft. However, this ex vivo graft manipulation causes immune deficiency and resistant infectious complications in adult patients.
Focus on lymphomas: Hodgkin Lymphoma
Prof. Anna Sureda (Barcelona, Spain) held a lecture To allograft or not to allograft patients with relapsed/refractory Hodgkin’s lymphoma in the era of new drugs. Indeed, she concluded that HLA-compatible allo-HSCT and haploidentical HSCT may be considered after failing auto-HSCT. However, the new drugs, e.g., nivolumab pre-trasplant, may increase efficiency of subsequent HSCT. Prof. Manuel Abecasis (Lisboa, Portugal) shared his experience in Stem cell transplantation as consolidation in peripheral T-cell lymphomas. This subtype of non-Hodgkin’s lymphoma may show early relapse/progression. Allo-HSCT is more effective that auto-HSCT in terms of overall and relapse-free survival. The data from ECHELON-2 trial has, generally, confirmed these results.
Prof. Boris Afanasyev (St. Petersburg, Russia) has reported own results in a lecture Allo-HSCT in relapsed/refractory R/R Hodgkin lymphoma: focus on immunotherapy, concluding that the development of reduced-toxicity conditioning regimes, new approaches to GVHD prophylaxis, bridge therapy with anti-CD30 immunoconjugates and immune checkpoints inhibitors have led to a significant improvement in the results of allo-HSCT.
Prof. Andreas Engert (Köln, Germany) presented with an overview entitled Hodgkin lymphoma including the latest aspects on checkpoint inhibiton. His report was based on stage-specific strategies in HL therapy. He mentioned organ damage after preceding chemo/radiation therapy, higher efficiency of combined treatment at earlier terms, high response rates with Brentuximab and especially, Nivolumab in refractory HL cases.
Dr. Vladislav Sarzhevskiy (Moscow, Russia) presented a report The role and place of autologous hematopoietic stem cell transplantation in the treatment of Hodgkin’s lymphoma which confirms good efficiency of autologous HSCT in R/R Hodgkin lymphoma. The pre-transplant therapy may include Brentuximab Vedotine or Nivolumab to reach better survival. These drugs show increasing importance as a treatment option in R/R HL.
In two short communications on the topic, the data from the R. Gorbacheva Institute (St. Petersburg, Russia) about Nivolumab treatment of R/R Hodgkin lymphoma were reported, including heterogeneity of clinical response and sufficient efficiency of the drug upon repeated treatment (Dr. Ludmila Fedorova). Dr. Kirill Lepik (St. Petersburg, Russia) has shown similar positive clinical effects in HL, when using sufficiently lower Nivolumab doses (40 mg) than at a standard dosage.
Prof. Alfried Kohlschütter (Hamburg, Germany) presented a lecture on Intrathecal enzyme replacement therapy for CLN2 disease, an inherited disorder caused by deposition of ceroid-lipofuscin in brain. The deficient Tripeptidyl Peptidase 1 preparation was delivered through a subcutaneous port to inject the solution to lateral brain ventricle. Motor and mental deterioration was stopped by this treatment.
Prof. Olga Aleynikova (Minsk, Republic of Belarus) reported The results of HSCT for pediatric acute leukemias in Republic of Belarus based on 377 patients with acute leukemias (AML and ALL) transplanted over 20 years. The results were compatible with general EBMT statistics on allo-HSCT. Mesenchymal stem cell treatment seemed to decrease the GVHD-related mortality.
Prof. Stefan Bielack (Stuttgart, Germany) discussed the topic What is the evidence for auto-HSCT in children with pediatric malignancies? focusing on extracranial solid tumors in children and adolescents, mostly, high-risk neuroblastoma which still is the hard-to-treat tumor. However, high-dose therapy + auto-SCT improves event-free survival to some degree. Efficiency of Ewing sarcoma therapy depends on presence and extension of metastatic lesions.
Dr. Inna Markova (St. Petersburg, Russia) told about Allogeneic hematopoietic stem cells transplant in children and adults with relapsed/refractory B-ALL: focus on anti-CD19, anti-CD22 monoclonal antibodies. Pre-transplant state is a significant factor of allo-HSCT efficiency. Treatment with Blinotumomab or Inotuzumab ozogamicin causes high survival of the patients.
Dr. Tatiana Bykova (St. Petersburg, Russia) discussed Graft failure and poor graft function in children undergoing allogeneic hematopoietic stem cell transplantation. Nowadays, the graft failure is not common after pediatric allo-HSCT occurring due to multiple donor and recipient factors. DLI, BOOST infusions, second transplants can be used as effective method of PGF treatment.
Dr. Andrey Kozlov (St. Petersburg, Russia) reported about Hematopoietic stem cell transplantation in children and adolescents with lymphomas analyzing a single-centre, 25-year experience of non-Hodgkin’s lymphomas with BEAM conditioning followed by auto-HSCT which can cure approximately half of children with relapsed/refractory lymphomas.
Bone marrow failure
A detailed report by Prof. Galina Novichkova (Moscow, Russia) summarized their early results concerning Immunosuppressive therapy and/or Elthrombopag in children and adolescents with acquired aplastic anemia. The comprehensive study did not show gross increase in overall rates of hematological responses with this drug, however, the response occurred sooner, being more pronounced.
A lecture by Prof. Robert P. Gale (Los Angeles, USA) Are Aplastic Anaemia, MDS and AML 1, 2 or 3 Diseases? concerned common features and fundamental differences in aplastic anaemia, MDS and AML. Despite partial overlap of etiological factors, spectrum of chromosomal aberrations and gene mutations, these disorders are, generally, regarded as distinct diseases, thus enabling distinct strategies for their diagnosis and specific treatment. Appropriate pre-malignant clones may have similar cytogenetics and mutations, then evolving to more malignant phenotype.
Prof. Alexander Kulagin (St. Petersburg, Russia) discussed Current management of aplastic anemia: focus on older patients (over 60 years). The main clinical problem is insufficient diagnostics that must include search for PNH clones and cytogenetic studies. Cyclosporin + ATG seem to be effective in this condition, however, with high rates of treatment failures.
Dr. Tatiana Rudakova (St. Petersburg, Russia) also presented a report on Risk factors, outcomes and therapeutic options for severe poor graft function (PGF) after allogeneic HSCT in adults. The hazards are associated with evolving MDS, haploidentical donors, bacterial and viral infections. Boost infusions, or re-transplantation of hematopoietic stem cells might be beneficial for the patient survival in these cases.
Dr. Vera Vasilieva (Moscow, Russia) has summarized their data on Clinical efficacy and immune effects of extracorporeal photopheresis (ECP) in patients with chronic GVHD. ECP of blood cells is effective and low-toxic option of therapy of chronic GVHD, with overall response rate is 63%.
Basic research in HSCT
Dr. Katia Beider (Tel Hashomer, Israel) discussed The role of microenvironment in multiple myeloma: potential therapeutic implications. In particular, the author discussed a possibly central role of CXCR4 in multiple myeloma which allows to explain clinical effects of everolimus and HDAC inhibitor panobinostat in myeloma treatment.
Prof. Hans-Jochem Kolb (München, Germany) discussed the topic of Immunotolerance by chimerism obtained after allogeneic HSCT. The cellular tolerance mechanisms include: depletion of T cell populations, e.g., due to ATG, cyclophosphamide treatment, activity of regulatory T lymphocytes, dendritic cells, mesenchymal stem cells, etc. A role of mixed chimerism in the development of tolerance is also suggested.
A practically significant aspect was discussed by Prof. Magne Borset (Trondheim, Norway) in his report Immune checkpoint (ICP) inhibition in the treatment of multiple myeloma. First clinical trials on ICP in multiple myeloma did not resolve the efficiency and safety issues. Several myeloma-specific antibodies are tried in myeloma treatment. Some metabolites, e.g., adenosine, may modulate immune response to myeloma cells, as shown in animal and cellular models.
Prof. Dr. Boris Fehse (Hamburg, Germany) has provided important data on Usage of digital quantitative PCR for posttransplant diagnostics, mostly, for analysis of mixed donor chimerism, and diagnostics of minimal residual disease, as exemplified by residual disease in myeloid proliferative neoplasia. Digital PCR diagnostics seems to be more effective when searching for several target genes.
Brief report by Larisa Kuzmina (Moscow, Russia) concerned, mostly, successful usage of mesenchymal stem cells (MSCs) in treatment of steroid refractory acute GVHD. The authors did not find any specific markers of MSCs predicting good clinical response.
Dr. Grigory Efimov (Moscow, Russia) reported preliminary experimental data on usage of some minor-HLA-specific CD8+ T cells obtained by transfection of initial T cells by a lentivirus-based vector encoding polymorphic variant of ARHGAP45 gene, generally, overexpressed in AML.
As previously, the present meeting included a special symposium dedicated to gene therapy, especially, genetically modified immune cells. Prof. Gerard Wagemaker (Rotterdam, The Netherlands) in his State-of-the-Art Gene Therapy has given an introduction to current approaches in gene therapy based on transfer of virus-based and non-viral vectors. Most attention is now drawn to in vitro gene editing by CRISP/Cas9 technology and production of chimeric antigen receptor (CAR) T cells for immunotherapy of cancer. Meanwhile, the report mainly concerned gene correction of inherited disorders, e.g., Hurler Disease, Gaucher disease, beta thalassemia, Fanconi anemia etc. as well as advanced closed-type equipment for reliable gene transfer and infusion to the patients.
Dr. Zoltan Ivics (Langen, Germany) has presented his view of Non-viral therapeutic gene engineering developing a platform for transduction of the required gene fragments to the target cells based on the so-called Sleeping Beaty technology for gene transfer which could be used in context of specific CAR-T cell production, as well molecular technique for the mini-circle-based delivery of genetic material, e.g., to the CD34+ hematopoietic cells.
Dr. Eric Ehrke-Schulz (Witten, Germany) has reported about new adenoviral and adeno-associated virus-based vectors which enable more efficient gene editing by delivering the CRISPR/Cas9 components to different cell populations, thus causing potential correction of mutations in some muscular disorders, hemophilia, elimination of hepatitis B virus, etc.
Dr. Alyona Shakirova (St. Petersburg, Russia) presented her own data on the in vitro TALEN-mediated gene editing in hematopoietic stem cells taking into account possible toxicity to the target cells, and incidence of on- and off-target effects after the CCR5 gene transfection. She has demonstrated sufficient rates of biallelic CCR5 knockout events, thus making a step to future treatment of HIV infection.
Dr. Alexander Timin (St. Petersburg, Russia) has reported on bioengineering strategies to accelerate stem cell therapeutics exploiting various adaptable properties of nanoparticles and other microcarriers which may be used for loading, in vivo transport and controlled release in the tissues of interest by different physical or chemical factors (magnetic fields, thermal changes, ultrasonic effects etc.). Some versatile polymer-based platforms are proposed to the aims of controlled local release from the drug-containing nanoparticles. Dr. Albert Muslimov (St. Petersburg, Russia) has presented own data concerning Polymeric micro- and nano-carriers as a universal platform for delivery of biomolecules to the relevant cells. Such carrier microparticles may consist of complex multilayers. These particles based on carbonate and magnetic admixtures are shown to capture biological molecules, and were tested for effective interactions with some target cells, especially those with active endocytosis.
A special session concerned current regulations in the field of cellular therapy. Dr. Mikhail Samsonov (Moscow, Russia) has presented his opinion about Russian legislative acts concerning implementation of cell and gene therapy methods. Huge research efforts in this area abroad has already lead to development and accelerated review for some potential useful commercial products (new drugs, CAR-T cells) which now are subject to numerous clinical studies as immunotherapeutic drugs.
Mr. Vadim Merkulov (Moscow, Russia) told about some problems with expertise and approval of medicinal cellular products already enacted in Russia since 2015 and discussed some practical details of applications the new products from academic researchers presented for review procedures, as based on the Federal Law No.180 and amended documents. Prof. Michael Maschan (Moscow, Russia) has described in brief his own experience with application of CAR-T cells against CD19, a new cellular product for treatment of acute lymphoblastic leukemia as well as closed system for their production.
Dr. Sergey Kulemzin (Novosibirsk, Russia) has reported about regulatory controversies and hurdles that encounter for academic institutions trying to register and perform clinical trials with novel cellular products (e.g., CAR-T cells) at the level of federal authorities responsible for their approval.
Dr. Zoltan Ivics (Langen, Germany) has summarized European regulations concerning approval of new cellular products and compared them with appropriate legislation in USA, showing sufficient controversies, however, suggesting improvements in this field, taking into account certain flexibility with reviewing terms and understanding social value of distinct medicinal products to be implemented.
Dr. Michael Zaiac (Basel, Switzerland) provided some examples of successful implementation and official European approval of several biological drugs and cell products for immunotherapy including laboratory facilities for separation, gene transfection and further production of therapeutic cell-based preparations directly at the transplantation clinics.
Professor Hans-Jochem Kolb (München, Germany) in his lecture State-of-art cell therapy discussed modern toolset for cellular and gene therapy aimed for boosting immune response to malignant cells in leukemias and lymphomas. To this purpose, CAR-T cells and monoclonal antibodies of appropriate specificity could be used in various combined schedules of cancer treatment, first of all, in B cell leukemias and some lymphomas.
An impressive presentation by Dr. Boro Dropulic (Gaithersburg, USA): CAR-T: hematology and beyond concerned, in particular, current issues of CAR-T cells which are now implemented not only for immune therapy of malignancies, but also for reduction of HIV-1 burden in infected humans. He shared his experience with lentiviral vectors providing CARs targeting against conserved sites on the HIV-1 envelope, thus causing sharp decrease in cellular HIV infection.
Dr. Sergey Kulemzin (Novosibirsk, Russia) has argued for natural killer cells as a plausible cytotoxic cell population which could be genetically manipulated and used for targeted treatment of cancer pathologies.
Dr. Alexey Petukhov (St. Petersburg, Russia) has described their initial experience in clinical implementation of CAR-T cell technologies at the V. Almazov center using local laboratory facilities for clinical-scale production of CD19-specific CAR-T cells for autologous infusion. CAR-T cell characteristics from several production cycles were presented showing good quality and reproducibility of gene-modifying procedures.
Dr. Tatiana Belovezhets (Novosibirsk, Russia) discussed some benefits and challenges associated with development of CD20-specific CAR-T cells which contained gene sequences ofatumumab, an anti-CD20 monoclonal antibody. Dr. Anton Chikaev (both – Novosibirsk) presented the conventional version of CD19-specific CAR-T cell design using both previously known gene transduction cassettes, as well as original modifications of these constructs.
Prof. Boris Fehse (Hamburg, Germany) has also presented his experience in a report on cell therapy with CAR-T cells specific for CD19, in the Hamburg clinic. He presented some results of Axi-cel (Yescarta) implementation, as a part of ZUMA-1 trial in lymphoma. Toxicities may include neurological complications, cytokine release syndrome. CAR-T cell kinetics in vivo was monitored using digital PCR, thus allowing long-term outcome evaluation.
Prof. Michael Maschan (Moscow, Russia) has reported their data concerning clinical implementation of CAR-T cells against CD19 processed according a GMP technology provided by the Miltenyi Prodigy system. Positive clinical effects of CAR-T cells were shown in several patients with B cell leukemias. Dr. Michael Zaiac (Basel, Switzerland) addressed mostly practical usage and development of CAR-T cells for treatment of non-Hodgkin’s lymphomas, as a commercial product which is now available as, e.g., Tisagenlecleuc el. Different aspects of its efficiency and regulatory issues in different countries were discussed. Possible toxicities of CAR-T cells are also referred, including neurotoxic effects, cytopenias, infections etc.
HIV infection: place of gene therapy and HSCT
A special session was dedicated to better understanding of HIV infection. The broad discussion was opened by Dr. Denis Gusev (St. Petersburg, Russia) who described the main trends of HIV epidemiology in St. Petersburg as a typical situation in a big city.
Dr. Julian Schulze von der Wiesch (Hamburg, Germany) told about a European program (ICISTEM) aimed for better characterization of HIV reservoirs, as well as more exact molecular typing, and prospectives of hematopoietic transplantation as a tool of HIV infection cure.
Dr. Alexander Taranin (Novosibirsk, Russia) discussed some non-viral antigens as possible tools to enhance anti-HIV immunity upon potential vaccination.
Professor Boris Fehse (Hamburg, Germany) has presented history and current achievements in usage genome editing (mostly, targeting CCR5 receptor) aiming for achieving decreased susceptibility of HIV-infected patients to further transfer of the virus to CD4 lymphocytes and other target populations. The report by Dr. Boro Dropulic (Gaithersburg, USA) also concerned recently designed gene constructs aimed for prophylaxis and treatment of HIV-1 infection.
Dr. Kristina Zakurdaeva (Moscow, Russia) presented her viewpoint on the public aspects and regulatory problems associated with development of novel medicinal gene-modified cell products.
The XIII Symposium was concluded by special lecture by Professor Dieter Hoelzer (Frankfurt, Germany) How do we proceed to frontline immunotherapy in ALL and what will be the place of HSCT? The comprehensive review concerned a number of new therapeutic options in ALL which may improve clinical outcomes, in addition to allogeneic HCST performed in high-risk and refractory cases. Targeted therapy includes monoclonal antibodies (Rituximab, Ofatumomomab, Inotuzumab Ozogamicin, Blinatumomab), as well as evolving CAR-T cell therapy, immune checkpoint inhibitors, tyrosine kinase inhibitors. It was concluded that the frontline immune therapy cannot yet replace allo-HSCT, because of many unresolved clinical issues.
A special session was dedicated to different issues of post-transplant rehabilitation. Dr. Evgeniy Kulikov (St. Petersburg, Russia) reported about self-control of analgesia in painful mucositis developing after severe chemotherapy. Dr. Andrey Vashura (Moscow, Russia) dealt with main principles and cautions when using low-microbial diet in pediatric patients post-transplant. Impact of physical activities upon better recovery of HSCT patients during early hospital period was discussed by Drs. Fedor Terentiev and Alla Potapchuk (St. Petersburg, Russia). Some aspects of parenteral nutrition in transplant patients using lipid emulsions were reported by Ilya Leyderman (Ekaterinburg, Russia). Psychological rehabilitation post-transplant was discussed, mainly, in view of special educational programs for the patients subjected to HSCT (Alina Khain, Moscow, Russia), role of family members in physical and mental rehabilitation of children subjected to transplantation (Alisa Volkova and Tatiana Ionova, St. Petersburg, Russia). Specific sensomotor disturbances affecting postural stability post-HSCT were described by Dr. Serafima Chechelnitskaya (Moscow, Russia). A simple technique of motor capacity evaluation post-transplant was proposed by Dr. Nikolay Mitrakov (Moscow, Russia) which should be, however, validated in further studies.
A separate session for medical nurses concerned their special skills and competencies in HSCT clinics. The topics included general approach to nursing care in pediatric oncohematology (Natalya Khaletskaya, Minsk, Republic of Belarus) epidemiological screening for antibiotic-resistant infections (Olga Prokofieva, St. Petersburg, Russia), standards of nurse care in cases of graft-versus-host disease (Anna Apostolova, St. Petersburg, Russia), efficiency of chlorhexidine solutions in catheter-associated infections (Svetlana Grigorieva, Kazakhstan), usage of implanted venous access in cancer patients (Svetlana Seledtsova, Irkutsk, Russia), professional problems and adaptation of nurses in pediatric oncology (Natalia Klipinina, Moscow, Russia).