XIV R. Gorbacheva Memorial Symposium Hematopoietic Stem Cell Transplantation. Gene and Cellular Therapy: A general overview

Two pre-congress days (September 16-17, 2020) concerned the most relevant issues of modern drug treatment in hematology, oncology, HSCT and supportive care. The problems of infectious complications and their control were elucidated by Prof. Nikolay Klimko and Dr. Marina Popova (St. Petersburg, Russia). Among the keynote reports, one could mention the results of randomized study (RACE) concerning eltrombopag implementation into the first-line immunosuppressive treatment (IST) therapy in acquired aplastic anemia (AA), presented by Prof. Regis Peffault de Latour (Paris, France), the chairmen of SAA Working Group of the EBMT. Resistance and intolerance to targeted therapy of myelofibrosis, like as its significance for HSCT performance, was discussed by Prof. Claire Harrison, Donald McLornan (London, UK), Dr. Elena Morozova (St. Petersburg, Russia). Biological interpretation and results of the key studies of venetoclax in acute myeloblastic leukemia (AML) in elderly patients were presented by Andrew Wei (Melbourne, Australia). In a series of reports, Prof. Vadim Ptushkin, Gayane Tumian, Vladimir Vorobyev (Moscow, Russia), as well as Dr. Natalya Mikhailova, Marina Ivanova, Olga Pirogova, Sergey Gritsaev (St. Petersburg, Russia) and other speakers highlighted the most difficult and promising issues of lymphoma, chronic lymphoid leukemia (CLL) and multiple myeloma treatment. Advances in therapy of FLT3-positive AML with midostaurin were discussed at the session attended by Prof. Elena Parovichnikova (Moscow, Russia), Konstanz Doehner (Ulm, Germany), Francesko Buccizano (Rome, Italy), Sergey Bondarenko (St. Petersburg, Russia).

The morning session of September 18, 2020 was dedicated to the memory of Professor Boris Afanasyev. A special lecture was held by Prof. Ludmila Zubarovskaya. She highlighted his professional way in details, and his tremendous contribution to clinical and experimental hematology, implementation and development of HSCT in Russia. Professor Axel Zander (Hamburg, Germany) presented a 30-year story of cooperation between Hamburg and St. Petersburg in the field of hematopoietic stem cell transplantation (HSCT) and translational studies. Prof. Rumyantsev (Moscow, Russia) noted research merits of Prof. Afanasyev and his coordinating role for development of Russian hematological clinics.

Several special lectures concerned HSCT applications in acute leukemia (AL) treatment. Efficiency and reliability of allogeneic HSCT, along with current therapeutic options was demonstrated by Prof. Robert P. Gale (USA). Drawbacks and limitations of evidence-based clinical studies in HSCT and competing therapeutic options were listed by Dr. Ivan Moiseev (St. Petersburg, Russia). The aspects of HSCT applications combined with novel targeted drugs were discussed by Prof. Dieter Hölzer (Frankfurt, Germany). The issues of clinical decisions on HSCT timing within programmed therapies of AML were considered in the lecture presented by Prof. Elena Parovichnikova (Moscow, Russia). Further evidence on safety and efficiency of current haploidentical HSCT regimens was presented by Dr. Sergey Bondarenko (St. Petersburg, Russia). A comprehensive lecture by Prof. Hans-Jochem Kolb (Munich, Germany) concerned the role of malignant stem cells escaping immune surveillance, even in optimally treated leukemia.

The session Chronic hematological malignancies was opened by Prof. Moshe Mittelman (Tel-Aviv, Israel), who based on his long-term experience with myelodysplastic syndrome (MDS), a quite heterogenous disorder which needs highly individualized treatment approaches. Later on, Professor Nicolaus Kröger (Hamburg, Germany), the EMBT President, held a special lecture concerning high-risk MDS, where a number of specific mutations and chromosome markers are considered important risk factors requiring intensive therapy. Dr. Alina Kohkno (Moscow, Russia) presented data on HSCT option in treatment of this disorder. Professor Ruediger Hehlmann (Germany), summarized the data on additional chromosomal aberrations as a high-risk factor in the situations with advanced chronic myeloid leukemia (CML) assuming more intensive treatment in such cases. Similar aspects of HSCT were discussed by Dr. Elena V. Morozova (St. Petersburg, Russia).

Clinical aspects and experimental approaches to immune therapy in oncohematology were discussed at a special session. Professor Robin Foa (Rome, Italy) compared relative efficiency and expenditures of therapies with bispecific monoclonal antibodies and CAR-T cells in acute lymphoblastic leukemia (B-ALL). Promising antigenic targets and appropriate substances for immune therapy in multiple myeloma were discussed by Prof. Laurant Garderet (Paris, France). Studies in metabolic and regulatory mechanisms suggest novel molecular targets for multiple myeloma treatment detected, mostly, under experimental conditions, as reported by Prof. Magne Borset (Trondheim, Norway). Potential antitumor effects of distinct mushroom extracts were reported by Dr. Jon-Magnus Tangen (Oslo, Norway).

Several lectures concerned HSCT and gene therapy in non-malignant disorders. One should note a lecture by Prof. Gerard Wagemaker (Rotterdam, The Netherlands) where a number of inherited diseases were discussed as candidates for safe and effective gene therapy, as shown in experimental models. Prof. Andrea Bacigalupo (Rome, Italy) summarized current data on haploidentical HSCT (haplo-HSCT) in non-malignant disorders, focusing on appropriate conditioning regimens and graft-versus-host disease (GvHD) prophylaxis. Prof. Shinji Nakao (Kanazawa, Japan) reported on a novel clinical variant of immune-mediated graft dysfunction against retained complete donor chimerism. Prof. Dmitry Balashov (Moscow, Russia) reported on efficiency of TCRab cell depletion technique in haplo-HSCT. Prof. Belinda Pinto-Simoes (San-Paolo, Brazil) shared her experience with haplo-HSCT in bone marrow failure syndromes. Strategies of severe aplastic anemia treatment, role of conventional immunosuppressive therapy and HSCT were considered by Prof. Alexander Kulagin (St. Petersburg, Russia).

Pediatric session was opened by Professor Olga Aleynikova (Minsk, Republic of Belarus). She summarized their long-term experience with HSCT in treating leukemias and inherited diseases in the Republic of Belarus. Dr. Claudia Blattmann (Stuttgart, Germany) shared her data about long-term complications of chemotherapy and autologous HSCT in pediatric patients, focusing on diagnostics and management of chronic organ pathology and ototoxicity. Larisa Shelikhova (Moscow, Russia) presented their positive results of HSCT on the platform of TCRab cell depletion in acute leukemias. Single-center data from RM Gorbacheva Research Institute concerning haplo- and allogeneic HSCT in pediatric setting were presented by Dr. Olesya Paina and Prof. Elena Semenova (St. Petersburg, Russia). Dr. Kirill Kirgizov (Moscow, Russia) reported his own data on efficiency and arrangement of HSCT in pediatric solid tumors. Dr. Inna Markova discussed therapeutic effects of monoclonal antibodies in patients with refractory ALL.

A special session on lymphomas started with a comprehensive lecture by Prof. Anna Sureda (Barcelona, Spain) featuring different approaches to therapy of refractory/relapsing Hodgkin’s lymphoma. A report by Prof. Manuel Abecasis (Lisboa, Portugal) was focused on proper timing and relative efficiency of myeloablative and reduced-intensity conditioning regimens in lymphoid malignancies. Different approaches to targeted and immune therapy of lymphomas were demonstrated in the report by Kirill Lepik (St. Petersburg, Russia). A lecture by Dr. Katia Beider (Tel Hashomer, Israel) concerned individual efficiency of CAR-T cells, due to their aging or exhaustion, thus causing decreased therapeutic efficiency in B-cell malignancies.

Several reports were dedicated to complications of HSCT. E.g., Dr Jan Styczynsky (Bydgoszsz, Poland) provided an overview of fungal infections post-transplant, including diagnostic strategy and choice of antimycotic drugs. Dr. Dina Averbuch (Jerusalem, Israel) made a report on rational antibacterial therapy after HSCT in the era of antibiotic resistance. An optimized protocol of antimicrobial therapy based on evaluation of microbial colonization was presented by Dr. Marina Popova (St. Petersburg, Russia).

Two lectures concerned the issues of post-transplant veno-occlusive disease (VOD). A special report on clinical aspects of VOD was presented by Prof. Tapani Ruutu (Helsinki, Finland). Difficulties with hematological evaluation of altered erythrocytes and platelets after HSCT and in VOD were discussed by Dr. Gina Zini (Rome, Italy).

A special session dedicated to cell and gene therapy was traditionally performed in framework of the Symposium. Prof. Boris Fehse shared the results of cooperation between Hamburg and St. Petersburg in the field of molecular diagnostics and therapy over last 2 decades, with its implementation into medical practice. Dr. Ildar Barkhatov (St. Petersburg, Russia) reported about different molecular methods aimed to detection of donor chimerism, evaluation of mutational landscape and microenvironment of leukemia cells. An impressive report was performed by Andrey Gorchakov (Novosibirsk, Russia). His team has obtained and characterized specific neutralizing antibodies against the new SARS-CoV2 virus. Tatyana Belovezhets (Novosibirsk, Russia) presented their data on the sequence-specific analysis of CART cell activities aimed for better understanding precise mechanisms of their effects. Dr. Alexey Petukhov shared recent information on developments in the field of allogeneic CAR-T cell technologies at the V. Almazov Center in St. Petersburg.

Translational research was presented in several contributions. E.g., Gerard Wagemaker (Rotterdam, The Netherlands) described current situation in the field of gene therapy of several inherited disorders, focusing on clinical trials oriented for gene therapy.

Dr. Erik Ehrke-Schulz (Witten, Germany) reported on tailored adenovirus-based vectors exhibiting different tissue tropism, due to usage of distinct adenovirus subspecies. Another path of studies was presented in the lecture by Dr. Zoltan Ivich (Langen, Germany) who further developed an effective platform for a non-viral delivery of target genes based on the Sleeping Beaty transposon technique which could be used, e.g., for CAR-T cell production.

Dr. Alena Shakirova reported on efficiency of TALEN-mediated CCR5 gene editing in native human hematopoietic cells. A report by Dr. Claudi Mussolino (Freiburg, Germany) concerned problems and prospective tools for improved on-target gene editing in hematopoietic stem cells. Similar aspects, i.e., reduction of the off-target effects of gene-editing nucleases were concerned in the report by Shengdar Tsai (Memphis, USA).

A deep insight into potential applications of was presented by Dr. Fedor Urnov (Los Angeles, USA). He informed the audience about initial clinical trials on gene therapy of hemophilia B, sickle cell anemia and thalassemia. He suggests that this approach would be effective even for radiation protection in radiotherapy-treated patients. Another optimistic prognosis for current development of cellular and gene therapy was given by Prof. Hans-Peter Kiem (Seattle, USA).

Two reports concerned experimental nanoparticle carriers for delivery of biological molecules into target cells and re-directed distribution by magnetic fields, thermal effects etc. (Dr. Albert Muslimov, Dr. Alexander Timin (St. Petersburg, Russia).

Clinical aspects of cellular therapy were presented in a report by Prof. Michael Maschan (Moscow, Russia) in particular describing wide experience with CAR-T cell implementation in pediatric leukemias, and discussing their successful use and potential pitfalls. Dr. Olga Gavrilina also shared her experience in cell therapy of lymphomas. The Hamburg experience in treatment of B cell lymphomas with CD19 CAR-T cells was summarized by Dr. Francis Ayuk (Hamburg, Germany).

Consulting opportunities for developers of novel cellular products with expert bodies were discussed in details by Ekaterina Melnikova, the qualified Russian expert in the field. Dr. Mikhail Samsonov (Moscow, Russia) shared his viewpoint on current legislation in the area of cellular therapy and, especially, the needs for improved licensing and regulatory procedures for advanced medicinal cell products in Russia.

Poster communications covered all the research areas presented at the Meeting. Аbout 40 presentations were evaluated in online format, and were subjected to reviewing by the competent international panel of experts. The following posters were awarded at the R. Gorbacheva Memorial Meeting: 1^st prize was awarded to the study by Dr. Bella Ayubova et al. concerning notable clinical efficiency of gemtuzumab ozogamicin combined with FLAG regimen as a bridge therapy to HSCT in refractory and relapsed AML patients. The 2^nd place was taken by Dr. Zoya Konova et al. with their data on flow cytometry-based MRD detection as a strong prognostic factor for increased relapse risk after allo-HSCT. The poster presented by Dr. Olga Kudyasheva was also awarded (3^rd position). The study revealed safety and good clinical efficiency of autologous HSCT in AL amyloidosis.