# Shimon Slavin

Shimon Slavin (Hebrew: שמעון סלבין; born 17 May 1941) is an Israeli professor of medicine. He pioneered immunotherapy mediated by allogeneic donor lymphocytes and innovative methods for stem cell transplantation to cure hematological malignancies and solid tumors. He also used hematopoietic stem cells to induce transplantation tolerance to bone marrow and organ allografts.
More recently, he has been working on the use of multi-potent mesenchymal stem cells (MSCs) in regenerative medicine for the treatment of neurological, systemic, and orthopedic disorders.
He is currently serving as the medical and scientific director of Biotherapy International Center for Innovative Cancer Immunotherapy & Cellular Medicine in Tel Aviv, Israel, and as the medical director at Superinfection, a biotechnology company in Budapest, Hungary.

## Education and clinical work

Slavin graduated from the School of Medicine at the Hebrew University of Jerusalem and was awarded his medical degree in 1967. He served as a doctor in the Frogman Unit of the Israeli Navy until 1970. From 1970 to 1975, he trained at the Department of Internal Medicine at the Hebrew University of Jerusalem.
From 1975 to 1978, Slavin trained in clinical immunology/rheumatology at the Division of Immunology, Stanford University School of Medicine. In 1978, he trained in clinical bone marrow transplantation under the late E.D. Thomas at the Fred Hutchinson Cancer Research Center in Seattle, Washington.
Upon returning to Jerusalem, he opened the first Bone Marrow Transplantation Center at Hadassah University Hospital, which was later recognized as Israel's National Bone Marrow Transplantation and Cancer Immunotherapy Center.

## Clinical accomplishments

In early 1987, Slavin introduced the concept of cancer immunotherapy using donor lymphocytes infusion (DLI) for the treatment and prevention of recurrent disease. He also pioneered the use of adaptive allogeneic cell-mediated immunotherapy and cytokine-activated lymphocytes for both treating and preventing relapse following allogeneic and autologous stem cell transplantation for hematologic malignancies and solid tumors.
These observations confirmed the therapeutic benefits of cell therapy and led to the development of new concepts for treating hematologic malignancies and solid tumors. The focus was on utilizing well-tolerated non-myeloablative stem cell transplantation as a platform for cancer cell therapy, targeting killer cells against chemotherapy-resistant malignant cells. Using procedures developed by Slavin and his team, cancer treatment is based on a brighter approach rather than aggressive treatment with conventional chemotherapy. This approach is associated with reduced immediate and late procedure-related toxicity and mortality, aiming at the selective elimination of all malignant cells, including cancer stem cells.
As a rule, treatment of cancer focuses on a two-step approach: tumor debulking using conventional and innovative modalities, followed by immunotherapy of minimal residual disease. Innovative reduced-intensity conditioning (RIC) or non-myeloablative stem cell transplantation (NST) was pioneered by Slavin for safer stem cell transplantation in the treatment of malignant and life-threatening non-malignant disorders that can be corrected using stem cells. Post-transplant immunotherapy is indicated for all patients in need. RIC or NST enables much safer curative stem cell transplantation for every patient, regardless of age, including those with less than optimal clinical conditions who would not be eligible for standard myeloablative stem cell transplantation.
Baxter International recognized the potential of cell therapy and signed an agreement that resulted in significant investment with Slavin at Hadassah Medical Center. This investment aimed to further develop new approaches based on cell therapy for the treatment of cancer, autoimmune diseases, and organ transplantation. These approaches focused on new methods for regulation rather than non-specific suppression of the immune system. As a result, Slavin’s research center was established by Baxter International, headquartered in Chicago, USA, and also supported by the Danny Cunniff Leukemia Research Center. Slavin served as the founder and director of this research center from 1994 to 2007.
Slavin, along with his team, used a vector provided by the San Raffaele Hospital in Milan to pioneer the first successful use of gene therapy for the treatment of bubble baby born with adenosine deaminase deficiency in 2002. The treated infant has remained free of disease for more than 16 years without requiring any further treatment. The same procedure was successfully used by the Milan team to treat many additional patients, all of whom were cured by gene therapy.
More recently, Slavin introduced personalized anti-cancer immunotherapy, focusing on the use of activated donor lymphocytes targeted against cancer with monoclonal and bispecific antibodies. This approach efficiently eliminates cancer while inducing long-lasting anti-cancer immunity to prevent recurrent disease. Innovative cell-mediated immunotherapy is now applied in other centers for treating otherwise resistant cancers, including patients with triple negative breast cancer.
In parallel with the growing activities of Slavin's center and his international impact in cell therapy, new approaches were developed for induction of transplantation tolerance of host-vs-graft and graft-vs-host towards developing improved methods for allogeneic blood or marrow transplantation as well as transplantation of cellular and perfused organ allografts. Initially, Slavin pioneered the use of monoclonal antibodies anti-CD52 (Alemtuzumab, now approved by FDA as Lemtrada) for prevention of graft-vs-host disease (GVHD), the most serious complication of allogeneic stem cell transplantation, and later on for treatment of CLL and multiple sclerosis. Later, Slavin introduced the concept of post-transplant depletion of host-vs-graft and graft-vs-host reactive lymphocytes with induction of bilateral transplantation tolerance. These discoveries made it possible to extend the use of allogeneic stem cell transplantation using haploidentical donors instead of fully matched donors for safer allogeneic stem cell transplantation for every patient in need with hematological malignancies and solid tumors as well as for induction of transplantation tolerance to organ allografts. In parallel, Slavin introduced new approaches for treatment of life-threatening autoimmune diseases based on either autologous hematopoietic stem cell transplantation or more recently using multi-potent mesenchymal stem cells (MSCs) for regulation of the inflammatory anti-self reactivity in neuroinflammatory and neurodegenerative disorders focusing on multiple sclerosis.
Based on the cumulative experience using cell therapy, in recent years, Slavin and his team also focused on using multi-potential bone marrow, adipose tissue, or placenta & cord tissue-derived MSCs for regenerative medicine, pioneering the use of MSCs for the treatment of orthopedic indications including cartilage repair and new bone formation as well as for repair of renal function in addition to continuous treatment of neuroinflammatory, neurodegenerative disorders and traumatic neurological disorders.

## Scientific contributions

Slavin's primary research and clinically applied discoveries were represented in over 600 published articles and more than 900 national and international scientific presentations, resulting in global impact in several disciplines mostly related to cellular therapy for treating malignant and nonmalignant disorders. Immunotherapy of cancer by donor lymphocytes made it possible to treat otherwise resistant hematological malignancies and specific metastatic solid tumors in patients with multidrug-resistant cancer.
The unique efficacy of intentionally mismatched donor lymphocytes using killer cells activated before and following cell infusion was translated into a new paradigm for cellular therapy of cancer based on the use of the transient circulation of non-engrafting donor lymphocytes targeted against minimal residual disease as a new approach for the potential cure of cancer at an early stage of the disease.
Introducing NST and RIC made it possible to provide curative stem cell transplantation for a large number of patients in need with no lower or upper age group, including patients in poor performance status. Still, it would not be otherwise candidates for conventional myeloablative allogeneic stem cell transplantation. Using NST and RIC provided a safe approach for transplantation of patient's susceptible to conventional cytoreductive conditioning including older patients, patients with Fanconi's anemia and chronic granulomatous disease.
Later on, introducing the concept of post-transplant deletion of alloreactive lymphocytes by cyclophosphamide by Slavin's team made it possible to provide a relatively safe and non-expensive transplant procedure for patients with no matched donor available using a haploidentical family member.
Slavin applied the same principle for successful induction of transplantation tolerance to organ allografts pioneered successfully for the first recipient of kidney allograft alive and well >10 years out. Observations by Slavin's team indicating that re-induction of self-tolerance could be induced by lymphoablative treatment followed by autologous stem cell transplantation provided the rationale for the use of a similar approach for successful treatment of patients with life-threatening autoimmune disorders including multiple sclerosis and systemic lupus erythematosus.
In 1977, Slavin discovered the first animal model of B-cell leukemia/lymphoma (BCL1), which provided an opportunity to understand better the biology of B cells and to develop new therapeutic strategies based on the preclinical animal model.
Together with Dr. Herman Waldmann, Slavin was the first to introduce the use of an anti-CD52 monoclonal antibody (CAMPATH-1; Alemtuzumab and currently Lemtrada) that was initially used by Slavin for prevention of graft-versus-host disease (GVHD) and subsequently by others for prevention and treatment of allograft rejection and subsequently approved by FDA for treatment of multiple sclerosis.
Slavin's initial success applying bone marrow-derived mesenchymal stem cells (MSCs) for the treatment of neuroinflammatory and neurodegenerative disorders, together with Professor Karussis, provided the rationale for using in vitro differentiated MSCs and possibly for future application of secretory products of MSCs, such as extracellular vesicles and exosomes.