In Memoriam: Soldano Ferrone MD, PhD (1940–2023)

Abstract

Dr. Soldano Ferrone died on January 10, 2023 at age 82 after an 8 week-long battle with COVID. At the time of his death, Soldano was Professor in Residence, Departments of Surgery and of Orthopedic Surgery, Massachusetts General Hospital. He has previously held leadership positions in multiple academic Institutions, including Scripps Clinic and Research Foundation, Columbia University, New York Medical College, Roswell Park Cancer Institute and University of Pittsburgh Hillman Cancer Center. Soldano was a pioneer in the field of cancer immuno-oncology and immunotherapy, and for 60 years he devoted his life and efforts to the development of novel, more effective therapies for cancer. His productive research has paved the way for the translation of many of immune therapies, including monoclonal antibodies, adoptively transferred activated T cells, NK cells and most recently, CART cells, to the clinic. He has been internationally renowned as an outstanding investigator in immunobiology of melanoma, physician, educator and mentor to numerous young scientists and clinicians. We deeply mourn his loss and want to remember his enormous contributions to science and honor his memory. Soldano began his life-long quest for novel treatments of human diseases as a medical student in Milan, Italy. While majoring in hematology, he played a major role in identifying abnormalities of human red blood cells that are responsible for their increased sensitivity to the lytic action of complement and the development of paroxysmal nocturnal hemoglobinuria (PNH). As a young investigator, Dr. Ferrone studied interactions between lymphocytes, human leukocyte antigen (HLA)-specific antibodies and complement. He demonstrated that false negative results in the lymphocytotoxic reaction used for HLA typing were caused by anticomplementary factors present in HLA-specific alloantisera. He discovered that natural antibodies reacting with human lymphoid cells represent one of the mechanisms underlying the superior cytolytic activity of rabbit complement in the complement dependent cytotoxicity assay with human lymphoid cells. This work represented a major contribution to the field of HLA typing. In the late 1970's working together with Dr. Ralph Reisfeld, Soldano successfully applied the hybridoma methodology to the development of monoclonal antibodies reacting with HLA class I, HLA class II and human melanoma-associated antigens. These reagents proved to be hugely useful for studies of the expression and functions of HLA in normal and malignant cells. He demonstrated that malignant transformation of cells is frequently associated with the reduction in HLA class I expression. He identified the molecular mechanisms underlying these defects and showed their role in driving resistance to antitumor T cell-mediated immunity. Dr. Ferrone developed a unique set of monoclonal antibodies which recognized the components of the HLA class I processing machinery (APM). Utilizing these unique reagents he analyzed the expression of APM components in normal and malignant cells and showed that defects in the HLA class I APM components were frequent in malignant cells and associated with poor prognosis and survival in various malignant diseases. Furthermore, he showed that defects in APM component expression were most often caused by functional mechanisms rather than structural defects. Only rarely, loss of APM components was caused by structural defects such as, e.g., loss of the APM component TAP1 detected in a melanoma cell line. Also, Dr. Ferrone was among the first to show that immunologically functional HLA class II molecules are frequently expressed on melanoma cells and on malignant cells of epithelial origin. Utilizing both polyclonal and monoclonal antibodies, Dr. Ferrone went on to analyze the structural profile of HLA class II antigens and the antigenic profile of human melanoma cells. Furthermore, he showed that the adhesion molecule ICAM-1 is expressed not only on lymphoid cells but also on melanoma cells and that ICAM-1 expression in primary melanoma lesions associated with poor prognosis. Soldano identified several tumor antigens expressed by melanoma cells. Among them was the high molecular weight-melanoma associated antigen (HMW-MAA) also known as chondroitin sulfate proteoglycan-4 (CSPG4). He showed that CSPG4 is overexpressed in a high percentage of melanoma lesions with limited heterogeneity and has a restricted distribution in normal tissues. These criteria indicated that CSPG4 could be used as a marker for immunoscintigraphy and as a target for immunotherapy. Dr. Ferrone was the first to conduct a phase I-II clinical trial in patients with advanced melanoma utilizing mouse anti-idiotypic monoclonal antibodies, which mimic the HMW-MAA as immunogens and elicit HMW-MAA-specific cellular and humoral immune responses in patients with advanced melanoma. This response had a beneficial effect on the clinical course of the disease. More recently, Dr. Ferrone discovered that CSPG4 is useful for targeting tumor cells with chimeric antigen receptor transduced T cells. Anti-CSPG4 antibody proved to be useful for the isolation from melanoma plasma of exosomes produced by melanoma cells, and its use has led to a discovery of the protein profile selective for melanoma cell derived exosomes. In the last decade, Soldano continued the efforts to develop novel anti-cancer therapies and to understand the mechanisms underlying beneficial effects or the lack of response to immune checkpoint inhibitors (ICIs). This has led him to studies of tumor-induced immune suppression in melanoma and consideration of mechanisms responsible for tumor immune escape. These studies, all based on insights previously gained and the reagents he had in hand, motivated Dr. Ferrone to establish a series of successful collaborations with colleagues engaged in treatment of melanoma patients with ICIs. To address mechanisms of tumor resistance to immune therapies, he studied defective functions of T cells and NK cells in the tumor microenvironment (TME), defects of the APM in DC that interfere with antigen presentation, the role of cancer stem cells in modulation of anti-tumor responses, HLA class I downregulation in metastases of patients with progressive melanoma and lately, the role tumor-derived exosomes in cancer progression. Permeating his work was the theme that the tumor-induced impairments in HLA class I antigen processing and presentation represent the major underlying mechanisms of the tumor resistance to immune therapies. Another favorite theme was the need to identify new therapeutic targets that are not dysregulated by tumors; hence, he intensively explored the possibility that B7-H3 may be a valuable target for CAR-T cells in cancer. In aggregate, these studies represent an invaluable reservoir of information that Soldano shared with scientists and clinicians worldwide in many insightful reviews he penned and lectures he delivered. Soldano was an active and frequent participant of the melanoma group meetings. His invaluable contributions to the melanoma community have guided our research and have helped us to formulate, translate and introduce novel immune therapies to the clinic. Throughout his scientific career, Soldano was continuously supported by grants from the US National Institutes of Health, and his service on study sections and review panels was exemplary. He remained an active member of the scientific community and conducted laboratory experiments almost until the day he succumbed to COVID. While the scientific, translational and clinical significance of Dr. Ferrone's research is impressive, Soldano will be remembered for his creativity, tenacity, generosity and warm, friendly demeanor. He had immense passion for science, which he expressed, often forcefully and always with great humor, whether in English or Italian. Those of us who were privileged to work with Soldano cherish the times spent with him. We remember his insightful perceptions and thoughts on life in academia, scientific enterprise and insistence for excellence in our own work. Soldano was also a devoted husband to his wife, Agnes, a proud father of Dr. Cristina Ferrone and Dr. Marco Ferrone, both physicians, and a loving grandfather to Peter, Annamaria, Joseph and Andrew. We have lost one of the most valued and productive members of melanoma community. We honor his memory and hope to emulate his example in our work.