14 The Lasting Legacy of Donald Metcalf Brty Ku Samson

onald Metcalf, Among the many hon- MD, considered ors and awards he received “the father of were the Albert Lasker

oncology-times.com modern hematol- Award for Clinical Medical • Dogy,” died Dec. 15, at age 85, Research, the Gairdner surrounded by his family, in Foundation International Melbourne, . Award, the Professor Emeritus at the of the Royal Society, the University of Melbourne Victoria Prize, and the and the Cancer Council Lifetime Achievement Victoria’s Carden Fellow in Award from American the Division of Cancer and Association for Cancer February 10, 2015

Hematology at the Walter Research in 2007. • and Eliza Hall Institute of “As an experimental pa- Medical Research, he was thologist, I have studied the the first to discover colony- manner in which mature stimulating factors (CSFs), blood cells are formed by hormones that control white ancestral cells in the bone blood cell production to marrow. This required the bolster recovery after cancer development of clonal cul- treatment. ture systems, allowing the Metcalf worked at the progeny of individual cells Oncology Times Walter and Eliza Hall to be analyzed,” Metcalf Institute for 60 years, from wrote for a biographi-

1954 to 2014. After he devel- and Eliza Hall Institute Walter cal sketch for the National oped pancreatic cancer this DONALD W. METCALF, MD (1929-2014) Academy of Sciences at the past August, he continued time of his election as a his research at home until member in 1987. October, when he conducted his final weakened by chemotherapy. This led “The four CSFs were purified and experiment, his colleague, Douglas to development and eventual ap- can now be mass produced in re- Hilton, PhD, the Institute’s Director proval of the drug G-CSF (filgrastim, combinant form. The CSFs are now and a molecular biologist, said in an Neupogen). widely used clinically to stimulate interview. blood cell formation, particularly in Metcalf’s pioneering research fo- patients undergoing chemotherapy cused on the control of blood cell for- Revolutionized Stem Cell where the treatment damages bone mation and, specifically, leukemic cells. Transplantation marrow cells. We are currently gen- In 1965 he co-developed a series of spe- As well as boosting the immune system erating mice with homozygous inac- “He made the cialized culture techniques that allowed in chemotherapy patients and in other blood cell system scientists to grow various types of blood immune deficiencies, CSFs revolution- cells, after which he discovered colony- ized blood stem cell transplantation. It For more than the ‘poster stimulating factors, which control the was later found that CSFs also contrib- formation of white blood cells that re- ute to such diseases as rheumatoid ar- 50 years he child’ of medical sist infection. thritis, and medications that block CSF pursued his research and He and his colleagues next discovered function are currently entering clinical the effectiveness of two primary white trials. understanding shone a light into blood cell regulators—granulocyte-­ Metcalf later investigated stem cells, macrophage colony-stimulating factors CSF receptors, cell survival, and sup- of CSFs, and the darkness for and granulocyte colony-stimulating pressors of cell signaling. He was in- helped lead those who followed ­factors—to speed regrowth of blood volved in discovering a multiple-action cells after chemotherapy and bone growth factor, the leukemia inhibitory researchers him to work on marrow and peripheral blood factor. transplants. to identify and understanding other His early studies on white blood purify four tissues such as the cell regulators led him to hypoth- José Carreras esize that there was some hormonal Among the first patients in the world separate breast, skin, and process involved in controlling their to receive treatment with a colony- ­production—substances he called col- stimulating factor was opera tenor stimulating factors. colon.” ony stimulating factors. For more than José Carreras when he developed acute 50 years he pursued his understanding lymphoblastic leukemia that failed to of CSFs, and helped lead researchers respond to initial treatment. He re- tivation of genes encoding blood cell to identify and purify four separate ceived CSF therapy in 1987, recovered, regulatory factors or their receptors stimulating factors. He and his team and today continues to raise money to to establish the precise functions were also among the first researchers help leukemia patients and advance re- attributable to each factor. Parallel in the world to discover the genes for search through the establishment of the studies are using mutagenized recep- CSFs. José Carreras International Leukemia tors to establish the domains in each A leading researcher in interna- Foundation. receptor chain initiating each of the tional clinical trials of CSFs in the During the course of Metcalf’s ca- variety of signaling cascades required 1980s, Metcalf came to better un- reer, he mentored hundreds of research to mediate the pleiotropic actions derstand how and why these factors students and authored 700+ papers on each regulator has on responding boost immune cell numbers in cancer his findings; he also holds 21 patents. cells.” patients whose immune systems were continued on page 15 15 Oncology Times FDA Approves Gazyva Combo Treatment for CLL

he U.S. Food and Drug in combination with chlorambucil received Gazyva plus chlorambucil 8.8% of the patients who received TAdministration has approved a compared with use of rituximab plus or rituximab plus chlorambucil. The rituximab combination; and supplemental biologics license ap- chlorambucil and compared with use first stage of that trial included 589 • At two years, the rate of death plication for Gazyva (obinutuzumab) of chlorambucil alone. patients with previously untreated for patients receiving Gazyva plus in combination with chlorambucil for That latest data is from Stage 2 of CLL, which compared use of Gazyva chlorambucil was 9% compared with

the treatment of patients with previ- a Phase III, multicenter, open-label, plus chlorambucil with Gazyva alone. 20% for those who received chloram- •

ously untreated chronic lymphocytic The results showed: bucil alone. (Median overall survival February 10, 2015 leukemia (CLL). Gazyva, made by • Patients has not yet been reached.) Genentech, is a monoclonal antibody who received Gazyva that attaches to CD20 and attacks plus chlorambucil had Side effects for Gazyva include: cells directly and with the body’s im- a median progression- hepatitis B reactivation, progressive mune system. free survival of 26.7 multifocal leukoencephalopathy, in- In 2013, the drug became the first months compared fusion reactions, tumor lysis syn- drug to be approved by the FDA with 14.9 months for drome, infections, and low white

that had been granted Breakthrough the patients receiv- blood cell counts. The most com- • Therapy Designation (OT 12/10/13 ing the rituximab mon side effects are infusion reac- oncology-times.com issue). The latest approval is based randomized study (CLL11), which in- combination; tions, low white blood cell counts, on data that found significant im- cluded 663 previously untreated pa- • 26.1% of the patients receiv- low platelet counts, low red blood provements across multiple clinical tients with CLL who had co-existing ing the Gazyva combination had a cell counts, fever, cough, nausea, O endpoints when the drug was used medical conditions. Those patients complete response compared with and diarrhea. T

DONALD METCALF Metcalf char- Continued from page 14 acterized blood stem cells and Millions of their daughter Patients Helped cells, which pro- “Over the past 20 years, more than 20 duce multiple million cancer patients have been treated types of white with CSFs and, as a result, have been given blood cells that the best possible chance of beating their fight infection cancer,” Hilton said. “There can be no and prevent greater legacy for a medical researcher.” bleeding. In a tribute, he along with “In doing Professors Warren Alexander, PhD, so he made the and Nicos Nicola, PhD, Heads of the blood cell sys- Division of Cancer and Hematology tem the ‘poster A stamp was created in his honor in 2002 as part of at the Institute, wrote the following: child’ of medi- the Australian Legends series, which commemorate “‘Don,’ to most everyone with whom cal research and Australians “who have made lifetime contributions he worked, was a Colossus of science shone a light to the development of the Commonwealth’s national who, working at the Walter and Eliza into the dark- identity and character.” Hall Institute and supported by the ness for those Cancer Council of Victoria from 1954 who followed Nevertheless, Don knew he needed to 2014, stood astride the world of he- him to work on understanding other tis- collaborators who would take him out matology for 60 years. sues such as the breast, skin, and colon,” his comfort zone and help him fulfill “In 1964, studying leukemia, he and Hilton, Alexander, and Nicola wrote. his ambition of delivering health ben- Ray Bradley, from The University of “Despite Don’s profound funda- efits from his discoveries and so he Melbourne, discovered it was possible mental discoveries, which shaped our assembled a team of researchers who worked with him for 40 years. “Don’s ability to identify a glimmer of talent in younger researchers and mold “Decades ahead of its time, his model them into a cohesive, loyal, and vibrant of collaborative, multidisciplinary science team, that consistently came up with ground-breaking discoveries, was re- is now seen as almost mandatory if big markable. Decades ahead of its time, his model of collaborative, multidisciplinary problems are to be tackled and science shaped the culture of the Walter significant breakthroughs are to and Eliza Hall Institute and is now seen as almost mandatory if big problems are to be made in medical science.” be tackled and significant breakthroughs are to be made in medical science.” He is survived by his wife, to grow bone marrow cells in plates of basic understanding of how blood cells Josephine, four daughters, and six partly set agar jelly. Don’s genius lay not are made and work, he also mentored grandchildren. in this breakthrough, but in the realiza- hundreds of students—guiding many In recognition of his work with young tion that it could be used to understand into careers as oncology researchers. scientists, the Walter and Eliza Hall the cellular basis of blood cell produc- “Don also understood his limita- Institute of Medical Research established tion and to discover the hormones, tions. Although he was comfortable the Metcalf Scholarship Fund (www. which he named colony-stimulating with cells, he was wary of mol- .edu.au/in-memory-­metcalf) to O factors.” ecules such as DNA and protein. support promising young researchers. T