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[CANCER RESEARCH 39, 4301 -4307. November 1979| 0008-54 72 / 797 0039-OOOOS02.00 Childhood Leukemia as a Model for Cancer Research: The Richard and Hinda Rosenthal Foundation Award Lecture1 Joseph V. Simone SíJude Children s Research Hospital. Memphis, Tennessee 38(01 therapy during remission, phase-specific therapy, and the in terrelationships of phases of therapy were developed first in ALL. Since leukemia cell features, such as T-cell characteris tics, correlate with responsiveness to therapy, powerful new tools may be developed to improve the biological specificity of therapy. In addition to the gratifying results of therapy over the past two decades, childhood ALL continually offers opportun ities for biological research as well as improved therapy for ALL and other forms of disseminated cancer. Dr. Zubrod, Mr. and Mrs. Rosenthal, members and guests, I am deeply honored to receive this award, and I accept it as a representative of all the staff, past and present, of St. Jude Children's Research Hospital whose work over the past 17 years is responsible. I am indeed privileged to be a member of the St. Jude family. For those of you who have never been engaged in clinical research, and particularly therapeutic re search, it is difficult to convey how many dedicated people are involved in a successful venture. I shall attempt to impress on you with the next few illustrations some of the components that have contributed to our effort in a major way. Fig. 1a shows a chromosome to remind us of our debt to our scientific fore bears. In the chemotherapy of leukemia, the early work of Drs. Sidney Farber, David Karnofsky, Joseph Burchenal, Emil Frei, III, and their colleagues is particularly relevant. Fig. 1ösym bolizes our debt to the leukemia studies in animals, particularly in the laboratories of Drs. Howard Skipper and Frank Schabel, which have continually provided us with challenging concepts to help us develop more rational therapy for our patients. Their work continues to stretch our horizons. There are several important components that have made the leukemia studies productive at St. Jude Cnildren's Research Abstract Hospital. Fig. 1c serves to remind us that no endeavor can proceed without a constant source of energy. This represents Childhood acute lymphocytic leukemia (ALL) is a model for the enormous, growing support of our fund-raising organization the study of disseminated cancer. It is always disseminated put together many years ago by Danny Thomas. It also repre and relatively uniform, it is accessible to repetitive tissue sam sents our debt to all of you who, as taxpayers, support the pling, and we have highly effective chemotherapy for it. The National Cancer Institute, which in turn, has been a generous first systematic, controlled trials of cancer therapy were de supporter of our work. A successful endeavor usually has in its signed for patients with ALL by physicians with the courage and audacity to aim for cure of a "hopeless" disease. The early years at least one person with penetrating, unwavering, and far-reaching vision (Fig. 1d). Our visionary was Dr. Donald concept of leukemia cell subpopulations in each patient re Pinkel, without whom our leukemia studies would not exist. ceived major clinical support from ALL. The pharmacological The life blood of the clinical research endeavor is our patients sanctuary, typified by the meninges, was first discovered and and their parents (Fig. 1e). Without their faith and confidence specifically attacked in ALL. Combination therapy, aggressive in us, our studies would not be possible. Fig. 1f symbolizes the power provided by a wide variety of individuals essential to move our work. Staff members, fellows, nursing, medical rec ' Presented at the 1979 Meeting of the American Association for Cancer ords, pharmacy, and believe it or not, a helpful, cooperative Research in New Orleans. Louisiana. Supported by Grants CA20180. CA08480. CA21765. and CA23099 from the National Cancer Institute and ALSAC. administration make the operation go. Leukemia studies at St. Received August 9, 1979. accepted August 10, 1979 Jude have one person at the heart who is the central force (Fig. NOVEMBER 1979 4301 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1979 American Association for Cancer Research. J. V. Simone 1g). Dr. John Aur has made the studies move with his persist including responsiveness to specific therapeutic agents. This ence, dedication, and a legendary first-hand knowledge of is manifest in the clinical observation that selective therapeutic each and every patient. Finally, you might ask what my role pressures can lead to the emergence of resistant populations has been in these leukemia studies. If John Aur is the heart of of cells. It was natural to apply the principle of combination our group, then my role, shown in Fig. 1h, has been to provide therapy in an attempt to prevent therapeutic failure. This ap pedestrian support and locomotion. proach was already demonstrably effective in the antibiotic The thesis of my address is that studies of childhood ALL? chemotherapy of tuberculosis. A key concept developed in have been and will continue to be major sources of our under childhood leukemia with little preclinical direction is that of the standing of cancer in humans. This shall be a personal view, pharmacological sanctuary. By this is meant a specific anatom with admitted bias, and with pride in all of my colleagues world ical site which systemic circulating chemotherapy does not wide who have taken advantage of the opportunity to learn penetrate as well as other tissues. The classic example is the from this tragic disease. ALL is a model disease for the study development of CNS leukemia in the face of remission of the of disseminated cancer. This is so despite the fact that of all disease elsewhere in the body. Lastly, childhood leukemia is the cases of cancer estimated to occur in the United States the best example of a human disseminated cancer curable with annually, childhood ALL accounts for only 0.3% of the total chemotherapy. Whether this is accomplished by specific erad and only 10% of all leukemias (21). Why has such a relatively ication of every last leukemia cell is not known. infrequent disease had such profound impact on our thinking Impact on Therapeutic Strategy. Studies of childhood leu about cancer? kemia have had a major impact on our therapeutic strategy in Childhood Leukemia Model-Features. Childhood leukemia cancer. Systematic combination therapy for cancer begun in has proved to be a useful model because of several important this disease has been refined considerably over the years. The features. The disease, by definition, is always disseminated at concept of aggressive therapy during clinical remission, that diagnosis. Therefore, it has always demanded the use of sys is, maintaining pharmacological pressure to prevent regener temic rather than local therapy. Experience with systemic ther ation of tumor cells, was proposed, fostered, and proven early apy is 32 years old in childhood leukemia. Its clinical presen in the therapeutic history of this disease. Studies of childhood tation is relatively uniform, which has permitted standardization leukemia have played a major role in demonstrating the inter of specific and supportive therapy. Also, the diagnosis is not relationships of therapy. In a complete therapeutic regimen, it difficult to make in most instances. A key feature of this clinical is almost impossible to make a major change in one facet without influencing another. Lastly, in the late 1960's, it was research model is the ease of sampling of the tumor from marrow or blood which has permitted a wide variety of sequen recognized in some centers that much of the treatment for tial studies over the years. The foregoing features would be childhood leukemia could be given on an outpatient basis with less important if it were not for the availability of effective less interruption of the normal activities of a child. It is possible therapy since the introduction of aminopterin by Dr. Sidney to give aggressive, potentially curative chemotherapy in this Farber and his colleagues. A range of therapeutic responsive manner. In our own institution, we currently follow 550 patients ness has been essential for elaboration of its biological behav with leukemia and receive over 100 new patients a year. Yet ior. our average inpatient census is 7 leukemia patients. General Impact. Since the 1940's, studies in childhood Subpopulations of Cells-Combination Chemotherapy. I leukemia have had an enormous general impact on our under shall use examples drawn from our studies to illustrate some of standing of cancer therapy. The first systematically controlled the points I have made regarding the impact of this disease on therapeutic cancer trials were carried out in childhood leukemia our understanding of cancer. Table 1 provides clinical evidence in the now classic studies by Dr. Emil Frei, III, and the Acute of the existence of subpopulations of leukemic cells and the Leukemia Group B during the 1950's (8, 9). That group also effectiveness of combination therapy. Remission was induced had to develop criteria for responses and for toxicity of the in about 40 to 50% of patients who were given either predni- various treatment regimens so that studies in different institu sone or vincristine alone. When these 2 agents were combined, tions could be validly compared. Supportive therapy received the remission rate was increased to 90%, an almost perfect tremendous impetus in those leukemia studies, particularly at additive effect. This suggested either that there were 2 com the NIH under the direction of Dr. Emil J Freireich. In my view, pletely discreet populations of cells sensitive to only one of the however, the most important contribution made by the clinical agents or, more likely, subpopulations of cells with ranges of investigators working with this disease was their audacity in sensitivity to each of the agents and to the combination.

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