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In recent years, significant progress has been made in the clinical development and use of various types of cancer immunotherapy, all of which rely on the immune system to fight cancer. The majority of new cancer drug applications submitted to the Food and Drug Administration (FDA) are for immunotherapies or combinations involving immunotherapies. One type of immunotherapy is an immune checkpoint inhibitor. Cells in the human body have proteins that regulate the immune system response to foreign invaders (e.g., cancer cells, microorganisms). However, cancer cells can coopt these'checkpoint'proteins and thwart the immune system's ability to recognize and attack cancer cells. To help promote an immune response to cancer, researchers have developed immune checkpoint inhibitors that enable T-cells to recognize cancer cells as foreign and to prevent deactivation of an immune system response. To examine the challenges and opportunities to develop combination cancer therapies that include immune checkpoint inhibitors, the National Cancer Policy Forum held a workshop on July 16-17, 2018, in Washington, DC. This workshop convened stakeholders with a broad range of expertise, including cancer researchers, clinicians, patient advocates, and representatives from industry, academia, and government. This publication summarizes the presentations and discussions from the workshop.

Taken together the data presented in this review, and work by many other investigators, support the notion that DNA excision repair is important in a tumor cell's resistance to platinum compounds. Inhibition of this repair system by combination chemotherapy with the excision repair inhibitors HU and Ara-C produces synergistic cell kills and increased levels and persistance of DNA interstrand crosslinks. The studies with cis-DDP and ~-DDP in combination with UV­ induced thymine dimers suggest that there may be competition for DNA repair enzymes between the dimer and the platinum lesion. Whether the competing lesion is an intrastrand crosslink, interstrand crosslink, or platinum monoadduct (or all of these lesions) cannot be determined. The similarity between an intrastrand crosslink and a cyclobutane dimer suggests that these lesions may compete for repair. However, the increased peak levels of interstrand crosslinks, and increased persistence of these lesions at later time points suggest that this lesion may also be a substrate for the repair system. These observations may be of clinical relevance. Recently Dr. Kathy Albain of our institution has completed a Phase III I study using a 12 hour pretreatment with HU and Ara-C in patients prior to their cis-DDP therapy. She observed a significant number of responders in this trial (54). She is currently completing a second Phase IIII study substituting IV HU for the oral formulation. We anticipate initiating other clinical trials based upon these observations.

For many decades, cancer research concentrated heavily on'or­ ganic'aspects of the disease and ignored the role of trace elements and minerals in carcinogenesis and tumor growth. However, in recent years, spectacular progress has been made in'inorganic'cancer research: numerous inorganic substances were shown to possess car­ cinogenic properties. Quite unexpectedly, certain coordination compounds of platinum were found to have powerful antineoplastic properties, and a number of essential trace elements were demon­ strated to have profound effects on the genesis and growth of spontaneous, induced, or transplanted tumors. It therefore appeared desirable to call upon leading authorities in the field of inorganic cancer research to present their views in a conference dedicated specifically to their discipline. But since trace elements are nor­ mal constituents of foods, it seemed advantageous to include nutri­ tional aspects into the program. The fact that diet and nutrition influence tumor growth and development has been known or suspected for a long time. However, too little research has been done in this important field, resulting in a serious retardation of knowledge. Hence, this opportunity to cover nutritional aspects of cancer was taken, even though it was clear from the beginning that this broad field could not really be treated in the available time. It was necessary, for example, to exclude entirely the vast area of nutri­ tion as an adjuvant in cancer therapy, and even then, further limi­ tation of the scope of topics to be covered had to be made.

In anticipation of the opening of the H. Lee Moffitt Cancer Center and Research lnstitut~ on the campus of the University of South Florida, an international symposium,'The First Annual H. Lee Moffitt Symposium on Cancer Biology and Therapeutics'was held in Tampa, Florida on January 20-22, 1986. In this first symposium we decided to present a broad-based series of topics dealing with the major issues in the field of cancer. These topics ranged from the biochemistry of the cancer cell to the design of antineoplastic agents, through tumor cell heterogeneity, treatment of ltuman neoplasms to immunological aspects of cancer biology and tr~atment. The speakers chosen represented individuals of international acclaim who are very active in the area of cancer research and treatment. The symposium brought together scien­ tists/physicians from six nations including Austria, Canada, France, Hungary, West Germany, and of course, the United States. The congeniality of the participants promoted the friendly exchange of knowledge which, it is hoped, will greatly hasten the time when successful management of human cancer will become routine. Future symposia in this series will be highly focused and will deal with a single facet of this vast field of cancer research and treatment. Joseph G. Cory, Editor Andor Szentivanyi, Editor University of South Florida, 1986 V ACKNOWLEDGMENTS This volume presents the Proceedings of the H. Lee Moffitt International Syn~osium on Cancer Biology and Therapeutics which was held in Tampa, Florida on January 20, 21, and 22, 1986.

The idea for convening a Fourth International Symposium on Platinum Coordination Complexes in Cancer Chemotherapy was born in an assembly of researchers from the Vermont Regional Cancer Center and the Norris Cotton Cancer Center who shared a common interest in metal complexes. It was agreed by those assembled that sufficient time had passed since the Third International Symposium on Platinum Coor­ dination Complexes in Cancer Chemotherapy held in 1976 at the Wadley Institutes of Molecular Medicine in Dallas, Texas, during which several advances in the chemistry, biochemistry, pharmacology and clinical use of platinum complexes had occurred, to warrant a fourth symposium. Furthermore, intensive investigations in progress were bringing sophisticated methodologies to bear on the problems in the field, clinical trials were yielding interesting results, and unique approaches to cancer therapy were being designed. Therefore, an organizing committee was formed and planning culminated in the symposium which was held in Burlington, Vermont, June 22-24, 1983.

Proceedings of the Fifth International Symposium, held in Abano Terme (Padova), italy, June 29-July 2, 1987

The Workshop series of the'Koningin Wilhelmina Fonds'is a feature of the interest of this Foundation to promote research and education in the field of cancer, aiming to improve prognosis of the cancer patient. For almost a century, surgery has now been the main treatment modality for the cancer patient. During the past 50 years radiation therapy has developed as a second important modality of treatment. However, neither of the two modalities are able to cure the majority of cancer patients, as the disease is so often metastasized at presentation. Cancer chemotherapy is a modality which does have the potential to cure patients with this advanced stage of disease. In recent years the three modalities have been combined more and more, and here is one of the reasons why the prospectives for the cancer patient have improved so much. In addition, certain types of cancers, such as testicular car­ cinoma, childhood tumors, choriocarcinoma, non Hodgkin lymphomas and others, can now indeed often be cured by chemotherapy alone, even if the disease is advanced. The combination of drugs and the use of new drugs have greatly contributed to this development. There are two main groups of new drugs: analogs and new structures. A great number of analogs of conventional structures have been developed during the past ten years. A typical example of this group is adriamycin, which is an analog of dau­ nomycin.

The 2nd International Symposium on Combination Therapies brought together several hundred of the leading researchers, scientists and clinicians in this area to discuss new and emerging uses for biological response modifiers (BRM's) in the treatment of cancer and infectious diseases. The meeting was held during May 1-3, 1992 in Acireale, Sicily (Italy). It was hosted by Professor G. Nicoletti CU. of Catania) and organized by the Institute for Advanced Studies in Immunology and Aging (Washington, D. C.) in collaboration with the University of Rome'Tor Vergata,'the University of Catania and The George Washington University Medical Center. The synergy exhibited between BRM's and conventional therapies including bone marrow and other lymphoid cell transplants is a rapidly expanding area with significant promise for the treatment of human diseases. Advances in this area of biomedicine are leading to the rapid development of new therapeutic approaches that are being applied clinically as both primary and adjuvant therapy to enhance the effectiveness of conventional treatments. The 2nd International Symposium on Combination Therapy provided a setting for the exchange of new scientific information regarding the emerging uses for BRM's alone or in combination with conventional therapies. The 1st International Symposium on Combination Therapies was held in 1991 in Washington, D. C.

This volume, the last in this series on cancer growth and Moreover, the current status of plant-derived vinca alka­ progression, is a companion volume to Volume IX and loids and non-alkaloid natural products is summarized. further explores established and novel approaches for the Advances in hyperthermia and additional approaches for therapy of patients with malignant neoplasms. The stra­ the therapy of malignancies are also presented. tegies reflected in these volumes are direct extrapolations The volume continues with chapters on bone marrow from the basic science of cancer biology, growth and pro­ transplantation as well as hematologic and nutritional sup­ gression described in earlier volumes of this series. Some port for the cancer patient. Blood pressure in the cancer approaches are directed towards the eradication or modifi­ patient, therapy for nausea and vomiting as well as pain are cation of the properties of heterogeneous malignant tumor discussed. The last chapter is devoted to the problems of the cells at various stages of tumor progression, while other terminally ill, including evaluations of the burden relatives approaches are directed towards modification of the host and friends of the cancer patient have to bear. antitumor defense systems, e. g., enhancement of host anti­ It is clear that important advances in the basic science of tumor immune reactivity.

The International Society of Chemotherapy meets every two years to review progress in chemotherapy of infections and of malignant disease. Each meeting gets larger to encompass the extension of chemotherapy into new areas. In some instances, expansion has been rapid, for example in cephalosporins, pen­ icillins and combination chemotherapy of cancer - in others slow, as in the field of parasitology. New problems of resistance and untoward effects arise; reduction of host toxicity without loss of antitumour activity by new substances occupies wide attention. The improved results with cancer chemotherapy, es­ pecially in leukaemias, are leading to a greater prevalence of severe infection in patients so treated, pharmacokinetics of drugs in normal and diseased subjects is receiving increasing attention along with related problems of bioavailability and interactions between drugs. Meanwhile the attack on some of the major bacterial infections, such as gonorrhoea and tubercu­ losis, which were among the first infections to feel the impact of chemotherapy, still continue to be major world problems and are now under attack with new agents and new methods. From this wide field and the 1,000 papers read at the Congress we have produced Proceedings which reflect the variety and vigour of research in this important field of medicine. It was not possible to include all of the papers presented at the Congress but we have attempted to include most aspects of cur­ rent progress in chemotherapy.

Proceedings of the Conference on Intra-arterial and Intracavitary Chemotherapy, San Diego, California, February 24-25, 1984

Over the past 30 years many significant advances have been made in the management of a number of disseminated malignant diseases. The prognosis for diseases such as childhood leukaemia, choriocarcinoma and Hodgkin's disease has gradually been transformed as better anti tumour agents have become available and their clinical use has been refined. During the past 10 years the advent of new agents, particularly cisplatin, bleomycin and the podophyllotoxins, has allowed the cure of disseminated testicular tumours. This degree of success has not, however, been achieved in the case of a number of other common cancers. Ovarian carcinoma is tantalisingly chemo-sensitive and although there are long term survivors from disseminated disease, these are only a small proportion of the total. Breast cancer, although'sensitive'to a multitude of drugs appears to have yielded neither survival benefit, nor cure to the efforts of therapists, while tumours such as those of the colon remain stubbornly unresponsive. Against this backcloth it is apparent that additional more selective treatments are needed if further impact is to be made on the problem of cancer. The development of such agents requires the integration of a multidisciplinary effort encompassing the fields of chemistry, biology and medicine. This symposium provided a forum for clinical and preclinical sCientists, where current aspects of cancer treatment were reviewed and approaches to the development of a new generation of more selective anticancer drugs discussed.

Biochemical Modulation at the present time defines an area of study in which the intracellular metabolism of a given anti­ cancer agent is modulated (usually by a noncytotoxic agent or a cytotoxic agent at sufficiently low dosage to make it non­ cytotoxic) in order to either increase the effectiveness of the particular agent against tumor cells or decrease its cytotox­ icity against normal cells. The major focus of modulation has been the agents 5-fluorouracil (FUra), arabinofuranosylcytosine (ara-C), methotrexate (MTX) and a few alkylating agents. The major thrust of the studies has been to increase the flow of the anticancer agent along the pathway responsible for the formation of the cytotoxic species: for example, FUra to FUTP or ara-C to ara-CTP. While in most cases the application of research re­ sults to clinical trials does not require the subsequent exper­ tise of the laboratory researchers, application of biochemical modulatory schemes to clinical protocols necessitate a dramatic break with the past procedures. As shown in the laboratory­ clinical loop below, close collaboration between the laboratory and clinical investigator is essential. While the laboratory REDEFINE TECHNOLOGY, TESTS OR QUESTIONS FOR FURTHER THERAPEUTIC ADVANCE CLINICAL EXPERIMENTAL PROTOCOL (LABORATORY) RESEARCH STUDIES DEFINE AND TEST APPROPRIATE SCIENTIFIC PARAMETERS results define rationally-based regimens, it is essential that the clinical protocols contain the requirement that clinical material (either tumor or normal tissues) be sampled to deter­ mine whether the biochemical modulation being proposed is in fact beinq accomplished.

The addition of chemotherapy as an effective means to treat cancer has had a major impact on selected human malignancies. Due to a general inability to dif­ ferentiate between normal and neoplastic cells, little selectivity exists in currently used oncolytic drugs. Consequently, significant toxicity to the patient is expected when systemic cancer chemotherapy is chosen as an appropriate therapeutic in­ tervention. Much of this toxicity, such as damage to the bone marrow, gastroin­ testinal tract, or hair follicles, is predictable based upon the fact that anticancer drugs kill actively dividing cells. These types of toxicities, while serious, are usually manageable and reversible and are, therefore, not often considered to be dose limiting. Unfortunately, several of the most important anticancer drugs also damage tissues in which the growth fraction is relatively small. Such toxicities can not be predicted based on the chemical structure of the drugs, are often not detected in preclinical studies, and are encountered frequently for the first time in clinical studies. Further, unlike most of the proliferative-dependent toxicities, the unpre­ dicted toxicities are usually irreversible or only partially reversible upon cessation of drug administration. Because of this, the unpredicted toxicities are referred to as dose limiting. They represent a significant barrier to the ultimate efficacy of several of our most important anticancer drugs.

Recent developments with respect to the biology and clinical use of retinoids in cancer therapy and prevention are comprehensively covered by experts in this new field. Newer aspects of molecular mechanisms of retinoid effects, the cellular biology and the developmental effects of these compounds are presented together with a comprehensive description of the latest findings of retinoid pharmacology, toxicology and clinical effects in a wide range of hematological and solid malignancies.

The European School of Oncology came into existence to respond to a need for informa­ tion, education and training in the field of the diagnosis and treatment of cancer. There are two main reasons why such an initiative was considered necessary. Firstly, the teaching of oncology requires a rigorously multidisciplinary approach wh ich is difficult for the Univer­ sities to put into practice since their system is mainly disciplinary orientated. Secondly, the rate of technological development that impinges on the diagnosis and treatment of cancer has been so rapid that it is not an easy task for medical faculties to adapt their curricula flexibly. With its residential courses for organ pathologies and the seminars on new techniques (laser, monocional antibodies, imaging techniques etc.) or on the principal therapeutic controversies (conservative or mutilating surgery, primary or adjuvant chemotherapy, radiotherapy alone or integrated), it is the ambition of the European School of Oncology to fill a cultural and scientific gap and, thereby, create a bridge between the University and Industry and between these two and daily medical practice. One of the more recent initiatives of ESO has been the institution of permanent study groups, also called task forces, where a limited number of leading experts are invited to meet once a year with the aim of defining the state of the art and possibly reaching a consensus on future developments in specific fields of oncology.

This monograph evaluates the carcinogenic risks to humans posed by the use of four antiretroviral agents, four DNA topoisomerase II inhibitors used in the treatment of cancer, and an additional three pharmaceutical agents (hydroxyures, phenolphthalein, and vitamin K substances). The volume marks the first IARC evaluation of nucleoside analogs that act as antiviral agents. The evaluation responds in part to recent findings that zidovudine (AZT), an effective antiretroviral agent now being given to pregnant HIV-infected women to prevent maternal-to-fetal transmission of the virus, is a transplacental carcinogen in mice. The opening monograph evaluates the carcinogenicity to humans of the antiretroviral nucleoside analogs zidovudine (AZT), zalcitabine (ddC), and didanosine (ddI), and the antiherpesvirus drug aciclovir. Of these, aciclovir and didanosine could not be classified on the basis of available data.^

Scientific Basis of Cancer Chemotherapy focuses on methods and approaches in the treatment of cancer, including detection, chemotherapeutic agents, and hormonal therapy. The selection first offers information on the detection of anti-cancer agents through screening tests and extracellular factors affecting the response of tumors to chemotherapeutic agents. Discussions focus on induced and transplanted tumors, alkylating agents, anti-folics, rate of excretion, dosage regimen, and extra-cellular deactivation. The text then elaborates on intracellular factors influencing the response of tumors to chemotherapeutic agents and chemotherapy and immune reactions. The publication ponders on dose schedules and modes of administration of chemotherapeutic agents in man and the methodology of controlled clinical trials. Topics include toxicity study in animals and clinical pharmacology; classification of chemotherapeutic agents according to their mechanism of action; and classical methodology. The book also takes a look at the biological basis of hormonal therapy of cancer and chemotherapy in the strategy of cancer treatment. The selection is highly recommended for health professionals and readers interested in cancer chemotherapy.

Nitrosoureas: Current Status and New Developments covers the preclinical and clinical status of nitrosoureas. The book presents preclinical studies on the development of the nitrosoureas; combination chemotherapy with nitrosoureas plus other anticancer drugs against animal tumors; EORTC studies with novel nitrosoureas; and chemical decomposition of chloroethylnitrosoureas. The text also includes preclinical studies on the metabolism of nitrosoureas; DNA crosslinking and the origin of sensitivity to chloroethylnitrosoureas; modification of DNA and RNA bases; and carbamoylating activity of nitrosoureas. Clinical studies on subacute and chronic toxicities associated with nitrosourea therapy; the toxicity of high-dose BCNU with autologous marrow support; and the clinical pharmacology of the nitrosoureas are also considered. The book further tackles clinical studies on nitrosoureas in the therapy of Hodgkin's disease; nitrosourea-containing combinations in small-cell lung cancer; adjuvant therapy of brain tumors with nitrosoureas; and clinical use of nitrosoureas in gastrointestinal cancer. Oncologists, toxicologists, biochemists, pharmacologists, and other scientists working in drug development will find the text invaluable.

The Novartis Foundation Series is a popular collection of the proceedings from Novartis Foundation Symposia, in which groups of leading scientists from a range of topics across biology, chemistry and medicine assembled to present papers and discuss results. The Novartis Foundation, originally known as the Ciba Foundation, is well known to scientists and clinicians around the world.

Cisplatin: Current Status and New Developments is a collection of papers presented at a symposium sponsored by the University of Alabama in Birmingham Comprehensive Cancer Center and the Bristol Laboratories in Syracuse,?ew York, and held on September 27-28, 1979, in Atlanta, Georgia. The symposium provided a forum for assessing developments with regards to cisplatin as an anticancer drug, with emphasis on its clinical application in a wide variety of adult and pediatric malignancies as well as the mechanism by which the drug appears to cause tumor cell death. Comprised of 39 chapters, this book begins with a preclinical overview of cisplatin, focusing on its mechanism of action, pharmacology, antitumor activity, analogs, and toxicity. The discussion then turns to the effects of cisplatin on DNA and the possible relationships to cytotoxicity and mutagenicity in mammalian cells; lethal activity of platinum compounds in combination with pyrimidine derivatives; and ultrastructural effects of cisplatin. Subsequent chapters focus on the rationale of combination chemotherapy; toxic side effects of platinum analogs; radiopharmacokinetics of cisplatin; and the use of cisplatin for the treatment of malignancies such as ovarian cancer and advanced adenocarcinoma of the prostate. This monograph will be useful to oncologists and pharmacologists.

Bleomycin Chemotherapy focuses on the clinical uses of bleomycin. Bleomycin, a group of glycopeptides isolated from Streptomyces verticillus, has a unique structure and mechanism of action among anticancer drugs. The drug's remarkable lack of bone marrow toxicity prompted its addition to myelosuppressive regimens and enabled treatment of patients with compromised hematopoietic function. Bleomycin is an integral component of one of the great triumphs of medical oncology—the curative treatment of metastatic testicular carcinomas. Similar curative potential has been demonstrated for bleomycin in combination with cisplatin and vinblastine in germ-cell cancers of the ovary. Bleomycin is included in several important treatment regimens for Hodgkin's disease and non-Hodgkin's lymphomas. The drug also has clinical activity against squamous carcinomas of various sites. These uses and other aspects, including the development of new bleomycin analogs, are discussed in the following chapters, which were first presented at a symposium jointly sponsored by the Northern California Cancer Program and Bristol Laboratories in San Francisco, California, 14-15 September 1984.

Symposium on Clinical Pharmacology reviews advances in clinical pharmacology, with emphasis on how to materially improve the efficacy of cancer chemotherapy. Topics range from absorption, protein binding, distribution, and excretion of antineoplastic drugs to factors affecting the biotransformation and activity of antitumor drugs. The transport of tumor-inhibitory agents across cell membranes is also examined, together with factors influencing drug selectivity and the mechanisms of clinical drug resistance. This volume is comprised of 23 chapters and begins with a brief summary of the different kinds of pharmacokinetic models and how detailed kinetic investigations of a drug in animals may provide further insight into modes of its clinical use. The next chapter considers the chief factors in determining the effective concentration of a drug at a receptor site as well as the duration and intensity of drug effect, citing antineoplastic agents as examples. The role of enzymatic activation and inactivation in drug selectivity is also discussed, along with the general mechanisms of clinical resistance to cancer chemotherapy; biochemical and pharmacological principles of combination chemotherapy; and the reaction and effects of nitrosoureas. This book will be of interest to clinicians, pharmacologists, and biochemists.

Immunity, Cancer, and Chemotherapy focuses on the interference of drugs on antibody response and transplantation immunity. The selection first offers information on the effects of immunosuppressive drugs on cellular changes after antigenic stimulation and specialized cell function in the lymphoid and reticuloendothelial cell series. Topics include effects of immunosuppressive drugs on the sensitization process; cellular changes in lymphoid tissue following sensitization; and demonstration of differences in antigen handling among cells of the reticuloendothelial system. The text also takes a look at allogeneic inhibition and its possible relation to cell-bound immunity in vitro and the effects of immunosuppressive drugs at various stages of differentiation of immunologically competent cells. The publication examines a study of antibody-containing cells in the course of immunization and cellular differentiation during immune responses studied with electron microscope and radioautography. The text also elaborates on ambiguity in the translation of genetic code into proteins, induced by aminoglycoside antibiotics and immunosuppressive agents and cellular kinetics of immune response. The selection is a dependable source of information for readers interested in effects of drugs on antibody response and transplantation immunity.