Biological response modifiers in human oncology and immunology

The topic of biological response modifiers has attracted the attention of many biomedical investigators, including immunologists, oncologists, pharmacologists, microbiologists, and biochemists, as well as clinical practitioners of medicine. This has occurred mainly because of the realization that the complex system of cellular and humoral interactions culminating in a productive immune response is under exquisite regulatory control for normal immune responses and that loss of control may markedly influence the capability of a host to respond in a productive manner to the numerous immunologic "insults" encountered in the environment. Furthermore, biological response modification is considered by many to be a natural offshoot of the relatively new application of "immunotherapy" to cancer. It is widely recognized that "immunotherapy" was practiced at the end of the last century and the beginning of this century when it was recognized that microbial infections were caused by distinct species of bacteria and that passive administration of serum containing antibody to these microbes or their products could, in many cases, favorably influence the outcome of an infectious process. Furthermore, in the area of infectious disease it became quite apparent that "vaccines" prepared from killed microorganisms, or products thereof, could render an individual specifically resistant to that microorganism and, in many cases, increase in a nonspecific manner resistance to other organisms. This became quite evident with the advent of the use of attenuated mycobacteria for vaccination against tuberculosis. The use of the attenuated bovine strain of Bacille Calmette-Guerin (BCG) ushered in an era of potential vaccination not only against a specific microbe but the induction of "nonspecific" immunity to other organisms. Nevertheless, it is quite evident that this idea of immunotherapy or immunomodulation in terms of infectious diseases was not pursued with much vigor because of the discovery of antibiotics. Thus, specific drugs were found to be not only effective in killing or inhibiting the growth of bacteria in vitro, but also in vivo. The "rediscovery" that BCG might be of some value in patients with certain malignancies, especially those of the lymphoid system, ushered in a new era of possible treatment of malignant disease by nonspecific immunotherapy. There has been much criticism concerning immunotherapeutic approaches in cancer. There are both proponents and detractors for the idea that malignancies may be controlled by immunologic methods better than by more conventional methods such as surgery, radiation, and chemotherapy. There are also proponents of the idea that immunotherapy should be used as an adjunct treatment for cancer. Regardless of the view of investigators in this field, it is apparent that there are many approaches now being taken attempting to specifically and nonspecifically stimulate the immune response of patients with tumors with a wide variety of immunomodulating agents. Furthermore, it is quite evident that in many other disease states, including those induced by infectious agents, genetic disorders, etc., there may be marked diminution of immune competence either at the level of individual immunological pathways or at the level of immune cells. Similarly, there are many pathologic situations in which enhanced immune responses, or inappropriate responses, contribute to the disease state. Thus, there has been much interest in developing immunomodulating agents and biological response modifiers, not only for cancer but for other aspects of immunology. Among those individuals concerned with immunomodulating agents are the immunopharmacologists who constitute a new group of investigators attempting to bridge the area between the two parental disciplines of immunology and pharmacology. In July 1982 the Second International Congress on Immunopharmacology was held in Washington, D.C. The organizers of the Congress proposed a specific satellite symposium be held in Tampa, FL, immediately following the Congress. The topic of the symposium was Biological Response Modifiers in Human Oncology and Immunology. This volume is based on the proceedings of that satellite symposium which brought together over 120 investigators from numerous countries to discuss in detail pros and cons of biological response modification in cancer and in the general field of human immunology. The volume consists of manuscripts derived from both symposium talks and contributed research papers involving both clinical and basic studies utilizing animal models. The first chapter represents the keynote address presented by Dr. Y. Yamamura, President of Osaka University. Dr. Yamamura summarizes various forms of cancer immunotherapy, including studies employing microbial adjuvants, synthetic adjuvants, monoclonal antibodies, and cytokines. The introduction is followed by a major section of the volume dealing with biological response modifiers derived from leukocytes. This section begins with a consideration of the interferons. A great deal of new information is available concerning these substances and this is reviewed by Drs. Stewart and Stebbing. The next group of chapters deals with monoclonal antibodies, substances of great importance which were not even considered possible less than a decade ago. The utilization of monoclonal antibodies in cancer therapy is reviewed by Dr. Oldham and others. Thymosin and thymic extracts, which have been studied for nearly two decades as possible immunomodulating agents, are reviewed in a number of papers concerning cancer immunology. Dr. Talal's chapter on interleukin completes this section of the volume and discusses these interesting intermediary soluble molecules which have been described and examined in recent years as important mediators of a wide variety of immune responses, especially those considered to be mediated by T cells and macrophages. The third section of the volume deals with biological response modifiers derived from microorganisms. A variety of microbial products and their potential usefulness is described. Dr. Kotani reviews in detail muramyl dipeptides and synthetic analogs which, in the last half dozen years or so, have been shown to have marked immunomodulatory effects. Subsequent chapters in this section deal with the influence of various other microbial products on tumor progression and immune status in a variety of clinical and animal studies. Synthetic biological response modifiers are discussed in the fourth section of the volume. Included in this section are sulfurcontaining compounds such as Imuthiol and other chemically defined drugs such as Isoprinosine and NPT 15392. A vast amount of information is reported concerning the effect of these substances on human and animal tumors as well as the effects on immune function. The subsequent section of the volume describes the acquired immunodeficiency syndrome (AIDS) including descriptions of the disease, the immune abnormalities involved and the potential for treatment with biological response modifiers. The volume is then completed with summaries of workshops on animal models for studying biological response modifiers and clinical models. It appears likely that the broad range of topics discussed in this volume will focus attention on the extremely rapid evolution of the subject of biological response modifiers in human immunology. It appears somewhat unique that the bioscientists from many from many disciplines, including biochemistry, pharmacology, immunology, microbiology, etc., have focused their interest and attention on the exciting possibility of restoring immunogresponsiveness and/or reversing immuniodeficiency in patients with diseases as diverse as cancer, autoimmunity and infections. It is hoped the publication of this series of papers will stimulate additional investigative work in the area of disease process alteration by biological modifiers.