Immunotherapy of Infectious Diseases: A Future for Long Forgotten Cures?

Jaap T. van Dissel dept Infectious Diseases Leiden University Medical Center The Netherlands

Infectious diseases continue to be a significant cause of morbidity and mortality in man. Although major advances have been made in diagnosis and understanding of the pathogenesis of infectious diseases, present antimicrobial chemotherapy has proven to be insufficient to combat many of the current pathogens. Emerging and re-emerging pathogens cause new infectious diseases, have become resistant to available antimicrobial drugs, or cannot be treated because therapy is not available or largely ineffective because of underlying host immune impairment. The number of individuals with a compromised immune system has risen rapidly, due to the HIV epidemic, and new advances in the treatment of cancer, transplantation and autoimmune diseases. Hence, there is a need for new approaches to the treatment of infectious diseases. Likely, such therapies will be given primarily as adjunct therapy, i.e., aimed to increase the efficacy of present antimicrobial chemotherapy and restore or redirect the immune response to microbial pathogens. In this respect, mention should be made also of interventions aimed at reducing the sometimes deleterious host inflammatory response in infections, e.g., the use of glucocorticosteroids to reduce mortality and adverse sequellae in pneumococcal meningitis. In the past, immunotherapeutic interventions by vaccination or serum therapy proved particularly effective in the prevention or treatment of infectious diseases caused by microbial pathogens that cause an acute infectious disease followed by life- long, natural immunity. For instance, in the 1890s following the discovery of diphtheria toxin, von Behring and Kitasato developed the concept of passive immunotherapy by administering toxin-antiserum to patients with diphtheria. In the next decades, serum therapy gained recognition as treatment for diphtheria, pneumococcal pneumonia, malignant scarlantina, and meningococcal meningitis. It became evident that serum therapy (i.e., antibodies) may act by neutralizing toxins, inhibition of attachment or lysis of micro-organisms, or by enhancing the function of immune cells in innate immunity, e.g., by promoting phagocytosis. At the same time, bacteriophages and non-specific immune stimulants (e.g., BCG) were explored as treatment of infectious diseases. Although historical records document their usefulness, it is difficult to judge the efficacy of these therapies because controlled randomized trials were not performed. Despite early successes, in the 1940s these immunotherapeutic interventions were rapidly replaced by antimicrobial chemotherapy. Use of chemotherapy didn’t suffer from the restriction of serotype-specific administration of serum therapy, and chemotherapeutic drugs proved more effective against a broad range of pathogens, could easily be purified and standardized and were far less toxic. Understandably, pharmaceutical industry preferred the cost-effective, broad spectrum antimicrobial chemotherapy over the smaller markets of the expensive, individualized immunotherapeutic drugs that often required pathogen-precise diagnosis and didn’t provide a clear benefit. As a consequence, few indications for administration of antibodies remain, e.g., replacement in hypogammaglobulinaemia, rabies and hepatitis post-exposure prophylaxis and tetanus. By contrast, preventive use of vaccines became common practice and has an enormous impact on human health. Moreover, many new examples of progress with vaccines are seen today, e.g., against human papillomavirus infection and related cervical cancer, varicella, genital herpes in woman, staphylococcus aureus, whereas first vaccine candidates against tuberculosis are in phase I-II studies. Several developments have renewed interest in immunotherapy of infectious diseases. Recent insights into host-microbe interaction and mechanisms of protective immunity should allow for a rational approach to the design of immunotherapeutic interventions. Although such an intervention may encompass a pathogen-specific modality, it will often be applied in adjunct setting and non-pathogen specific, e.g., intended to modulate the host effector cells and immune response. In this setting, chemotherapy exerts the direct inhibitory effect against the microbial pathogen. Non- specificity will allow for broad application and will thereby be more cost-effective than earlier pathogen-specific approaches. Still, opportunities for pathogen-specific interventions remain and include, for instance, antibody therapy against multi drug- resistant micro-organisms, or post-infection vaccination strategies in HIV and tuberculosis. Likely, many modalities will make use of humanized monoclonal antibody and cytokine technology and the development of advanced vaccination and cellular treatments. The cytokines G-CSF, GM-CSF, M-CSF, and IFN-gamma, by their ability to stimulate the function of macrophages, neutrophils and monocytes, have received attention as non-specific immunomodulatory agents used as adjunct treatment of various infectious diseases. IFN-gamma is approved for preventive use in chronic granulomatous disease. Immunotherapeutic interventions as adjunct therapy to chemotherapy are becoming increasingly popular in the treatment of viral, bacterial and fungal infections, e.g. IFN-alpha and ribavirin in hepatitis C, intravenous immunoglobulin in necrotizing fasciitis, various interventions in sepsis, and IL-12, IFN-gamma or G-CSF in combination with azoles or amphothericin B in disseminated fungal disease in the immunocompromised host. Also other directions are being explored, for instance anti-adhesion therapy of bacterial diseases are being developed, in particular for urinary tract infections. At the moment, clinical experience with immunotherapeutic interventions is limited and often investigational. The last decade has shown that the success and market for such drugs is difficult to predict (e.g., failure of anti-cytokine strategies in sepsis). Therefore, companies will be reluctant to undertake development of such drugs. The outlook in regard to vaccination is more promising. Comparative controlled clinical trials will be needed to evaluate the (long term) safety and efficacy, and define specific indications for the administration of the immunomodulatory drugs in therapeutic regimens.

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