Juergen H. Bertram

Treatment of cancer chemotherapy-associated thrombotic thrombocytopenic purpura/hemolytic uremic syndrome by protein A immunoadsorption of plasma

Background. Chemotherapy‐associated thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (C‐TTP/HUS) is a condition involving thrombocytopenia, microangiopathic hemolytic anemia, and progressive renal dysfunction that develops in 2–10% of patients with a history of malignant neoplasms treated with certain chemotherapeutic agents. Pathogenesis of the disease may depend on the following: (1) generation of endothelial lesions in the kidney microvasculature, resulting from drug toxic effects and/or generation of small soluble circulating immune complexes (CIC), and (2) generation of autoantibodies and/or CIC that trigger aggregation and deposition of platelets around the lesions.

Antitumor effects of immobilized protein A and staphylococcal products: Linkage between toxicity and efficacy, and identification of potential tumoricidal reagents

INTRODUCTION IMMOBILIZED protein A (SPA) has been used as experimental cancer therapy in animal models and in man. Striking antitumor responses were frequently observed and prompted an intensive search for the active bioreactants and the mechanism of action of this most unusual approach to cancer therapy. In recent years substantial clinical, biochemical and immunological research has been carried out in this area and several biomolecules which appear to contribute to the tumoricidal effects of plasma perfused over immobilized SPA have been identified. These and other major developments will be reviewed and based upon these findings we will advance an hypothesis to explain the tumoricidal activity of SPA-perfused plasma. This unifying concept may also reconcile some seemingly disparate observations obtained with various SPA perfusion systems and, perhaps, serve as a blueprint for future investigations in this field.

Use of protein A immunoadsorption as a treatment for thrombocytopenia in HIV-infected homosexual men: a retrospective evaluation of 37 cases.

Thirty-seven HIV-infected homosexual men with thrombocytopenia (less than 100 x 10(9)/l) received protein A immunoadsorption treatments to remove platelet-sensitizing immunoglobulin (Ig) G and circulating immune complexes (CIC) from plasma. Patients received an average of six treatments each, consisting of 250 ml plasma over a 3-week period. Clinical improvement in hemorrhagic symptoms associated with substantial increase in platelet counts was achieved in 18 patients. These responses were maintained over a median follow-up period of more than 7 months in 14 evaluable patients who were not lost to follow-up (three patients relapsed in 2 weeks and one received another therapy). Generally, moderate transient treatment-related side-effects included fever, musculoskeletal pain, chills and nausea. A transient serum sickness-like reaction was observed in seven patients, leading to termination of treatment in two. Clinical responses were associated with significant decreases in levels of platelet-sensitizing Ig, including CIC. Stimulation of broadly cross-reactive anti-antigen-binding fragment [F(ab)2], antibodies contributed to these responses. Protein A immunoadsorption is an effective alternative treatment for HIV-associated thrombocytopenia.

Acute Renal Failure Due to Bilateral Ureteral Obstruction by Metastases from Breast Cancer

Two female patients with metastatic breast carcinoma had acute renal failure secondary to metastatic ureteral obstruction. Retrograde pyelography showed bilateral segmental constriction and dilatation of the ureters with hydronephrosis. Drainage procedures reversed the renal failure in both patients. A review of the literature indicates that ureteral involvement is frequent in patients with malignancies.

Protein A Immunoadsorption

Protein A is a staphylococcal bacterial cell wall component that binds certain subclasses of IgG, other classes of mammalian immunoglobulins and immune complexes. Initial studies in tumour-bearing animals and in patients with cancer were based on the early premise that circulating immune complexes function as suppressor factors of anticancer immunity. Subsequently, the use of protein A in various autoimmune disorders was explored. All these early studies utilised protein A-bearing staphylococci as an extracorporeal immunoadsorbent to remove IgG and immune complexes. Although promising clinical responses in cancer and various autoimmune illnesses were observed, there was also substantial toxicity. We now understand this toxicity to be due to leakage of protein A and enterotoxins from the formalin-fixed Staphylococcus aureus. As a result, more stable protein A matrices were developed. The 2 leading extracorporeal protein A devices, the Immunosorba® and Prosorba® columns, utilise highly purified protein A covalently coupled to a relatively inert solid phase matrix. Although these devices differ in design and utilisation, both have demonstrated clinical effectiveness in several autoimmune illnesses, with manageable adverse effects. The Immunosorba® column has been licensed in the US for the treatment of immune-mediated haemophilia, and the Prosorba® column is approved for the treatment of idiopathic thrombocytopenic purpura. Use of the Prosorba® column in various other autoimmune disorders, including rheumatoid arthritis and renal graft rejection, is under investigation. There is also some evidence that certain cancers may respond to immunoadsorption therapy, provided that concomitant chemotherapy is used. In addition to its reported clinical benefit, protein A immunoadsorption may provide further insights into the clinical pathogenesis of immune-mediated disorders and certain cancers. Analysis of the composition of immune complexes from patients during therapy, including the nature of bound antigen, may substantially further our understanding of the role of these immune complexes in these disorders. Indeed, different modes of action may be operative depending upon the type of illness.