The Human Immunology and Cancer Program

The Human Immunology and Cancer Program (HICP) is a multifaceted basic and clinical scientific endeavor devoted to advancing understanding of the pathogenesis of primary (AL) amyloidosis and developing innovative diagnostic and therapeutic means; the ultimate goal is to eventually diminish or eradicate the calamitous effects of this disease. Our research efforts are directed towards the precise identification and characterization, through immunological, biochemical, and molecular biological techniques, of the protein components that are largely responsible for the devastating manifestations of this disorder. Based on this knowledge, we also are formulating innovative diagnostic and therapeutic approaches for patients with AL amyloidosis. Through use of both in vitro and in vivo experimental models, various chemical and biological substances are being tested to determine their capacity to break down amyloid deposits. Because certain maladies, such as Alzheimer's disease, also are caused by the abnormal deposition of other types of proteins, we anticipate that the results of our work will be beneficial to individuals with these conditions, as well.

Amyloid Research

AL amyloidosis (as well as other forms of the disease) is the subject of intense scientific investigation. Here at the Human Immunology and Cancer Program, we have extensive laboratory and support facilities staffed by dedicated professional and technical personnel who are engaged in research of this disorder. Also participating are international visiting scientists who are among the world's experts in this field. Medical care, including diagnostic procedures, treatment, and consultative services, are provided in a clinic devoted to people with AL amyloidosis. Thus, the patient is a participant and an integral part of the research efforts.

We have formulated medically based strategies designed to answer questions that are deemed critical to solving this devastating problem:

• How can the diagnosis of the disease be improved?

• What causes certain types of light chains (Bence Jones proteins) to form amyloid fibrils?

• Why are particular organs or tissues apparently "targeted" for fibril deposition and what accounts for the differences observed between patients in the organs predominately affected?

• How can fibrils be eliminated once laid down or even prevented from forming or depositing?

• Finally, is this disease dependent upon the injurious nature of the protein itself, or do people with this disorder have some sort of defect that causes these proteins to form amyloid, or do they lack antibodies or other substances that can help remove this material once deposited?

The fact that amyloidosis is not a single disease, but rather is a group of disorders that results from the pathologic deposition of at least 25 different proteins, necessitates that physicians have knowledge of the exact type of amyloid occurring in their patients since the prognoses of the various amyloidoses differ and each type requires individualized treatment. Because all forms of amyloid are similar in appearance when viewed through a microscope, they can not be distinguished from one another on this basis, and thus, alternative methods have been developed and utilized to identify indirectly the nature of this substance. However, to establish unequivocally the particular kind of amyloid present, it is necessary that this material be selectively removed from tissue and analyzed in the laboratory for determination of its exact chemical composition. This can be a formidable task and, until recently, required that a relatively large sample be used for study. Fortunately, we now have developed a "micro-technique" that makes it possible to gain such information from minute tissue specimens obtained by fine needle biopsy or fat aspiration.

Because patient as well as protein factors can be involved in the generation of amyloidosis, our research also is directed towards elucidation of antibody-related genes and the development of experimental models of this disease. Further, after proteins that make up the amyloid are isolated from tissue specimens and analyzed in the laboratory, we can compare them to other samples to determine if amyloid-forming proteins differ from those that are not involved in this process. Such information can be used as the basis for generation of drugs and other compounds that will be helpful in treatment. Additionally, work is underway to determine if tissue specific factors are present in particular organs that "attract" or bind light chains and result in fibril formation. If such a structure is identified, agents could be designed that would prevent the binding of light chain proteins to tissues and thus amyloid production would be prevented. We also are studying ways to elicit from the body a natural defense response that would eliminate these abnormal deposits before irreparable organ damage occurs and have developed certain reagents called monoclonal antibodies that are attracted specifically to the unique structure of amyloid proteins. When these antibodies are given to animals that have amyloid deposits, this material disappears rapidly. Our highest priority is to determine if such reagents would be beneficial in patients with AL amyloidosis. In this regard, the National Cancer Institute, through their "Rapid Access to Intervention Development (RAID)" program has prepared one of our "anti-amyloid" monoclonal antibodies in a form that can be administered to humans and plans to produce a sufficient amount of this clinical-grade reagent for a Phase I/II trial in patients with this disease. The use of this form of "passive" immunotherapy to remove amyloid deposits would be a major advance in the treatment of AL, as well as other amyloid associated diseases. Additionally, we currently are investigating the capability of one such amyloid-reactive monoclonal antibody, when labeled with a radioactive isotope, to serve as a PET imaging agent.

These areas of ongoing study that combine patient care and laboratory research ultimately offer hope to patients with AL amyloidosis. Because each case is unique and offers important information, continued research and careful study of individual patients will help achieve the goal of curing or preventing this devastating illness. Top