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Gregory R. Pacheco Castleman Disease Research Laboratory. Opening The Way To Novel Therapies for Castleman Disease. What is Castleman Disease?. Discovered by Dr. Benjamin Castleman in 1956 “Benign” enlargement of lymph nodes (not cancer)

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Gregory R. Pacheco Castleman Disease Research Laboratory

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    1. Gregory R. Pacheco Castleman Disease Research Laboratory Opening The Way To Novel Therapies for Castleman Disease

    2. What is Castleman Disease? • Discovered by Dr. Benjamin Castleman in 1956 • “Benign” enlargement of lymph nodes (not cancer) • Debilitating symptoms may be controlled with life-long therapy

    3. What is Castleman Disease? • Causes of Castleman Disease are unknown • Virus • Auto-immune Disease • Uncontrolled Inflammation • Parallels to: • Hodgkin Disease • Excessive host response to rare tumor cells • Rheumatoid Arthritis

    4. Castleman’s Original Publications • Benjamin Castleman 1906-1982Pathologist, Massachusetts General Hospital, Boston MAEditor, Clinical-Pathological Case Presentations, NEJM • Castleman B and Towne VW: Case Records of Massachusetts General Hospital, Case 40001. NEJM,1954; 26: 250 • Castleman B, Iverson L, Menendez VP: Localized mediastinal lymph-node hyperplasia resembling thymoma. Cancer, 1956; 9: 822-830

    5. Castleman Disease: Concerns • Some patients do not respond well to therapy • Multicentric Castleman Disease may progress to non-Hodgkin’s lymphoma or other malignancies • Often misdiagnosed • Constitutional symptoms can be debilitating • There is no standardized therapy and patients can succumb to CD

    6. Classification of Castleman Disease • Clinical: Unicentric vs. Multicentric • Histology Hyaline Vascular vs. Plasmacytic (microscopy) vs. Mixed Cellularity type • HIV Status Positive vs. Negative • HHV8 Status Positive vs. Negative • Interleukin 6 Excess vs. no excess

    7. Unicentric Castleman Disease • Single slow-growing lymph node mass, e.g. neck, chest, abdomen, or groin • Symptoms, if any, caused by pressure effect of the enlarging lymph nodes • Usually Hyaline Vascular type, usually HIV and HHV8 negative • Usually no progression to, or association with other tumors

    8. Symptoms and signs ofMulticentricCastleman Disease • Enlarged lymph nodes in multiple areas • Enlargement of liver and spleen • Fever and night sweats • Loss of appetite • Tiredness • Edema: swelling of legs, fluid in abdomen, fluid behind lungs

    9. Typical Laboratory Findings inMulticentricCastleman Disease • Anemia • Low blood protein levels (albumin) • Laboratory signs of “inflammation” caused by increased interleukin 6 production • Increased sedimentation rate (ESR) • Increased C-reactive protein (CRP) • Increased fibrinogen (clotting factor)

    10. Castleman Disease and Interleukin 6 • Interleukin 6 (IL6) is made by cells in the Castleman nodes • IL6 stimulates Castleman nodes to grow • IL6 overproduction is found in all types of multicentric Castleman Disease • IL6 makes patients sick: loss of appetite, weight loss, night sweats, tiredness

    11. The Interleukin 6 Connection • Dysregulated interleukin-6 expression produces a syndrome resembling Castleman disease in mice. Brandt et al, JCI 86, 1990

    12. Anti-Interleukin 6 Receptor Antibody Therapy Controls Multicentric CD Before therapy After 2 months After 6 months

    13. How To Standardize Therapy • Central Pathology Review • Imaging Guidelines • Establish Castleman Disease Consortium (CDC) For diagnosis, research, therapy, and long-term follow-up • Molecular Diagnosis & Targeted Therapy

    14. Current Research • Castleman Disease research has been limited • The Pacheco Castleman Disease Research Lab is investigating: • disease etiology • why some patients exhibit increased interleukin 6 levels and others do not • SNPs in the interleukin 6 genes may be the cause of its overproduction • Subtle genetic differences seen among individuals • SNPs have been linked to other related diseases and disorders, including some malignancies.

    15. Seed funding will lead to improved patient outcomes No laboratory research Seed funding Federal grants Clinical trials Limited therapies Early studies Larger studies Novel therapies Preliminary data Awareness Etiology revealed Improved outcomes Misdiagnosis

    16. Gregory R. Pacheco The Gregory R. Pacheco Castleman Disease Research Laboratory Studies the etiology of Castleman Disease, with the goal of shedding light on its cause and leading to more efficacious treatments and the possibility of a cure.

    17. Flow Cytometer This powerful instrument is used for the identification and characterization of individual cells in a mixed population.

    18. Tissue Bank, Tissue Culture, PCR The Pacheco Lab houses the largest bank of Castleman Disease patient samples in the world, and a suite of equipment for tissue culture and molecular studies.

    19. Additional Questions • Does truly unicentric CD really exist? • Hyaline-vascular vs. plasma-cell variants: what drives the difference? • Viral/self-sustaining inflammatory disease process? • Gene expression profiling/tissue array: lymph nodes, blood lymphocytes, dendritic cells, endothelial cells • Proteomics • Perform serial sampling from multiple sites after therapy

    20. How to Advance Research • Concerted International Effort First CD conference in Santa Fe, New Mexico • Scientific/Clinical Infrastructure Tissue/Serum Bank, consensus for methods of procurement, triaging, studies to be performed • Funding Mechanisms NIH (Orphan Disease), IMF, MMRF, LLS, Pharma • Patient Advocates

    21. Thank You • The Pacheco Family • The George Hoag Family Foundation • Castleman Disease patients for entrusting us with their care and for participating in the research • MIRT clinical faculty, research faculty, and support staff