Transcript Document
Therapeutic Cancer Vaccines Edgar G. Engleman, MD The Immune System • The immune system is our major defense against viruses, tumors and other “foreign invaders” • It uses white blood cells and antibodies to fight invaders • The immune system is extraordinarily precise and powerful, and when successfully deployed, its targets are destroyed with little or no collateral damage Tumors and the Immune System • Tumors present a unique challenge because they consist mainly of normal tissue components (“self”) and the immune system is trained to avoid attacking self • The solution is to either overcome the reluctance of the patient’s immune system to attack the tumor, or produce tumor-specific antibodies or white blood cells outside of the body and inject them into patients Immunotherapy with Monoclonal Antibodies • Antibodies recognizing constituents of tumors can be produced using recombinant DNA methods • These antibodies, when injected into patients, are safe and well tolerated and are becoming standard treatments for several types of tumors • But each antibody recognizes only a single tumor constituent, must be administered repeatedly over time, and is only partly effective Redirecting the Immune System Against Cancer Using Vaccines • Old concept: the inability of the immune system to recognize and attack tumors is inherent and irreversible • New discovery: the old concept is false. By introducing tumor constituents directly to the sentinels of the immune system (dendritic cells), potent anti-tumor immunity is generated Dendritic Cells (DC) are Present in Blood and Most Tissues Blood DC A Skin Langerhans cells B Kidney DC C Rat Tracheal DC Murine Tracheal DC E Heart DC F D Human Bronchiole DC G Dendritic Cells: Center of the “Immuniverse” Lymph node Bone Marrow Stem cell CD34+ CD8 5 1 DC progenitor production in the bone marrow Induction of an immune response CD4 DC NK B Antibodies 2 Migration to peripheral tissue 4 Migration to lymph nodes Epidermis Langerhans cells Dermis Lymphatics Dermal DC 3 Sampling of the environnment Skin “danger signals” e.g. foreign matter Dendritic Cells (DC) as Therapeutic Vaccines • Goal: Induce anti-tumor immunity using DC pulsed with tumor components • Methods – Obtain DC from patient blood – Load DC with tumor components – Return DC to patients Preparation and Administration of DC Vaccine Tumor Ag Leukapheresis DC Generation and Maturation Ag loading Immune & Clinical Monitoring Vaccination Ag-Loaded DC Successful Therapeutic Vaccination in a Patient with Metastatic Colon Cancer Dendritic Cell Vaccination for the Treatment of Prostate Cancer From: Small EJ, Schellhammer PF, Higano CS, Redfern CH, Nemunaitis JJ, Valone FH, Verjee SS, Jones LA, and Hershberg RM. Placebo-controlled phase III trial of immunologic therapy with Sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 24:3089-94, 2006 The Future for Immunotherapy is Bright • More monoclonal antibodies, including antibodies to prostate cancer • Drugs that target and activate dendritic cells • Drugs that target and activate other white blood cells – T cells, NK cells, B cells