Scientific Report 2003-2004 - Cleveland Clinic Lerner Research ...

Continued from Page 167active training program for postgraduatelevel fellows. Currently, we have fourpostdoctoral fellows and one surgical residentfrom Otolaryngology. The training programfocuses on areas of tumor immunology, molecularbiology and clinical immunotherapy ofcancer.Research programs within the Centerconcentrate around the central theme of T-lymphocyte responses to autochthonous tumorcells. By applying immunological and molecularbiological techniques, we wish to define the roleof the host immune system in preventing,controlling and eradicating malignant T cells.Such an approach requires both extensive basicresearch utilizing animal tumor models andhuman experimentation through designed clinicalprotocols. In animal studies, the transfer oftumor-immune T lymphocytes has been demonstratedto be the most effective means oferadicating established primary as well asmetastatic tumors. This form of immunotherapyof cancer, referred to as “adoptive immunotherapy,”requires the generation of tumorsensitizedT cells in numbers sufficient fortreatment in clinical settings.A few years ago, results from animalstudies and laboratory investigations weresufficient to allow extrapolation for a plan of asystemic immunotherapy of humans withmalignancies. The basic procedures involvevaccination of patients with their own tumorcells, followed by retrieval of the draining lymphnodes to provide a source of tumor-reactiveimmune T lymphocytes. After further stimulationand propagation of these lymph node T cellsin vitro, they are reinfused into the patient forthe treatment of tumor. Since the approval bythe Food and Drug Administration in July 1995of an Investigational New Drug application, wehave extended this protocol to treat a number ofdiverse cancers including malignant gliomas,advanced renal cell carcinoma, squamous cellcarcinoma of the head and neck, and metastaticmalignant melanoma. This effort has been acollaborative interaction between the Center andseveral other departments, including NeurologicalSurgery, Otolaryngology, Urology, PlasticSurgery, General Surgery and Hematology/Oncology. Because of the collegial atmosphereand strong support provided by CCF, we havemade significant progress toward standardizationof the procedures and analysis of toxic sideeffects of the treatment.The first disease we proposed to treat withautologous T lymphocytes was glioblastomamultiforme (GBM). The procedure for generatingT cells has been modified several times, basedon laboratory research findings. Ten patients,most of them with recurrent GBM, have beentreated with modified procedures. Three of thosepatients showed MRI-documented tumorregression. Analysis of survival also suggests thatthere might be a prolongation of survival in thisgroup of patients as compared to the results of asingle-drug (carmustin polymer) trial in patients atsimilar stages of disease. Data generated fromthis trial provided preliminary results for asuccessful R01 grant application. In the meantime,we started to treat patients with metastaticrenal cell cancer and cancer of the head and neck.Since July 1997, 22 patients with renal cellcarcinoma have enrolled and completed thetreatment procedure. It may be too early to drawa clear conclusion on the outcome of thetherapeutic efficacy, but clearly, treatment withautologous T cells poses little or no toxicity. Ourprotocol differs from many others in a veryimportant way in that it is readily modifiedaccording to concurrent research results. One ofthe potential refinements of this protocol is theisolation of L-selectin-negative T cells from thedraining lymph nodes for generation of mosteffective tumor-sensitized lymphocytes. In animalstudies, L-selectin-negative T cells representapproximately 20% of the total lymph node TContinued on Page 169Suyu Shu, Ph.D.168