SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

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C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M CAIO MAX S. ROCHA LIMA, M.D. Associate Professor of Medicine DESCRIPTION OF RESEARCH Dr. Rocha Lima’s research focuses on developing novel treatments in patients with cancer (mainly lung cancer and gastrointestinal malignancies). Researchers in his laboratory work to identify prognostic factors in patients with cancer. They also are cooperating in the development of molecular finger-printing for gastrointestinal cancer patients. They are studying 33,000 genes in pancreatic cancer and colorectal cancer as an attempt to identify different gene expression patterns (tumor phenotype) and their correlation with overall survival, benefit to different types of treatment, and tumor aggressiveness. The investigators also are working to identify chromosomes alleles related to drug metabolism from buffy coat (leucocytes) and correlating with chemotherapy toxicity. SELECTED PUBLICATIONS 2002 Rocha Lima, CM, Herndon, JE 2nd, Kosty, M, Clamon, G, and Green, MR. Therapy choices among older patients with lung carcinoma: an evaluation of two trials of the Cancer and Leukemia Group B. Cancer 94:181-87, 2002. Rocha Lima, CM, Savarese, D, Bruckner, H, Dudek, A, Eckardt, J, Hainsworth, J, Yunus, F, Lester, E, Miller, W, Saville, W, Elfring, GL, Locker, PK, Compton, LD, Miller, LL, and Green, MR. Irinotecan plus gemcitabine induces both radiographic and CA 19-9 tumor marker responses in patients with previously untreated advanced pancreatic cancer. Journal of Clinical Oncology 20:1182-91, 2002. Rocha Lima, CM and Centeno, B. Update on pancreatic cancer. Current Opinion in Oncology 14:424-30, 2002. Rocha Lima, CM and Joppert, MG. Topoisomerase I-based nonplatinum combinations in non-small-cell lung cancer. Oncology (Huntington) 16:25-31, 2002. Freitas, JR and Rocha Lima, CM. Therapy of advanced non-small-cell lung cancer with irinotecan and gemcitabine in combination. Clinical Lung Cancer 4 (Supplement 1): S26-90, 2002. 2003 Coutinho, AK and Rocha Lima, CM. Metastatic colorectal cancer: systemic treatment in the new millennium. Cancer Control 10:224-38, 2003. Rocha Lima, CM and Chiappori, A. Treatment of relapsed small-cell lung cancer—a focus on the evolving role of topotecan. Lung Cancer 40:229- 36, 2003. Bhargava, P, Jani, CR, O’Donnel, JL, Stuart, KE, and Rocha Lima, CM. Gemcitabine and irinotecan in locally advanced or metastatic biliary cancer. Oncology 17: 23-26, 2003. Chiappori, AA and Rocha Lima, CM. New agents in the treatment of small-cell lung cancer: focus on gemcitabine. Clinical Lung Cancer 4 (Supplement 2): S56-63, 2003. Simon, GR, Ruckdeschel, JC, Williams, C, Cantor, A, Chiappori, A, Rocha Lima, CM, Antonia S, Haura, E, Wagner, H, Robinson, L, Sommers, E, Alberts, M, and Bepler, G. Gefitinib (ZD1839) in previously treated advanced non-small-cell lung cancer: experience from a single institution. Cancer Control 10:388-95, 2003. Rocha Lima, CM, Leong, SS, Sherman, CA, Perkel, JA, Putman, T, Safa, AR, and Green, MR. Irinotecan and gemcitabine in patients with solid tumors: phase I trial. Oncology (Huntington) 16:19-24, 2002. UM/Sylvester Comprehensive Cancer Center Scientific Report 2004 53
C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M HIGHLIGHTS/DISCOVERIES Novel treatments with the following agents were designed and tested clinically by Dr. Rocha Lima: • IrinoGem (gemcitabine and irinotecan in combination) for pancreatic cancer and lung cancer (both small and non-small cell lung cancer). • DocGem in lung cancer. • ETopoTax in small cell lung cancer. His clinical efforts with the agent IrinoGem resulted in establishing it as a new clinical treatment option for pancreatic cancer. JOSEPH D. ROSENBLATT, M.D. Professor of Medicine and Division Chief of Hematology-Oncology DESCRIPTION OF RESEARCH Dr. Rosenblatt’s research focuses on the development of novel immune therapy and gene therapy strategies for cancer. Current research has focused on the potential role of recruitment of immune effector cells, using the local elaboration of both constitutive and inflammatory chemokines, such as secondary lymphoid chemokine (SLC), DC-CK1 and/or RANTES respectively, on the development of an anti-tumor response. Chemokine delivery has been investigated alone, or in combination with, expression of the costimulatory ligands CD80 (B7.1) or CD40L. Several delivery strategies have been investigated including the use of retroviral vectors, and/or the use of herpes simplex virus (HSV) amplicon vectors in several murine tumor models. Preliminary results suggest that the recruitment of naïve T cells using SLC is a particularly effective means of enhancing the anti-tumor immune response, particularly when combined with CD40Linduced co-stimulation. This strategy is being formally investigated using the OT-1 transgenic mouse model, which has a constitutively expressed T-cell receptor with defined anti-ovalbumin specificity and the murine tumors expressing the target ovalbumin antigen, for effects on tumor-induced tolerance and the development of systemic immunity. In a separate effort, the utility of HSV-derived helper virus-free amplicons is being tested for efficacy in augmenting the immunogenicity and antigen-presenting capability of fresh chronic lymphocytic leukemia cells (CLL). Both CD40L and CD80, and/or the tumor necrosis factor (TNF) ligand family member LIGHT have been targeted to fresh CLL cells using the helper free HSV amplicons. Results suggest the augmented ability of such CLL cells to present antigen in an allogeneic mixed-lymphocyte-tumor cell reaction, and/ or to serve as stimulatory cells for the derivation of autologous cytolytic T cells in vitro without deleterious effects on MHC-I expression is seen with HSV helper virus-containing preparations. A novel means of immune effector molecule delivery, which combines the antigen binding capabilities and localization characteristics of antibodies with the local delivery of a co-stimulatory molecule, anti-angiogenic peptide, or a chemokine, also is under investigation. Antibody fusion proteins targeting the human breast and ovarian cancer her2/neu antigen, linked to the extracellular domains of the B7.1 and/or 41BB-L costimulatory ligands, have been synthesized and their in vitro ability to bind to cognate antigenic targets and to deliver a local co-stimulatory signal has been documented. Additional fusions currently being developed in the laboratory include fusion of the anti-angiogenic peptide endostatin to anti-her2/neu antibody sequences, as well as fusion of the inflammatory chemokine RANTES. Selective targeting of immune effector cells using both local chemokine vector administration or antibody-fusion protein administration is being evaluated further. A novel antibody-fusion that targets delivery of endostatin to the site of her2/neu-expressing tumors has also been synthesized in collaboration with Seung-Uon Shin, M.D., and shows excellent efficacy in preclinical models. This fusion appears to substantially improve the results obtained with either antibody or endostatin alone. Currently, Dr. Rosenblatt’s laboratory is studying efficacy using a novel B-cell deficient mouse model, which allows testing of antibody 54 UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
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SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

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