Abstracts for the 25th Annual Scientific Meeting of the International ...

More documents

Recommendations

Info

Abstracts J Immunother Volume 33, Number 8, October 2010 that SGI-110 strongly up-regulated their constitutive levels of expression in neoplastic cells of all investigated histotypes. This latter observation was confirmed at protein level by flow cytometric analysis of the intracytoplasmic levels of CTA, in melanoma cells. Concomitantly, flow cytometric analyses revealed that treatment with SGI-110 up-regulated the expression of HLA class I antigens, HLA-A2 allospecificity and the co-stimulatory molecule ICAM-1. Altogether, these preliminary in vitro experimental evidences strongly suggest that SGI-110 may represent an attractive therapeutic agent to comprehensively increase immunogenicity and immune recognition of neoplastic cells from solid tumors, and provide the scientific rationale for its clinical development to design new and more effective combined chemo-immunotherapeutic approaches in patients with solid malignancies. 4-1BB Activation Induces the Master-regulator Eomes and A Broad-spectrum TH1 Phenotype Which Synergizes with CTLA-4 Blockade to Reject B16 Melanoma Michael A. Curran*, Myoung-joo Kim*, Aymen Al-Shamkhaniw, James P. Allison*. *Howard Hughes Medical Institute, Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY; w Tenovus Research Laboratory, Southampton General Hospital, Southampton, United Kingdom. Antibodies which block the co-inhibitory receptor CTLA-4 or which activate the co-stimulatory receptor 4-1BB can promote the rejection of some murine tumors, but fail to cure poorly immunogenic tumors like B16 melanoma. We find that combining these two antibodies in the context of a Flt3-ligand, but not a GM- CSF, based B16 melanoma vaccine promoted synergistic levels of tumor rejection. 4-1BB activation elicited strong infiltration of CD8+ T cells into the tumor and drove the proliferation of these cells, while CTLA-4 blockade did the same for CD4+ effector T cells. Anti-4- 1BB depressed regulatory T cell infiltration of tumors and this effect was dominant over the tendency of aCTLA-4 to expand them. 4-1BB activation strongly stimulated TH1-type inflammatory cytokine production in the vaccine and tumor draining lymph nodes as well as in the tumor itself. The addition of CTLA-4 blockade further increased IFN-g production from CD4+ effector T cells in the vaccine draining node and the tumor. A hallmark of 4-1BB agonist antibody treatment is the upregulation of the lectin KLRG1 on tumor infiltrating CD8+ and CD4+ T cells. We find that these KLRG1+ T cells in the tumor express high levels of multiple killing-associated genes and may be responsible for the increased anti-tumor cytotoxicity which has been attributed to a4-1BB treatment. Further investigation revealed that formation of these cells is driven by high-level expression of the master-regulatory transcription factor Eomesodermin (Eomes) in both the CD8+ and CD4+ T cell compartments. To determine the pathway leading from 4-1BB agonist antibody to induction of Eomes expression, we have characterized the direct effects of a4-1BB on cytokine production from antigen presenting cells. Further, we have used a series of gene-specific knockout mice to validate candidate cytokines and transcription factors involved in this pathway. These findings reveal a previously unappreciated role for Eomes in generating extremely potent tumor-specific effector T cells which may be critically important for understanding and augmenting the effects of TNF-receptor family agonist antibodies as well as for T cell adoptive transfer therapies. Clinical Efficacy of the Anti-Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) Monoclonal Antibody Ipilimumab in Pretreated Metastatic Uveal Melanoma Patients Riccardo Danielli*, Paola Queirolow, Alessandro Testoriz, Ruth Plummery, Vanna Chiarion SileniJ, Maresa Altomonte*, Luana Calabro´ *, Anna Maria Di Giacomo*, Ruggero Ridolfiz, Michele Maio*. *Medical Oncology and Immunotherapy, University Hospital-ITT, Siena; w Medical Oncology A, IST, Genoa; zMelanoma and Sarcoma, IEO, Milan; JMedical Oncology, IOV, Padua; zImmunotherapy and Somatic Cell Therapy, IRST, Meldola, Italy; yNorthern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom. Background: The fully human anti-CTLA-4 monoclonal antibody ipilimumab potentiates anti-tumor T cell responses. Ipilimumab has improved overall survival (OS) of advanced cutaneous melanoma patients (pts) in a phase III trial; however, no data are available of its clinical effectiveness in uveal melanoma where no effective treatment is available. We report the European experience (6 Institutions) with ipilimumab in metastatic uveal melanoma pts. Methods: Thirteen stage IV pts (8 male, 5 female), median age 57 (30 to 76) years, ECOG performance status 0 to 1, with uveal melanoma progressing to 2 median (1 to 4) previous therapies for metastatic disease received ipilimumab within an Expanded Access Program. All pts had history (1) or evidence (12) of liver metastases, 1 of brain metastases and 3 of elevated (>1 upper limit of normal) LDH. In the induction phase (IF) pts received ipilimumab (10 mg/Kg i.v.) q3 weeks (wk 4 cycles; after a 12 weeks rest, treatment was repeated q12 weeks in the maintainance phase (MF) starting from week (wk) 24. Tumor assessment (TA) per modified WHO criteria was evaluated at baseline, at weeks 12 and 24, then q12 weeks. Adverse Events (AE) and immune related AE (irAE) were collected according to Common Terminology Criteria for Adverse events version 3.0. Results: All pts received at least one ipilimumab dose, 9/13 completed all IF cycles while the remaining 4 pts were prematurely withdrawn for disease progression; 5 pts entered the MF. No objective tumor responses were observed; however, TA at wks 12, 24 and 36 showed stable disease (SD) in 2/9, 3/6 and 1/4 pts, respectively. As reported for metastatic cutaneous melanoma pts, slow, steady tumor volume decline and appearance of new lesions that subsequently shrunk was observed. No grade 3/4 AEs were reported. Three pts (23%) had grade 3 IrAEs (1 trombocytopenia, 1 diarrhea, 1 ALT/AST elevation) that resolved after steroid therapy. Median OS as of March 1, 2010 was 36 weeks (range 2 to 102 wk). One patient, maintaining SD at >2 years from initial ipilimumab administration, is still on treatment. Conclusions: Ipilimumab treatment of metastatic uveal melanoma pts is feasible and safe. A sizeable proportion of pts experienced prolonged SD and extended survival. These evidences, strongly identify uveal melanoma as a promising indication for ipilimumab treatment to be investigated in phase II trials. Monoclonal IgE Targeting Prostate Specific Antigen (PSA) or HER2/NEU (HER2) as a Tumor Specific Immunotherapeutic Strategy T. Daniels*, G. Helgueraw, R. Quintero*, E. Ortiz-Sánchez*, J. Rodríguez*, B. Schultesz, M. Penichet*, C. Nicodemusz. *UCLA, Los Angeles, CA; w CONICET & FFyB, University of Buenos Aires, Buenos Aires, Argentina; zAdvanced Immune Therapeutics, Charlestown, MA. Biological treatments of both breast cancer (BCa) and prostate cancer (PCa) have proven efficacy, however these malignancies continue to be leading causes of cancer deaths worldwide. To improve the treatment of BCa and PCa, we have developed two monoclonal IgE antibodies specific for HER2 and PSA respectively. HER2 is cell surface antigen over-expressed in 30 percent of BCa and PSA is a secreted antigen that accumulates locally in prostate tissue and PCa. Both antigens have been used for tumor targeting and both are associated with circulating forms (secreted PSA & shed extracellular domain of HER2 (ECDHER2)). We hypothesized that an IgE mediated local acute inflammatory response in the tumor microenvironment would result in tumor destruction and that a subsequent adaptive anti-tumor immune response that would lead to further elimination of disease. We also hypothesized that IgE through interaction with Fce bearing antigen presenting cells could facilitate antigen processing and cross presentation of PSA or HER2 to enhance the adaptive cellular immune response. To target HER2 we used the variable regions of 894 | www.immunotherapy-journal.com r 2010 Lippincott Williams & Wilkins
J Immunother Volume 33, Number 8, October 2010 Abstracts the scFv C6MH3-B1 obtained from a human phage library and to target PSA we used the variable regions of a murine anti-human PSA antibody AR47.47. In both cases, the DNA encoding the variable regions were cloned into either the human k light chain or human e heavy chain expression vectors to yield the fully human anti-HER2 IgE and the mouse/human chimeric anti-PSA IgE. Both IgE antibodies, expressed in murine myeloma cell lines, are properly assembled and secreted, bind antigen (determined by ELISA, immunoprecipitation, or flow cytometry), and bind cellsurface FceR (detected by flow cytometry). Anti-HER2 IgE significantly blocked the proliferation of SK-BR-3 human BCa cells in vitro. In addition, antigen presentation assays using human dendritic cells loaded with anti-HER2 IgE complexed with ECDHER2 and with anti-PSA IgE complexed with PSA showed enhancement in the percentage of interferon-g producing CD4 and CD8 T cells as compared to priming with antigen alone. Both antibodies have initial evidence of anti-tumor activity. A pilot intravenous infusion of anti-HER2 IgE in Cynomolgus monkeys who have FceR that interact with human Fce was well tolerated. Consistent with expected tissue redistribution, the infused antibody was absent from the circulation within one week. Both antibodies are capable of enlisting a potent range of human effector cells and show promise for the immunotherapy of solid malignancies. The Role of Interleukin-12 in Modulating the Production of Interleukin-18 and Interferon-Gamma in Patients with Breast Cancer: Correlation to Clinicopathological Data Soheir R. Demian*, Mona El-Sayed*, Enas Aliw, Bassma Mersal*. *Immunology, Medical Research Institute; w Medical Research Institute, Alexandria University, Alexandria, Egypt. Breast cancer is an important public health problem. It is the commonest form of cancer in women throughout the world. Previous reports have indicated that out-come of malignant neoplasia in humans is often accompanied by defective cellular immunity. To induce more effective antitumor immune response, increasing the producton of Th1-cytokines are needed. The aim of this work was to investigate the regulatory effects of recombinant interleukin-12 (rIL-12) on interleukin-18 (IL-18) and interferongamma (IFN-g) production in patients with breast cancer as correlated with clinicopathological data. Peripheral blood mononuclear cells were isolated from all patients and cultured without and with rIL-12 supplementation. The levels of IL-18 and IFN-g in culture supernatants were detected before and after IL-12 addition using enzyme- linked immunosorbant assay. Statistical analysis of data revealed that, the supplementation of cultures with IL-12 significantly increases the mean values of both IL-18 and IFN-g in different clinicopathological parameters. In univariate analysis by age, tumor size, grade, number of lymph nodes, ER-BR, HER2 neu and IL-18 level, It was found that patients with IL-18 level higher than median at the time of diagnosis had higher survival results than those with lower value. In multivariate analysis the tumor size and HER2 neu were found to have independent prognostic value (P
Page 1 and 2: ABSTRACTS VACCINE COMBINATIONS Abst
Page 3 and 4: J Immunother Volume 33, Number 8,
Page 35: J Immunother Volume 33, Number 8,

Abstracts for the 25th Annual Scientific Meeting of the International ...

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?