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Abstracts for the 25Th Annual Scientific Meeting of the International Society for Biological Therapy of Cancer

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Abstracts for the 25Th Annual Scientific Meeting of the International Society for Biological Therapy of Cancer ABSTRACTS VACCINE COMBINATIONS Abstracts for the 25th Annual Scientific Meeting of the International Society for Biological Therapy of Cancer (Primary Authors are Italicized) surface marker that was used as a reporter gene. All ten constructs were used to generate RD114-pseudotyped RVV that were tested, by flow cytometry, for their ability to induce tCD34 expression in ADOPTIVE T-CELL TRANSFER: transduced human PBL. This parameter was used to select the most THE NEXT WAVE efficient combinations of miRNA backbone and cloning site, in terms of transgene expression. Thus, mir-142-, mir-155- and mir- 150-derived amiRNAs yielded the highest percentage of CD34 Development of a g-Retroviral Vector for the Expression of positive cells. Of note, vectors expressing mir-223-based amiRNAs Artificial miRNAs in Human T Lymphocytes induced almost negligible expression of transgene, as opposed to previous reports using lentiviral vectors, stressing the relevance of Daniel Abate-Daga, Tristen S. Park, Douglas C. Palmer, Nicholas P. Restifo, Steven A. Rosenberg, Richard A. Morgan. vector-specific step-wise optimization. This platform may allow for Surgery Branch, National Cancer Institute. NIH, Bethesda, MD. the validation of gene silencing as an enhancer of T cell activity, as Since its discovery, RNA interference has not only emerged as a well as a delivery vehicle for tumor-specific T cell receptors (TCR) new field of study but also provided a series of versatile tools for or Chimeric Antigen Receptors (CAR) genes concomitantly with the study of a wide range of biological processes. While chemically silencing molecules in the context of adoptive cell therapy. synthesized short interfering RNAs (siRNA) and short hairpin RNAs (shRNA) expressed under RNA Pol III promoters have been satisfactorily utilized in basic genomic studies, their wide- spread application in therapeutic settings is still hampered by Depletion of NK Cells Enhances the Effectiveness of technical issues. Although the necessity of repeated administration Adoptive Cell Therapy with Naive Tumor-specific CD4+ of siRNAs had been overcome by using vector-encoded shRNAs, it T Cells Through Surface Bound IL-15 has been reported that these may induce toxicity due to saturation Kristina Harris*, Lukas Pfannenstielw, Malcolm Lane*, Paul A. of host cell processing machinery. To address this, chimeric Antony*. *Program in Molecular Microbiology and Immunology and structures that mimic endogenous miRNAs, termed artificial the Department of Pathology; w Department of Head and Neck miRNA (amiRNA), have been developed based on mir-30 and Surgery, University of Maryland School of Medicine, Baltimore, MD. mir-223 backbones. In this work, we sought to develop a CD8+ T cells have been the primary focus of immunotherapy of gammaretroviral (RVV) vector to conjointly express a transgene cancer with little focus on CD4+ T cells. Immunotherapy and amiRNAs based on miRNAs naturally expressed in human involving in vitro differentiated T cells given after lymphodepleting lymphocytes. A set of five amiRNAs were synthesized that contain regimens significantly augments antitumor immunity in animals the sequence of either mir-142, mir-155, mir-223, mir-146b and mir- and human patients with cancer. However, the mechanisms by 150 primary transcripts, in which each wild type stem region has which lymphopenia augments adoptive cell therapy are still been replaced by a control sequence with no specificity for any emerging. We demonstrate that naı¨ ve tumor/self-specific CD4+ human gene. Each of these chimeric contructs was cloned into T cells naturally differentiated into T helper type 1 (Th1) cytotoxic BglII or BsrGI sites located in the intronic region of pMSGV2- T cells in vivo and caused the regression of established tumors and tCD34 plasmid, which encodes for a truncated form of CD34 depigmentation in lymphopenic hosts. Therapy was independent of FIGURE 1. A, Depletion of NK cells enhances adoptive cell therapy of established melanoma with naive tumor/self-specific CD4+ T cells. B, Enhanced autoimmune vitiligo with NK depletion and adoptive cell therapy with naive tumor/self-specific CD4+ T cells. J Immunother Volume 33, Number 8, October 2010 www.immunotherapy-journal.com | 859 Abstracts J Immunother Volume 33, Number 8, October 2010 vaccination, exogenous cytokine support, CD8+-, B-, NK and NK The expression of cancer testis antigens (CTA) is restricted to T cells. Surprisingly NK depletion further enhanced tumor therapy tumor cells and non-MHC expressing germ cells of testis, thus they by increasing T cell numbers, autoimmune vitiligo, and serum are attractive targets for adoptive immunotherapy. Synovial proinflammatory chemokines and cytokines. This effect may be sarcoma X (SSX) breakpoint proteins are encoded by a family dependent on increased levels of surface-bound IL-15 on CD11c+ of 10 homologues genes SSX: 1 to 10 located at chromosome MHC class II+ cells which occurs after NK depletion. These data Xp11.23. SSX-2 is expressed in a significant proportion of human show a potential role for IL-15 in enhancing antitumor therapies cancers including in melanomas, head and neck cancers, lympho- which incorporate CD4+ T cells (Fig. 1 previous page). mas, multiple myeloma, pancreatic cancer, prostate cancer, sarcomas, hepatocellular and colon carcinomas, but not in normal tissues. Therefore, SSX-2 is a promising target for T cell based adoptive immunotherapy of cancer. In an effort to develop TCRs Evaluation of CXCR3 and CCR5 Polymorphisms and Gene- to engineer peripheral blood lymphocytes (PBL) for tumor therapy, Expression as Predictive Biomarkers of Clinical Response to we isolated four HLA-A2 restricted TCRs from natural T cell Adoptive Therapy in Melanoma Patients clones generated from tumor-infiltrated lymph nodes from two Davide Bedognetti*w, Lorenzo Uccellini*, Ena Wang*, Mark E. melanoma patients seropositive for SSX-2 and whose tumor Dudleyz, Zoltan Pos*, Maria Libera Ascierto*, Valeria De expressed SSX-2. Retroviral vectors were constructed expressing Giorgi*, Hui Liu*, Jingou Chen*, Mario Roberto Sertoliw, TCR a and b chains incorporating 2A ribosomal skip peptide. PBL Francesco M. Marincola*, Steven A. Rosenbergz. *Department were transduced with SSX-2 TCRs and tested for peptide reactivity of Transfusion Medicine, CC, National Institutes of Health; and tetramer binding. PBL engineered with three of the four TCRs zSurgery Branch, NCI, National Institutes of Health, Bethesda, showed SSX-2: 41 to 49 (KASEKIFYV) peptide specific reactivity, MD; w Department of Oncology, Biology, Genetics, University of tumor cell recognition and tetramer binding. One of the TCR Genoa, Genoa, Italy. (TRAV14/DV*01, TRBV15*02-CB1) exhibited tetramer binding in Background: Adoptive cell therapy induces objective responses in both CD4 and CD8 cells, and this TCR was selected for further approximately 50% of patients with metastatic melanoma. The development. Analogous peptides homologous to SSX-2: 41 to 49 recruitment of T lymphocytes through CXCR3, CCR5-ligand are present in the other members of SSX family of proteins chemokines is critical for the development of immune-mediated (differing by only 1 or 2 amino acids) and peptide epitopes derived rejection. A common single nucleotide polymorphism of CXCR3 from SSX-3, 4, 5, 9 and 10 were recognized by the SSX-2: 41 to 49 (rs2280964) has been associated with variation in chemotactic TCR in co-cultures assay with peptide pulsed T2 cells at activity. CCR5 polymorphism D32 (a deletion of 32 bases encoding concentrations of >10 ng/mL while SSX-2 peptide was recognized a protein not expressed on cell surface), has been recently at <10 pg/mL. High levels of antigen specific interferon-g (IFN-g) correlated with poor prognosis in metastatic melanoma patients. secretion was observed following culture of TCR engineered PBL We postulated that polymorphisms of CXCR3, CCR5 genes may with several SSX-2+/HLA-A2+ tumor cell lines including influence the migration of tumor-infiltrating lymphocytes (TIL) on melanoma (938-A2 mel, SK MEL 37, T567A, 624, 1300), glioma tumor site and, eventually, the tumor regression. (U251), ovarian carcinoma (SKOV3), 293-A2 and COS-A2 cells Methods: One-hundred-forty-two TIL samples, belonging to 142 that were retrovirally transduced with SSX-2 gene. Co-culture of melanoma patients enrolled in consecutive adoptive therapy trials, TCR engineered PBL with SSX-2- and/or HLA-A2- cell lines were evaluated. Genotyping (rs2280964, D32 mutation) was produced only background levels of IFN-g. Based on these results, performed by sequencing. Gene-expression profiling of infused this TCR may be an attractive candidate for potential cancer gene TIL was assessed by Affymetrix Human Gene ST 1.0 array therapy. (CXCR3, 27 probes; CCR5, 30 probes). DNA/RNA data were correlated with each other, with clinical response. Results: No significant correlations between genotype, gene expression were detected, neither between CXCR3 polymorphisms, response. Surprisingly, CCR5D32 carriers (N = 25; heterozygous, In Vitro Generation of Multiantigen-Specific CD4+ and N = 24; homozygous, N = 1) had a better overall response (OR: CD8+ T Cells for Adoptive Immunotherapy CR, complete remission or PR, partial remission) compared to Anna Foerster, Verena Lasmanowicz, Olaf Brauns, Sven Kramer, wildtype patients (OR: 68% vs. 46%, respectively, P<0.05). The Ju¨ rgen Schmitz, Stefan Miltenyi, Georg Rauser, Mario under-expression of CXCR3, CCR5 genes was independently Assenmacher, Anne Richter. Miltenyi Biotec GmbH, Bergisch correlated with CR (P<0.05). Interestingly, the co-underexpres- Gladbach, Germany. sion of both genes was even more accurate in the prediction of CR: Adoptive transfer of T cell populations with specificities for several 28% (11/39) in CXCR3CCR5-low group compared to 5% (5/103) antigens is a promising strategy to treat cancer or prevent multiple in the other patients (P<0.0001). Moreover, the protein-prediction infections in immunocompromised patients. Here, we describe a model was also predictive of OR: 64%(28/44) in CXCR3CCR5-low protocol to generate multivirus-specific T cells, using pools of group, 44% (43/98) in the other patients (P<0.05).
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