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Abstracts J Immunother Volume 33, Number 8, October 2010 cellular stress by chemotherapeutic drug (cisplatin) following which the cells were sensitized to mortalin shRNA induced apoptosis. Based on the data, a model for mortalin and p53 interactions in cancer (physiologically a stressed condition) cells and use of mortalin-shRNA for selective killing of cancer cells is documented. Since p53 mutations are found in more than 80% of the tumors, mortalin shRNA is proposed as an effective cancer cell specific therapeutic tool. Immunomodulation of T Cell-Mediated Activity by Cancer Stem Cells Isolated from Human Glioblastoma Cristina Maccalli*, Tiziano Di Tomaso*, Ena Wangw, Stefania Mazzoleniz, Gloria Sovena*, Rossella Galliz, Francesco M. Marincolaw, Giorgio Parmiani*. *Unit of Immuno-biotherapy of Solid Tumors; zNeural Stem Cell Unit, San Raffaele Foundation Scientific Institute, Milan, Italy; w Department of Transfusion Medicine, National Institutes of Health, Bethesda, MD. The main objectives of our study was to assess whether cancer stem cells (CSCs) isolated from glioblastoma multiforme (GBM) can represent a target for immunotherapeutic treatment for GBM patients. We have previously reported that GBM CSC have a low immunogenic profile, eliciting mostly TH2-mediated responses in autologous settings and inhibit allogeneic T cell proliferation compared to their FBS-cultured non-CSC (FBS tumor cells) pairs (Di Tomaso et al, 2010). This immune-inhibitory activity mediated by GBM CSCs was independent on the secretion of TGFb-1 or 2, that were preferentially down-modulated in CSC lines, nor on IL-10 and IL-13 that were undetectable in the supernatant of these cell lines. We found that both CSCs and FBS tumor cells expressed immune response inhibitory molecules, such as CTLA-4, PD-1 and PDL-1. Furthermore, a differential gene signature that was confirmed at the protein level for some immunological-related molecules was also found between CSC and FBS lines. This latter analysis provided information of some candidate molecules associated with CSCs that we are functionally investigating. A candidate negative immunoregulatory molecule is represented by the indoleamine 2,3-dioxygenase (IDO), a molecule implicated in the generation of immune tolerance. By RT-PCR we detected the expression of the mRNA of this molecule in both CSCs and FBS tumor cell lines with high increase following IFN-g treatment of the cells. We assessed the functional activity of IDO determining by a colorimetric assay IDO-mediated tryptophan catabolism in culture supernatants, and, notably, in some cases a higher activity was associated with IFN-g treated CSCs but not with their FBS tumor counterparts. Interestingly, IDO-mediated activity was inhibited by treatment of these cells with the specific inhibitor 1-Methyl Tryptophane (1-MT). Thus, these results indicate that IDO can represent a candidate molecule mediating immunosuppressive functions of GBM CSCs. We are currently carrying out experiments to demonstrate whether the blocking of IDO in GBM cells can increase the efficiency in raising CSC-specific T cell responses. Altogether, these results indicate a lower immunogenicity and higher suppressive activity of GBM CSC compared to autologous FBS lines and the need to identify immunomodulatory agents that can efficiently restore the expression of immunogenic molecules on CSCs. Anti-Tumor Efficacy of MVA-BN s -HER2 is Mediated by HER-2-specific Th1-immunity and the Control of Tumor- Induced Immunosuppression Stefanie J. Mandl, Ryan Rountree, Katie Dalpozzo, Lisa Do, John Lombardo, Peter Schoonmaker, Thierry Giffon, Reiner Laus, Alain Delcayre. BN-ImmunoTherapeutics, Mountain View, CA. MVA-BN s -HER2 is a candidate immunotherapy product for the treatment of HER-2-positive breast cancer that has shown biological activity in Phase I clinical trials (Legrand et al. Abstract iSBTc 2010). MVA-BN s -HER2 is derived from the highly attenuated vector MVA-BN s and encodes a modified form of the HER-2 protein, referred to as HER2. HER2 comprises of the extracellular domains of HER-2 and has been modified to encode two universal T-helper cell epitopes from tetanus toxin. We have previously demonstrated in pre-clinical models that both adaptive and innate mechanisms contribute to the anti-tumor activity of MVA-BN s -HER2. Here we further explore the adaptive arm of immune responses elicited by treatment with MVA-BN s -HER2 and present insight into the mechanism of action of MVA-BN s - HER2-induced anti-tumor activity in a murine model of experimental pulmonary metastasis (CT26-HER-2). Treatment with MVA-BN s -HER2 induced potent Th1-dominated anti-HER-2 antibody and T cell responses in mice. More importantly, immunotherapy consisting of a single dose of MVA-BN s -HER2 exerted significant anti-tumor efficacy which was accompanied by a high density of CD8+ T cells in the tumor. Phenotypic analysis of the tumor infiltrating lymphocytes (TIL) revealed a population of highly activated, HER-2-specific, CD8+CD11c+ T cells. Notably, MVA-BN s -HER2 treatment was able to override the immunosuppressive responses generated by the growing tumor by reducing the frequency of Treg cells, thus resulting in a significant improvement in the ratio of CD4 and CD8 T effector cells to Treg cells in the tumor. In contrast, treatment of tumor-bearing mice with HER2 protein formulated in Complete Freud’s Adjuvant (CFA) induced a strong Th2-biased immune response to HER-2. However, this did not lead to significant infiltration of the tumor by CD8+ T cells, the reduction of the frequency of Treg cells, or antitumor efficacy. The respective roles of CD8, CD4, or CD25 positive T cells in the anti-tumor activity of MVA-BN s -HER2 and in this tumor model per se were further investigated by in vivo depletion of specific T cell populations. Depletion of CD8+ cells strongly reduced the anti-tumor activity of MVA-BN s -HER2, confirming that CD8 T cells are required for protection. Depletion of CD4+ or CD25+ cells confirmed that tumor-induced Treg cells promote tumor growth. Taken together, our data demonstrate that MVA- BN s -HER2 controls tumor growth through a combination of the induction of Th1-biased HER-2-specific immune responses and the control of tumor-induced Treg cells. Allogeneic Transplantation and Tumor-Specific Vaccination Promote Infiltration and Eradication of Advanced Prostate Cancer Teresa Manzo*wz, Rodrigo Hess Michelini*w, Massimo Freschiy, Maurilio Ponzoniy, Elizabeth SimpsonJ, Matteo Bellone*z, Anna Mondino*w. *Program in Immunology and Bio-Immuno-gene therapy of Cancer; w Lymphocyte Activation Unit; zVita-Salute San Raffaele University; yDepartment of Pathology; zCellular Immunology Unit, San Raffaele Scientific Institute, Milano, Italy; JDepartment of Immunology, Hammersmith Hospital, Imperial College, London, United Kingdom. Central and peripheral mechanisms of tolerance hinder protective immunity against tumor. We recently reported that non myeloablative allogeneic transplantation and tumor-specific vaccination overcome tumor-specific tolerance allowing acute rejection of spontaneous prostate cancer and prolonging disease-free survival (Hess Michelini, Cancer Res. 2010). This was distinctively due to the concomitance of high affinity tumor- and minor histocompatibility (H) antigen-specific T cells. To envisage clinical translation of this strategy we evaluated its efficacy in the context of inevitable multiple minor H antigen disparities generally observed between donor/recipient pairs. In spite of donor T cells infiltrating normal tissues and of clinical signs of graft versus host responses, prostate cancer rejection was also found in this setting. Rather than providing reciprocal T cell help at the time of priming in peripheral lymphoid organs, concomitant minor H antigen-and tumor specific T cell responses allowed potent tumor infiltration. Confocal images showed that in recipients of minor H antigen mismatched lymphocytes CD3+ and CD8+ T cells were found juxtaposed to prostate epithelial cells with higher expression of MHC class I molecules and of minor H antigens. This was paralleled by the enrichment of IFN-g, perforin and granzyme B mRNA, and 902 | www.immunotherapy-journal.com r 2010 Lippincott Williams & Wilkins
J Immunother Volume 33, Number 8, October 2010 Abstracts caspase 3+ cells, which reflected tumor rejection. Together our data indicate that non-myeloablative allotransplantation followed by tumor-specific vaccination promotes potent graft versus tumor responses by enabling massive tumor infiltration and leading to the rejection of advanced prostate cancer. Thus, this combined strategy should be attempted for the cure of patients with solid tumors. Ipilimumab Monotherapy in Melanoma Patients with Brain Metastases-Update of a Phase II Study K. Margolin*, O. Hamidw, D. McDermottz, I. Puzanovy, M. SznolJ, J.I. Clarkz, J. Wolchok#, F.S. Hodi**, K. Hellerww, D. Lawrencezz. *University of Washington, Seattle, WA; w The Angeles Clinic and Research Institute, Santa Monica, CA; zBeth Israel Deaconess Medical Center; **Dana-Farber Cancer Institute; zzMassachusetts General Hospital, Boston, MA; yVanderbilt- Ingram Cancer Center, Nashville, TN; JYale Cancer Center, New Haven, CT; zLoyola University Medical Center, Maywood, IL; #Memorial Sloan-Kettering Cancer Center, New York, NY; wwBristol-Myers Squibb Company, Plainsboro, NJ. We present results from a Phase II trial (CA184-042) to assess the anti-CTLA-4 antibody ipilimumab (IPI) safety and activity in advanced melanoma patients (pts) with brain metastases (mets). Pts were corticosteroid-free (Arm A; n = 51) or required a stable dose of corticosteroid for symptoms or edema (Arm B; n = 21). All pts had measurable brain mets with at least one lesion 0.5 to 3 cm or Z2 lesions 0.3 to 3 cm in diameter. Prior treatment of non-index lesions with whole brain (WBRT) and/or stereotactic radiotherapy (SRT) was allowed. IPI was given IV, 10 mg/kg, every 3wks for 4 doses; responding or stable pts were to receive maintenance IPI 10 mg/kg, every 12 weeks. Tumors were assessed (modified WHO criteria) every 6 weeks; objective response (OR) and stable disease (SD) as best response required confirmation at 4 weeks. In Arm A, 4 had prior SRT and 17 prior WBRT (no pt had both); in Arm B, 5 had prior WBRT. Considering all lesions (global response of brain and extracranial tumor) at Wk12, 5/51 pts in Arm A had a partial response (PR) and 4/51 pts had SD [global disease control rate (DCR) 17.6% (95% CI 8.4-30.9)]. For brain alone, 8 pts in Arm A had PR and 4 SD [DCR 23.5% (95% CI 12.8-37.5)]. Starting from the Wk12 landmark, response durations ranged from 3 to 17+ months and duration of SD from 1 to 11+ months. Median progression-free survival (PFS) was 1.4 months (95% CI 1.2-2.5). In Arm B, pts achieved global PR (n = 1), PR in brain (n = 1), SD in brain (n = 1) and PR (n = 1) in non-CNS tumor with a median PFS of 1.2 months (95% CI 1.2-1.3). CNS AEs were similar regardless of steroid use in pts in Arm B: CNS AEs of any grade occurred in 39/51 pts (76.5%) (16 Grade 3 to 4; 31.4%) in Arm A, and in 14/21 pts (66.7%) (7 Grade 3 to 4; 33.3%) in Arm B. The most common events (>10% pts) were headache, dizziness, and seizures; all attributed to tumor. There was no association between brain edema or cerebral hemorrhage and OR. The frequency and distribution of autoimmune AEs outside of the CNS were similar to all other experience with this dose and schedule of IPI. In conclusion, IPI treatment appears to be similarly active against advanced melanoma brain mets and non-CNS mets. IPI was well tolerated with no unique toxicities in melanoma pts with brain mets; pts on low doses of corticosteroids may also benefit from treatment with IPI. Clinical and Immunological Response in Castration-Resistant Prostate Cancer Patients Treated with an Epidermal Growth Factor (EGF)-Based Vaccine Zaima Mazorra*, Xitlally Popa*, Beatriz García*, Camilo Rodríguez*, Jorge Garcíaw, Antonio Bouzów, Joaquín Gonzálezz, Karla Fuentes*, Zuyen González*, Carmen Viada*, Tania Crombet*. *Clinical Research Direction, Center of Molecular Immunology; w National Institute of Radiobiology and Oncology; zHermanos Ameijeiras Hospital, Havana, Cuba. EGF is a potent growth factor that is believed to enhance the proliferation of cancer cells. Recently, it was reported that 100% of castration-refractory prostate tumors overexpress the Epidermal Growth Factor Receptor (EGFR). We have developed a new active specific immunotherapy based on EGF deprivation. In this study we characterize the humoral and clinical response in advanced prostate cancer patients included in an ongoing Phase II clinical trial. Castration-resistant metastatic prostate cancer patients were randomized to receive the EGF vaccine or best supportive care. At least two vaccinations were given before the first line of chemotherapy treatment (mitoxantrone), with subsequent monthly vaccination after concluding chemotherapy. The primary end points were immunogenicity and safety. A subset of patients was studied for immunological response. With this schedule of treatment, anti-EGF IgG antibody titers were more than 20 times higher than those previously obtained, without any increase in adverse events. Ninety-six percent of vaccinated patients developed a good antibody response (GAR), while none of the controls did. Notably, 50% of patients were classified as very good antibody responders (SGAR). The global immune response was not affected with chemotherapy treatment. On the other hand, 41% of evaluated patients showed an immunodominant antibody response against the central region on the EGF molecule (loop B). A trend to better survival was found for vaccinated patients that showed an immunodominance by the loop B. Concerning to clinical response, 104 patients were evaluated. There was a trend to an increased survival for vaccinated patients (median = 17.1 mo) compared with controls (median = 10.13 mo), without a significant change in PSA levels. The survival advantage for vaccinated patients compared with controls was statistically significant in the subgroup of patients with more undifferentiated tumors. In summary, this study has shown that combination of EGF vaccination at high dose, with chemotherapy is feasible and well tolerated in castrationresistant prostate cancer patients. Most patients developed high anti- EGF antibody titers and immunodominance toward loop B seems to be associated with clinical benefit. In poor prognostic patients, vaccination was associated with increased survival. The High-Dose Aldesleukin (HD IL-2) ‘‘Select’’ Trial in Patients with Metastatic Renal Cell Carcinoma (mRCC) D. McDermott*, M. Ghebremichaelw, S. Signorettiw, K. Margolinz, J. Clarky, J. SosmanJ, J. Dutcherz, T. Logan#, L. Appleman**, M. Atkins*. *Beth Israel Deaconess Medical Center; w Dana Farber Cancer Institute, Boston, MA; zUniversity of Washington, Seattle, WA; yLoyola University Medical Center, Chicago, IL; JVanderbilt University Medical Center, Nashville, TN; zMontefiore Medical Center, New York, NY; #Indiana University, Indianapolis, IN; **University of Pittsburgh Medical Center, Pittsburgh, PA. Background: HD IL-2 received FDA approval for mRCC in 1992, producing a 14% major response (CR+PR) rate and durable remissions in Phase II trials. Retrospective studies suggested that tumor features could predict for benefit (Atkins et al, Clin Cancer Res 2003). The Cytokine Working Group conducted this prospective trial to identify patients (pts) likely to respond to HD IL-2. Methods: In this multicenter, prospective study pts with histologically confirmed mRCC, ECOG PS 0-1 and adequate organ function received HD IL-2. The primary endpoint of the study was to determine if the major response rate (RR) of pts with ‘‘good’’ predictive features was significantly higher than a historical, unselected population. All pts were consented to provide archived tumor tissue that would be used for pathology risk classification. Results: One hundred twenty eligible pts enrolled between November 2007 and July 2009. Seventy-two percent had ECOG PS 0, 71% were MSKCC intermediate risk, 96% had clear cell (cc) RCC and 99% had prior nephrectomy. There were 2 treatmentrelated deaths. At the time of this analysis the investigator assessed RR was 28% (34/120) (7 CR, 27 PR) and was significantly greater than the historical RR (95% CI = 21%-37%, P = 0.0016). r 2010 Lippincott Williams & Wilkins www.immunotherapy-journal.com | 903
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