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Abstracts J Immunother Volume 33, Number 8, October 2010 progression was 5.3 months and median tumor-specific survival time was 15.6 months. Interestingly, studies of much larger groups of patients showed same PFS times with sorafenib or IFN-alpha, however with side-effects that are much greater. Immune monitoring revealed that vaccine-induced T cell responses could be detected in a majority of the patients with high responses to vaccine lysates which increased in 9 patients during vaccination. The majority of patients acquired increased effector T cell reactivity to several surrogate peptides that were derived from shared tumor-associated antigens. Surprisingly, a statistical significant decrease of natural Tregs was also observed in these patients during vaccination. Conclusion: The feasibility of this vaccine study at low cost, saving time and logistics-alongside low toxicity and immunestimulatory potential supports further evaluation in combination therapies and as adjuvant therapy in patients with minimal residual disease. Antibody Response Following Immunotherapy Identifies Novel Antigens that are Expressed by Circulating Tumor Cells in Men with Hormone-Refractory Prostate Cancer Sachin Puri*, James A. Thompson*, Janet C. Siebertw, Tarsem L. Moudgil*, Daniel Haley*, Christian H. Poehlein*, Edwin Walker*, Nathalie Sacksz, Kristen Hegez, Hong Ming Hu*y, Carlo Bifulco*, Walter J. Urba*, Brendan Curti*, Bernard A. Fox*J. *Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer Center; Departments of yRadiation Oncology; JMolecular Microbiology and Immunology, OHSU, Portland, OR; w CytoAnalytics, Denver, CO; zCell Genesys Inc., South San Fransisco, CA. A major obstacle to monitoring the immune response to immunotherapy is the wide spectrum of potential targets the immune response may recognize. Even vaccination with peptide may lead to epitope spreading against an unrelated or unknown tumor antigen. Given these possibilities, how is it possible to study the immune response? We hypothesize that development of a strong T cell response will lead to the generation of a B cell response against the same antigen. Therefore, identification of a new antibody response following immunotherapy may provide a surrogate for generation of an anti-tumor T cell response. To begin to address this hypothesis a protein array (8217 human proteins spotted in duplicate, Invitrogen) was used to assess the spectrum of antibodies generated by immunotherapy. The Phase I/II clinical trial randomized patients to GVAX immunotherapy (two prostate cancer cell lines that secrete GM-CSF, Cell Genesys Inc.) alone or in combination with nonmyeloablative chemotherapy and adoptive transfer of PBMC. Pre and week 11 aphereses were obtained to elutriate monocytes and cryopreserve PBMC for immune monitoring. Comparing pre and week 11 sera generated a top 50 ‘‘hit’’ list of proteins recognized by a strong post-treatment antibody response in 2 or more patients. Next we sought to determine whether these genes were expressed by the patient’s tumor. Since no tumor biopsies were available, a method was developed to enumerate circulating tumor cells (CTC) in cryopreserved blood samples (Cell Search, Vedidex). We subsequently FACS sorted CTC, isolated and amplified RNA and performed RT-PCR for three genes, not previously described as tumor-associated antigens, that were identified by a strong post-treatment antibody response. Expression of these three genes was confirmed in pretreatment CTC, documenting that the immune response was targeting a potentially relevant target. Current experiments are evaluating whether a T cell response developed against the specified antigens. In conclusion, this strategy combines protein array and CTC analysis to provide an innovative approach to identify an immune response against previously undescribed targets. We predict this approach will help explain the mechanism of action of successful immunotherapy. Supported by The Prostate Cancer Foundation, DAMD PC02009, Robert W. Franz and the Chiles Foundation. Immunological Findings in a Phase II Immunotherapy Study Using Allogeneic Lung Cancer Cells Modified to Express Alpha(1,3)Gal Epitopes in Patients with Advanced Non- Small Cell Lung Cancer Gabriela R. Rossi*, Nicholas N. Vahanian*, John C. Morrisw, Anatoli Malyguinez, Susan Stroblz, Lucinda Tennant*, Jay Ramsey*, Charles J. Link*. *Tumor Immunology, NewLink Genetics, Ames, IA; w Metabolism Branch, NCI, Bethesda, MD; zCMI, SAIC, Frederick, MD. Alpha(1,3)-galactose (aGal) epitopes are highly immunogenic in man. In animal models, vaccination with aGal expressing allogeneic tumor cells induced tumor rejection and improved survival. In a phase I/II trial immunotherapy study, we evaluated the safety and immunogenicity of vaccination with allogeneic human lung cancer cells genetically modified to express aGal epitopes (HyperAcute s -HAL) vaccine. The immunological monitoring consisted of testing for anti-aGal Ab and anti-CEA Ab by ELISA. HAL vaccines express cell surface CEA. The cellular immunological response was evaluated by ELISPOT (IL-5 and IFN-g). Serum samples were collected before and after immunization at several time points. PBMC were collected before immunization, after patients receive at least 4 and 8 vaccines. PBMC were co-cultured with autologous DC pulsed with apoptotic/necrotic tumor cells from 4 NSCLC cell lines, three of which were the parental cell lines used to generate HAL vaccine. The fourth cell line that was not part of the HAL vaccine. As expected all patients had anti-aGal Ab before immunization. After immunization all patients responded increasing the anti-aGal Ab 2-to 100 folds. Preliminary analysis suggests that maintaining the anti-aGal Ab levels after immunization might be a correlative biological marker with survival. On the other hand data suggests that the fold increased in the anti-aGAL Ab had no apparent correlation with better survival. Thirty one patients were tested for the presence of anti-CEA Ab and 19 patients responded with significant increased anti-CEA Ab values after immunization. Analysis of the overall survival of patients analyzed suggests no correlation in patients responding increasing the anti-CEA Ab compared to patients with no change in the anti-CEA Ab levels. We detected vaccine induced IFN-g production after immunization in 13 patients out of 18 patients evaluated. Data indicates that IFN-g response correlates with favorable overall survival. The majority of the patients tested have detectable IL-5 reactivity induced after vaccination. Patients responding with higher levels of IFN-g and IL-5 also showed reactivity to H522, a lung cancer cell line non-component of HAL, suggesting that reactivity to shared tumor antigens might be induced after vaccination with Hyper- Acute vaccines to patient’s own tumor cells. In conclusion data suggest that cytokines induction after vaccination and the persistence but not the fold increased in the anti-aGal values correlated with better survival in tested patients. Exosome-targeting of Tumor Antigens Expressed by MVA-BN s -PRO Improves Antigen Immunogenicity and Enhances Anti-Tumor Efficacy Ryan Rountree, Stefanie Mandl, Katie Dalpozzo, John Lombardo, Lisa Do, Peter Schoonmaker, Reiner Laus, Alain Delcayre. BN-ImmunoTherapeutics, Mountain View, CA. Exosomes are small, 50 to 100 nm diameter vesicles secreted by most cell types. They have become the subject of increasing interest due to studies demonstrating activating effects of exosomes on immune cells through several different mechanisms. Furthermore, the immunogenicity of antigens can be improved when targeted to localize to exosomes. 1 This targeting can be achieved by engineering in-frame fusions of antigens with the C1C2 domain of a protein naturally localized to exosomes called Lactadherin. MVA-BN s -PRO is a candidate immunotherapy product for the treatment of prostate cancer that has shown biological activity in Phase I clinical trials (McLeod et al. Abstract iSBTc 2010). MVA- BN s -PRO encodes two transgenic antigens, prostatic acid 908 | www.immunotherapy-journal.com r 2010 Lippincott Williams & Wilkins
J Immunother Volume 33, Number 8, October 2010 Abstracts phosphatase (PAP) and prostate-specific antigen (PSA), and is derived from a clonal isolate of the highly attenuated Modified Vaccinia Ankara virus stock known as MVA-BN s . To test if exosome-targeting would improve the immunogenicity of PAP and PSA, two additional versions of the vector were produced, targeting either PAP (MVA-BN s -PAP-C1C2) or PSA (MVA- BN s -PSA-C1C2) to exosomes, while leaving the second transgene untargeted. Treatment of mice with MVA-BN s -PAP-C1C2 led to a striking increase in the immune response against PAP. Anti-PAP antibody titers developed more rapidly and reached levels that were 10 to 100-fold higher than mice treated with MVA-BN s -PRO. Furthermore, treatment with MVA-BN s -PAP-C1C2 increased the frequency of anti-PAP T cells 5-fold compared to treatment with MVA-BN s -PRO. These improvements translated into a greater frequency of tumor rejection in a PAP-expressing solid tumor model. Likewise, treatment with MVA-BN s -PSA-C1C2 increased the antigenicity of PSA as compared to treatment with MVA- BN s -PRO, but to a lesser extent than that of targeting PAP to exosomes. Treatment with MVA-BN s -PSA-C1C2 resulted in significant anti-tumor efficacy in a PSA-expressing tumor model, with a trend of improved efficacy compared to MVA-BN s -PRO. These experiments confirm that targeting antigen localization to exosomes is a viable approach for improving the therapeutic potential of MVA-BN s -PRO in humans. Reference 1. Delcayre A, et al. Blood Cells Mol Dis. 2005;35:158. Introduction: The field of cancer vaccines has dramatically moved forward. However, the identification of biomarkers for selecting patients adequate for cancer vaccination would be pivotal for further development of this field. To identify reliable biomarkers, we characterized gene expression profiles (transcriptome) in patients with advanced prostate cancer undergoing the personalized peptide vaccination. Methods: Gene expression profiles were characterized by the DNA microarray technology (Illumina; total 30,000 probes) in PBMC from patients that showed better or worse responses to the peptide vaccination (survival time > 900 or
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