Phase I Trial of Overlapping Long Peptides from a Tumor Self-Antigen and Poly-ICLC Shows Rapid Induction of Integrated Immune Response in Ovarian Cancer Patients
Paul Sabbatini,Takemasa Tsuji,Luis Ferran,Erika Ritter,Christine Sedrak,Kevin Tuballes,Achim A. Jungbluth,Gerd Ritter,Carol Aghajanian,Katherine M. Bell-McGuinn,Martee L. Hensley,Jason A. Konner,William P. Tew,David R. Spriggs,Eric W. Hoffman,Ralph Venhaus,Linda Pan,Andres M. Salazar,Catherine M. Diefenbach,Lloyd J. Old,Sacha Gnjatic +20 more
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The current study shows that NY-ESO-1 OLP vaccine is safe and rapidly induces consistent integrated immune responses (antibody, CD8+ and CD4+) in nearly all vaccinated patients when given with appropriate adjuvants.Abstract:
Purpose: Long peptides are efficiently presented to both CD4 + and CD8 + T cells after intracellular processing by antigen-presenting cells. To investigate the safety and in vivo immunogenicity of synthetic overlapping long peptides (OLP) from a human tumor self-antigen, we conducted a phase I clinical trial with OLP from cancer-testis antigen NY-ESO-1 in various adjuvant combinations. Experimental Design: Twenty-eight patients with advanced ovarian cancer in second or third remission were enrolled sequentially in three cohorts and received at least one vaccination. Patients in Cohort 1 ( n = 4) received 1.0 mg OLP, Cohort 2 ( n = 13) received OLP in Montanide-ISA-51, and Cohort 3 ( n = 11) received OLP + 1.4 mg Poly-ICLC in Montanide-ISA-51 on weeks 1, 4, 7, 10, and 13. Humoral and cellular responses were evaluated by standardized immunomonitoring techniques (ELISA, ELISPOT assay, intracellular cytokine staining, and tetramer staining). Results: The vaccine was generally well tolerated with injection site reactions and fatigue that resolved. NY-ESO-1–specific antibody and CD8 + T cells were undetectable after vaccination with OLP alone, but were found in 6 of 13 (46%) and 8 of 13 (62%) patients, respectively, after vaccination with OLP+Montanide, and in 10 of 11 (91%) and 10 of 11 (91%) patients, respectively, after vaccination with OLP+Montanide+Poly-ICLC. NY-ESO-1–specific CD4 + T cells were detected in all patients with greater frequency and polyclonality when Montanide-ISA-51 was used for vaccination. Inclusion of Poly-ICLC as an adjuvant further accelerated the induction of NY-ESO-1–specific immune responses. Conclusions: The current study shows that NY-ESO-1 OLP vaccine is safe and rapidly induces consistent integrated immune responses (antibody, CD8 + and CD4 + ) in nearly all vaccinated patients when given with appropriate adjuvants. Clin Cancer Res; 18(23); 6497–508. ©2012 AACR .read more
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Madhav V. Dhodapkar,Mario Sznol,Biwei Zhao,Ding Wang,Richard D. Carvajal,Mary Louise Keohan,Ellen Chuang,Rachel E. Sanborn,Jose Lutzky,John D. Powderly,Harriet M. Kluger,Sheela Tejwani,Jennifer Green,Venky Ramakrishna,Andrea Crocker,Laura Vitale,Michael Yellin,Thomas P. Davis,Tibor Keler +18 more
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References
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Simultaneous Humoral and Cellular Immune Response against Cancer–Testis Antigen NY-ESO-1: Definition of Human Histocompatibility Leukocyte Antigen (HLA)-A2–binding Peptide Epitopes
Elke Jäger,Yao-Tseng Chen,Jan W. Drijfhout,Julia Karbach,Mark Ringhoffer,Dirk Jäger,Michael Arand,Hisashi Wada,Yuji Noguchi,Elisabeth Stockert,Lloyd J. Old,Alexander Knuth +11 more
TL;DR: It is shown that antigen-specific humoral and cellular immune responses against human tumor antigens may occur simultaneously in a single patient and a general strategy is provided for identifying the CTL-recognizing peptides of tumor antIGens initially defined by autologous antibody.
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Recombinant NY-ESO-1 protein with ISCOMATRIX adjuvant induces broad integrated antibody and CD4(+) and CD8(+) T cell responses in humans.
Ian D. Davis,Weisan Chen,Heather Jackson,Phillip Parente,Phillip Parente,Mark Shackleton,Mark Shackleton,Mark Shackleton,Wendie Hopkins,Qiyuan Chen,Nektaria Dimopoulos,Tina Luke,Roger Murphy,Andrew M. Scott,Andrew M. Scott,Eugene Maraskovsky,Grant A. McArthur,Duncan MacGregor,Sue Sturrock,Tsin Yee Tai,Simon Green,Andrew Cuthbertson,Darryl W. Maher,Lena Miloradovic,Susan V. Mitchell,Gerd Ritter,Achim A. Jungbluth,Yao-Tseng Chen,Yao-Tseng Chen,Sacha Gnjatic,Eric W. Hoffman,Lloyd J. Old,Jonathan Cebon,Jonathan Cebon +33 more
TL;DR: In an unplanned analysis, vaccinated patients appeared to have superior clinical outcomes to those treated with placebo or protein alone, suggesting the vaccine is safe and highly potent immunologically.
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Immunohistochemical analysis of NY‐ESO‐1 antigen expression in normal and malignant human tissues
Achim A. Jungbluth,Yao-Tseng Chen,Elisabeth Stockert,Klaus J. Busam,Denise Kolb,Kristin Iversen,Keren Coplan,Barbara Williamson,Nasser K. Altorki,Lloyd J. Old +9 more
TL;DR: A method for the immunochemical detection of NY‐ESO‐1 in paraffin‐embedded tissues has been developed and used to define the expression pattern of NY-ESO-1 in normal tissues and in a panel of human tumors.
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Induction of tumor-specific CD4+ and CD8+ T-cell immunity in cervical cancer patients by a human papillomavirus type 16 E6 and E7 long peptides vaccine.
Marij J. P. Welters,Gemma G. Kenter,Sytse J. Piersma,Annelies P G Vloon,Margriet J. G. Löwik,Dorien M A Berends-van der Meer,Jan W. Drijfhout,A. Rob P. M. Valentijn,Amon R. Wafelman,Jaap Oostendorp,Gert Jan Fleuren,Rienk Offringa,Cornelis J. M. Melief,Sjoerd H. van der Burg +13 more
TL;DR: The HPV16 E6 and E7 synthetic long peptides vaccine is highly immunogenic, in that it increases the number and activity of HPV16-specific CD4+ and CD8+ T cells to a broad array of epitopes in all patients.
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CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefit
Jianda Yuan,Sacha Gnjatic,Hao Li,Sarah Powel,Humilidad F. Gallardo,Erika Ritter,Geoffrey Y. Ku,Achim A. Jungbluth,Neil H. Segal,Teresa S. Rasalan,Gregor Manukian,Yinyan Xu,Ruth Ann Roman,Stephanie L. Terzulli,Melanie Heywood,Evelina Pogoriler,Gerd Ritter,Lloyd J. Old,James P. Allison,Jedd D. Wolchok +19 more
TL;DR: New York-ESO-1-specific T cell responses increased in frequency and functionality during anti-CTLA-4 treatment, revealing a polyfunctional response pattern of IFN-γ, MIP-1β and TNF-α.
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