scholarly journals Engagement of the ICOS pathway markedly enhances efficacy of CTLA-4 blockade in cancer immunotherapy

2014 ◽  
Vol 211 (4) ◽  
pp. 715-725 ◽  
Author(s):  
Xiaozhou Fan ◽  
Sergio A. Quezada ◽  
Manuel A. Sepulveda ◽  
Padmanee Sharma ◽  
James P. Allison
Keyword(s):  
Prostate Cancer ◽  
Monoclonal Antibody ◽  
Immune Responses ◽  
Tumor Cell ◽  
Cancer Patients ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Strong Support ◽  
Antitumor Effects ◽  
Tumor Cell Vaccines

Cytotoxic T lymphocyte antigen-4 (CTLA-4) blockade with a monoclonal antibody yields durable responses in a subset of cancer patients and has been approved by the FDA as a standard therapy for late-stage melanoma. We recently identified inducible co-stimulator (ICOS) as a crucial player in the antitumor effects of CTLA-4 blockade. We now show that concomitant CTLA-4 blockade and ICOS engagement by tumor cell vaccines engineered to express ICOS ligand enhanced antitumor immune responses in both quantity and quality and significantly improved rejection of established melanoma and prostate cancer in mice. This study provides strong support for the development of combinatorial therapies incorporating anti–CTLA-4 and ICOS engagement.

Autoimmunity in a Phase I Trial of a Fully Human Anti-Cytotoxic T-Lymphocyte Antigen-4 Monoclonal Antibody With Multiple Melanoma Peptides and Montanide ISA 51 for Patients With Resected Stages III and IV Melanoma

2005 ◽  
Vol 23 (4) ◽  
pp. 741-750 ◽  
Author(s):  
Kristin Sanderson ◽  
Ronald Scotland ◽  
Peter Lee ◽  
Dongxin Liu ◽  
Susan Groshen ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Immune Responses ◽  
T Lymphocyte ◽  
Mononuclear Cells ◽  
Cytotoxic T Lymphocyte ◽  
Peptide Vaccine ◽  
Disease Relapse ◽  
Peripheral Blood Mononuclear ◽  
Dose Cohort ◽  
Lymphocyte Antigen

Purpose Nineteen patients with high-risk resected stage III and IV melanoma were immunized with three tumor antigen epitope peptides from gp100, MART-1, and tyrosinase emulsified with adjuvant Montanide ISA 51 and received a fully human anti-cytotoxic T-lymphocyte antigen-4 (anti–CTLA-4) monoclonal antibody MDX-010. Each of three cohorts received escalating doses of antibody with vaccine primarily to evaluate the toxicities and maximum-tolerated dose (MTD) of MDX-010 with vaccine. MDX-010 pharmacokinetics and immune responses were secondary end points. Patients and Methods Peptide immunizations with MDX-010 were administered every 4 weeks for 6 months and then every 12 weeks for 6 months. A leukapheresis to obtain peripheral-blood mononuclear cells for immune analyses was performed before treatment and after the sixth vaccination. Patients were observed until relapse. Results Grade 3 gastrointestinal (GI) toxicity (diarrhea or abdominal pain) was observed in three patients in the highest dose cohort and one in the middle dose cohort who seemed to be autoimmune. That defined the MTD with vaccine on this schedule at 1 mg/kg. Of eight patients with evidence of autoimmunity, three have experienced disease relapse. Of 11 patients without autoimmune symptoms, nine have experienced disease relapse. Significant immune responses were measured by tetramer and enzyme-linked immunospot assays against gp100 and MART-1. Conclusion Dose-related autoimmune adverse events, predominantly skin and GI toxicities, were reversible. Patients mounted an antigen-specific immune response to a peptide vaccine when combined with a human anti–CTLA-4 antibody.

scholarly journals Identification of Ny-Eso-1 Epitopes Presented by Human Histocompatibility Antigen (Hla)-Drb4*0101–0103 and Recognized by Cd4+T Lymphocytes of Patients with Ny-Eso-1–Expressing Melanoma

2000 ◽  
Vol 191 (4) ◽  
pp. 625-630 ◽  
Author(s):  
Elke Jäger ◽  
Dirk Jäger ◽  
Julia Karbach ◽  
Yao-Tseng Chen ◽  
Gerd Ritter ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Immune Responses ◽  
Cancer Patients ◽  
T Lymphocyte ◽  
Tumor Antigens ◽  
Cytotoxic T Lymphocyte ◽  
Critical Role ◽  
Class Ii ◽  
Hla Class Ii ◽  
Hla Class Ii Alleles

NY-ESO-1 is a member of the cancer-testis family of tumor antigens that elicits strong humoral and cellular immune responses in patients with NY-ESO-1–expressing cancers. Since CD4+ T lymphocytes play a critical role in generating antigen-specific cytotoxic T lymphocyte and antibody responses, we searched for NY-ESO-1 epitopes presented by histocompatibility leukocyte antigen (HLA) class II molecules. Autologous monocyte-derived dendritic cells of cancer patients were incubated with recombinant NY-ESO-1 protein and used in enzyme-linked immunospot (ELISPOT) assays to detect NY-ESO-1–specific CD4+ T lymphocyte responses. To identify possible epitopes presented by distinct HLA class II alleles, overlapping 18-mer peptides derived from NY-ESO-1 were synthetized and tested for recognition by CD4+ T lymphocytes in autologous settings. We identified three NY-ESO-1–derived peptides presented by DRB4*0101–0103 and recognized by CD4+ T lymphocytes of two melanoma patients sharing these HLA class II alleles. Specificity of recognition was confirmed by proliferation assays. The characterization of HLA class II–restricted epitopes will be useful for the assessment of spontaneous and vaccine-induced immune responses of cancer patients against defined tumor antigens. Further, the therapeutic efficacy of active immunization using antigenic HLA class I–restricted peptides may be improved by adding HLA class II–presented epitopes.

scholarly journals Comparison of cytotoxic T lymphocyte responses against pancreatic cancer induced by dendritic cells transfected with total tumor RNA and fusion hybrided with tumor cell

2015 ◽  
Vol 240 (10) ◽  
pp. 1310-1318 ◽  
Author(s):  
Jiang Chen ◽  
Xiao-Zhong Guo ◽  
Hong-Yu Li ◽  
Di Wang ◽  
Xiao-Dong Shao
Keyword(s):  
Pancreatic Cancer ◽  
Immune Responses ◽  
Tumor Cell ◽  
Tumor Cells ◽  
T Lymphocyte ◽  
Tumor Antigens ◽  
Cytotoxic T Lymphocyte ◽  
Study Patient ◽  
Autologous Tumor ◽  
Ctl Responses

Pancreatic cancer (PC) is a deadly human malignancy. Dendritic cell (DC)-based immunotherapy with whole tumor antigens demonstrates potential efficiency in cancer treatment. Tumor RNA and tumor fusion hybrid cells are sources of whole tumor antigens for preparing DC tumor vaccines. However, the efficacy of these sources in eliciting immune responses against PC has not yet to be directly compared. In the present study, patient-derived PC cells and DCs were fused (DC–tumor hybrids) and primary cultured PC cell-derived total RNA was electroporated into autologous DCs (DC–tumor RNA). The antitumor immune responses induced by DC–tumor hybrids and DC–tumor RNA were compared directly. The results showed that both RNA and hybrid methodologies could induce tumor-specific cytotoxic T lymphocyte (CTL) responses, but pulsing DCs with total tumor RNA could induce a higher frequency of activated CTLs and T-helper cells than fusing DCs with autologous tumor cells. In addition, DC–tumor RNA triggered stronger autologous tumor cell lysis than DC–tumor hybrids. It could be concluded that DCs pulsed with whole tumor RNA are superior to those fused with tumor cells in priming anti-PC CTL responses. Electroporation with total tumor RNA may be more suitable for DC-based PC vaccination.

scholarly journals Antibody-modified reduced graphene oxide film for circulating tumor cell detection in early-stage prostate cancer patients

RSC Advances ◽  
2019 ◽  
Vol 9 (17) ◽  
pp. 9379-9385 ◽  
Author(s):  
Binshuai Wang ◽  
Yimeng Song ◽  
Liyuan Ge ◽  
Shudong Zhang ◽  
Lulin Ma
Keyword(s):  
Prostate Cancer ◽  
Graphene Oxide ◽  
Oxide Film ◽  
Tumor Cell ◽  
Cancer Patients ◽  
Reduced Graphene Oxide ◽  
Early Stage ◽  
Circulating Tumor Cell ◽  
Cell Detection ◽  
Reduced Graphene

We report the fabrication of an antibody-modified reduced graphene oxide film, which can be used to efficiently detect CTCs in PCa patients with PSA levels of 4–10 ng mL−1.

scholarly journals The 3′ CCACCA Sequence of tRNAAla(UGC) Is the Motif That Is Important in Inducing Th1-Like Immune Response, and This Motif Can Be Recognized by Toll-Like Receptor 3

2006 ◽  
Vol 13 (7) ◽  
pp. 733-739 ◽  
Author(s):  
Zhijun Wang ◽  
Li Xiang ◽  
Junjie Shao ◽  
Zhenghong Yuan
Keyword(s):  
Immune Responses ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Hepatitis B Surface Antigen ◽  
Toll Like Receptor ◽  
Anticodon Loop ◽  
T Helper ◽  
D Loop ◽  
Th 1 ◽  
Ctl Responses

ABSTRACT In this article, the immunogenicity of tRNA and the recognition of tRNA by Toll-like receptors (TLRs) are analyzed. Analyses of the effects of different tRNAAla(UGC) fragments (tRNAAla1-76 [corresponding to positions 1 through 76], tRNAAla26-76, tRNAAla40-76, tRNAAla62-76, tRNAAla1-70, tRNAAla26-70, tRNAAla40-70, and tRNAAla62-70) on the immune responses of hepatitis B surface antigen (HBsAg) were performed with BALB/c mice. Results show that tRNAAla1-76, tRNAAla26-76, tRNAAla40-76, and tRNAAla62-76 adjuvants not only induced stronger T helper (Th) 1 immune responses but also cytotoxic-T-lymphocyte (CTL) responses relative to tRNAAla1-70, tRNAAla26-70, tRNAAla40-70, and tRNAAla62-70 adjuvants in HBsAg immunization. A deletion of the D loop (tRNAAla26-76), anticodon loop (tRNAAla40-76), or TψC (tRNAAla62-76) loop of tRNAAla(UGC) does not significantly decrease the adjuvant characteristic of tRNAAla(UGC). However a deletion of the 3′-end CCACCA sequence (tRNAAla1-70, tRNAAla26-70, tRNAAla40-70, and tRNAAla62-70) of tRNAAla(UGC) significantly decreased the adjuvant characteristic in Th1 and CTL immune responses. Moreover, the recognitions of different tRNAAla(UGC) fragments by TLR3, TLR7, TLR8, and TLR9 were analyzed. Results show that a deletion of the 3′ CCACCA sequence of tRNAAla(UGC) significantly decreased the recognition by TLR3. We concluded that the 3′ CCACCA sequence of tRNAAla(UGC) is the important motif to induce Th1 and CTL responses and this motif can be effectively recognized by TLR3.

scholarly journals Tumor-specific CD8+ T lymphocytes derived from the peripheral blood of prostate cancer patients byin vitro stimulation with autologous tumor cell lines

2002 ◽  
Vol 98 (1) ◽  
pp. 57-62 ◽  
Author(s):  
Franck Housseau ◽  
Daniel A. Langer ◽  
Samuel D. Oberholtzer ◽  
Anitha Moorthy ◽  
Hyam I. Levitsky ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Lymphocytes ◽  
Tumor Cell ◽  
Cancer Patients ◽  
Cell Lines ◽  
Peripheral Blood ◽  
Autologous Tumor Cell ◽  
Autologous Tumor ◽  
Tumor Cell Lines ◽  
Cd8 T Lymphocytes

HPV16-specific cytotoxic T lymphocyte responses are detected in all HPV16-positive cervical cancer patients

2005 ◽  
Vol 96 (1) ◽  
pp. 92-102 ◽  
Author(s):  
Victor Valdespino ◽  
Clara Gorodezky ◽  
Vianney Ortiz ◽  
Andreas M. Kaufmann ◽  
Edgar Roman-Basaure ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Patients ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Lymphocyte Responses
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