Quantitating Therapeutically Relevant T-Cell Responses to Cancer Vaccines

Hobeika, Amy; Clay, Timothy M.; Mosca, Paul J.; Lyerly, H. Kim; Morse, Michael A.

doi:10.1615/critrevimmunol.v21.i1-3.190

Cited by 15 publications

(7 citation statements)

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“…To assess CD4+ and CD8+ T cell responses, PMBC samples from individual patients were assayed for IFN-γ and tumor necrosis factor alpha (TNF-α) expression using a BD Accuri™ C6 Flow Cytometer and intracellular cytokine staining methods previously described [35,36]. Briefly, 10 6 PBMC cells/well were incubated 6 hours with 2.0 µg/ml CEA peptide pool, 2.0 µg/ml SIV nef negative control peptide pool, or media alone.…”

Section: Methodsmentioning

confidence: 99%

Extended evaluation of a phase 1/2 trial on dosing, safety, immunogenicity, and overall survival after immunizations with an advanced-generation Ad5 [E1-, E2b-]-CEA(6D) vaccine in late-stage colorectal cancer

Balint

Gabitzsch

Rice

et al. 2015

Cancer Immunol Immunother

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A phase 1/2 clinical trial evaluating dosing, safety, immunogenicity, and overall survival on metastatic colorectal cancer (mCRC) patients after immunotherapy with an advanced generation Ad5 [E1-, E2b-]-CEA(6D) vaccine was performed. We report our extended observations on long-term overall survival and further immune analyses on a subset of treated patients including assessment of cytolytic T cell responses, T-regulatory (Treg) to T-effector (Teff) cell ratios, flow cytometry on peripheral blood mononuclear cells (PBMC), and determination of HLA-A2 status. An overall survival of 20% (median survival of 11 months) was observed during long-term follow-up and no long-term adverse effects were reported. Cytolytic T cell responses increased after immunizations and cell-mediated immune (CMI) responses were induced whether or not patients were HLA-A2 positive or Ad5 immune. PBMC samples from a small subset of patients were available for follow-up immune analyses. It was observed that the levels of carcinoembryonic antigen (CEA) specific CMI activity decreased from their peak values during follow-up in 5 patients analyzed. Preliminary results revealed that activated CD4+ and CD8+ T cells were detected in a post immunization sample exhibiting high CMI activity. Treg to Teff cell ratios were assessed and samples from 3 of 5 patients exhibited a decrease in Treg to Teff cell ratio during the treatment protocol. Based upon the favorable safety and immunogenicity data obtained, we plan to perform an extensive immunologic and survival analysis on mCRC patients to be enrolled in a randomized/controlled clinical trial that investigates Ad5 [E1-, E2b-]-CEA(6D) as a single agent with booster immunizations.

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Section: Methodsmentioning

confidence: 99%

Extended evaluation of a phase 1/2 trial on dosing, safety, immunogenicity, and overall survival after immunizations with an advanced-generation Ad5 [E1-, E2b-]-CEA(6D) vaccine in late-stage colorectal cancer

Balint

Gabitzsch

Rice

et al. 2015

Cancer Immunol Immunother

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“…In general, the precise mechanisms leading to CTL-mediated tumor regression in vivo remain to be fully elucidated and may reflect both direct (lytic) and indirect (nonlytic or cytokine-based) pathways (6,7,(13)(14)(15)(16)(17). If CTL do mediate tumor regression in vivo by direct cytotoxicity, this may occur via two major effector mechanisms involving the secretion of perforin/granzymes and/or ligation of Fas by FasL expressed by the Ag-activated CTL.…”

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confidence: 99%

The Fas/Fas Ligand Pathway Is Important for Optimal Tumor Regression in a Mouse Model of CTL Adoptive Immunotherapy of Experimental CMS4 Lung Metastases

Caldwell

Ryan

McDuffie

et al. 2003

The Journal of Immunology

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The mechanisms of CTL-mediated tumor regression in vivo remain to be fully understood. If CTL do mediate tumor regression in vivo by direct cytotoxicity, this may occur via two major effector mechanisms involving the secretion of perforin/granzymes and/or engagement of Fas by Fas ligand (FasL) expressed by the activated CTL. Although the perforin pathway has been considered the dominant player, it is unclear whether Fas-mediated cytotoxicity is additionally required for optimal tumor rejection. Previously, we produced H-2Ld-restricted CTL reactive against the CMS4 sarcoma, which expresses a naturally occurring rejection Ag recognized by these CTL and harbors a cytokine (IFN-γ plus TNF)-inducible, Fas-responsive phenotype. The adoptive transfer of these CTL to syngeneic BALB/c mice with minimal (day 3 established) or extensive (day 10 established) experimental pulmonary metastases resulted in strong antitumor responses. Here we investigated whether a FasL-dependent CTL effector mechanism was important for optimal tumor regression in this adoptive immunotherapy model. The approach taken was to compare the therapeutic efficacy of wild-type to FasL-deficient (gld) CTL clones by adoptive transfer. In comparison with wild-type CTL, gld-CTL efficiently mediated tumor cytolysis and produced comparable amounts of IFN-γ, after tumor-specific stimulation, as in vitro assessments of Ag recognition. Moreover, gld-CTL mediated comparably potent antitumor effects in a minimal disease setting, but were significantly less effective under conditions of an extensive tumor burden. Overall, under conditions of extensive lung metastases, these data revealed for the first time an important role for a FasL-dependent CTL effector mechanism in optimal tumor regression.

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“…Whole tumor cells are rendered replication-defective by radiation and are frequently combined with nonspecific immunostimulants [1,24,25]. Two allogeneic whole-tumor-cell vaccines – GVAX and ONY-P1 (described below) – are currently being investigated in clinical trials.…”

Section: Allogeneic Whole-tumor-cell Vaccinesmentioning

confidence: 99%

“…Phase I and II studies were performed, demonstrating both safety and clinical activity of this vaccine [11,25]. Based on these results, Cell Genesys launched two Phase III trials of GVAX.…”

Section: Allogeneic Whole-tumor-cell Vaccinesmentioning

confidence: 99%

Promising Novel Immunotherapies and Combinations for Prostate Cancer

et al. 2009

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The field of therapeutic cancer vaccines is currently in a state of active preclinical and clinical investigation, and certain novel therapies involving tumor immunotherapy have recently come to the forefront of prostate cancer research. While no therapeutic cancer vaccine has yet been approved by the US FDA, recent findings have demonstrated that new paradigms of combination therapies involving vaccines, employed in clinical trials with appropriate design and end points, may ultimately lead to cancer vaccines being used to treat various malignancies. Several characteristics of prostate cancer make it an ideal target for immunotherapy. Its relative indolence allows sufficient time to generate immune responses, which usually take weeks or months to mount. In addition, prostate cancer-associated antigens direct the immune response to prostate cancer cells, thus sparing normal tissue. This review focuses on the future of promising new vaccines and novel perspectives in the treatment of prostate cancer.

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Quantitating Therapeutically Relevant T-Cell Responses to Cancer Vaccines

Cited by 15 publications

References 0 publications

Extended evaluation of a phase 1/2 trial on dosing, safety, immunogenicity, and overall survival after immunizations with an advanced-generation Ad5 [E1-, E2b-]-CEA(6D) vaccine in late-stage colorectal cancer

Extended evaluation of a phase 1/2 trial on dosing, safety, immunogenicity, and overall survival after immunizations with an advanced-generation Ad5 [E1-, E2b-]-CEA(6D) vaccine in late-stage colorectal cancer

The Fas/Fas Ligand Pathway Is Important for Optimal Tumor Regression in a Mouse Model of CTL Adoptive Immunotherapy of Experimental CMS4 Lung Metastases

Promising Novel Immunotherapies and Combinations for Prostate Cancer

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