scholarly journals IMMU-09. COMBINATION IMMUNE TREATMENT OF A HIGHLY AGGRESSIVE ORTHOTOPIC MURINE GLIOBLASTOMA WITH CHECKPOINT BLOCKADE AND MULTI-VALENT NEOANTIGEN VACCINATION

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi120-vi121
Author(s):  
Connor Liu ◽  
Maximilian Schaettler ◽  
Jay Bowman-Kirigin ◽  
Dale Kobayashi ◽  
Chris Miller ◽  
...  
Keyword(s):  
T Cell ◽  
Specific Antigen ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Checkpoint Blockade ◽  
Immune Recognition ◽  
Cell Responses ◽  
Recent Success ◽  
Whole Exome ◽  
Survival Studies

Abstract Recent success using immunotherapies to treat a growing range of cancer types has reinvigorated efforts to identify effective immune-based treatments for glioblastoma (GBM). However, the limited clinical benefit observed in GBM patients treated with checkpoint blockade immunotherapy (CBI) has indicated a need for more rigorous approaches to augment host-immune recognition and killing of GBM. Of the myriad barriers to effective brain tumor immunotherapy, one potentially critical consideration is that a more systematic approach to tumor-specific antigen identification and targeting is necessary to potently stimulate and direct T cells to treat GBM. Therefore, in this study we set out to identify endogenous tumor neoantigens in the anti-PD-L1 resistant murine glioblastoma, CT2A, and assess the efficacy of neoantigen vaccination in combination with anti-PD-L1 treatment. In order to identify candidate CT2A neoantigens, we employed DNA whole exome sequencing, RNA sequencing, and in silico neoantigen prediction analyses. High-affinity H-2Kb and H-2Db candidate CT2A neoantigens were screened for immunogenicity by IFN-γ ELISPOT assays. Of the 30 top-ranking neoantigen candidates, 13 demonstrated immunogenic CD8+ T cell responses in the spleens of mice vaccinated with mutant peptides. Assessing for endogenous reactivity, we identified neoantigen specific CD8+ T cell responses in the intracranial TIL and draining lymph nodes to two H2-Kb restricted, Epb4H471L and Pomgnt1R497L, and one H2-Db restricted neoantigen, Plin2G332R. Survival studies showed that therapeutic neoantigen vaccination with Epb4H471L, Pomgnt1R497L, and Plin2G332R, in combination with anti-PD-L1 checkpoint blockade was superior to either neoantigen vaccination or anti-PD-L1 therapy alone. Thus, by applying a cancer immunogenomics approach to identify endogenous neoantigen reactivity in an aggressive and treatment resistant murine glioblastoma, we provide a preclinical framework to investigate the effects of multi-modality immunotherapeutic interventions in anti-glioma immunity.

Assessment of combined vaccination and immune modulation as an anti-tumour therapy

2021 ◽  
Author(s):  
◽  
Emma Victoria Petley
Keyword(s):  
T Cell ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Checkpoint Blockade ◽  
Inkt Cell ◽  
Current Therapy ◽  
Checkpoint Inhibition ◽  
Cell Responses

<p>Glioblastoma multiforme (GBM) is a common and lethal type of brain cancer, with a very poor prognosis. Current therapy consisting of surgical resection, radiation and chemotherapy produces a median survival of only 12-15 months. Therefore, there is a need to develop new therapeutic approaches for the treatment of GBM.  This thesis investigates a new series of synthetic cancer vaccines, conjugating tumour-associated antigens (TAAs) to an isomer of ɑ-Galactosylceramide (ɑ-GalCer), a potent invariant natural killer T (iNKT) cell agonist with documented adjuvant activity. Upon antigen encounter, activated iNKT cells are capable of licensing dendritic cells (DCs) through CD40:CD40L interactions and cytokine production. The licensed DCs subsequently stimulate potent CD8⁺ T cell responses, capable of killing cancerous tissue. Conjugation of ɑ-GalCer to the TAA-derived peptide was achieved via an enzymatically cleavable linker sensitive to cathepsin B activity. This strategy allows co-delivery of the active components, with the rationale that the same DC will be able to co-present both ɑ-GalCer for iNKT cell activation, and peptide to induce an enhanced CD8⁺ T cell responses.  The conjugate vaccines assessed in this thesis were able to induce iNKT cell activation and produce CD8⁺ T cell cytoxicity. However, this did not correlate with in vivo antitumour activity, as the vaccine that incorporated the TAA survivin, produced minimal cytotoxicity but potent anti-tumour responses against an implantable model of glioma.  Enhancing T cell-mediated immune responses has been validated by immune checkpoint inhibition for the treatment of cancer. However, many patients do not respond to the therapy. It is thought that this subset of patients may lack pre-existing T cell responses, which are required for the efficacy of checkpoint inhibition. Therefore, there is considerable interest in whether the use of vaccines that stimulate T cell activation can improve responses to checkpoint blockade and other immune modulating drugs. The survivin vaccine was combined with the immune checkpoint blockade inhibitors ɑ-PD-1, ɑ-CTLA-4 and ɑ-LAG-3, the co-stimulatory agent a-4-1BB, or administered with T regulatory cell (TREG) depletion, to reveal the immunogenicity of the vaccine.  This research revealed that combining the survivin vaccine with the immune checkpoint inhibitor ɑ-CTLA-4 improved overall survival of mice, compared to the vaccine alone. This finding suggests that this combined therapy may be a useful immunotherapeutic strategy for the treatment of GBM.</p>

Assessment of combined vaccination and immune modulation as an anti-tumour therapy

2021 ◽  
Author(s):  
◽  
Emma Victoria Petley
Keyword(s):  
T Cell ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Checkpoint Blockade ◽  
Inkt Cell ◽  
Current Therapy ◽  
Checkpoint Inhibition ◽  
Cell Responses

<p>Glioblastoma multiforme (GBM) is a common and lethal type of brain cancer, with a very poor prognosis. Current therapy consisting of surgical resection, radiation and chemotherapy produces a median survival of only 12-15 months. Therefore, there is a need to develop new therapeutic approaches for the treatment of GBM.  This thesis investigates a new series of synthetic cancer vaccines, conjugating tumour-associated antigens (TAAs) to an isomer of ɑ-Galactosylceramide (ɑ-GalCer), a potent invariant natural killer T (iNKT) cell agonist with documented adjuvant activity. Upon antigen encounter, activated iNKT cells are capable of licensing dendritic cells (DCs) through CD40:CD40L interactions and cytokine production. The licensed DCs subsequently stimulate potent CD8⁺ T cell responses, capable of killing cancerous tissue. Conjugation of ɑ-GalCer to the TAA-derived peptide was achieved via an enzymatically cleavable linker sensitive to cathepsin B activity. This strategy allows co-delivery of the active components, with the rationale that the same DC will be able to co-present both ɑ-GalCer for iNKT cell activation, and peptide to induce an enhanced CD8⁺ T cell responses.  The conjugate vaccines assessed in this thesis were able to induce iNKT cell activation and produce CD8⁺ T cell cytoxicity. However, this did not correlate with in vivo antitumour activity, as the vaccine that incorporated the TAA survivin, produced minimal cytotoxicity but potent anti-tumour responses against an implantable model of glioma.  Enhancing T cell-mediated immune responses has been validated by immune checkpoint inhibition for the treatment of cancer. However, many patients do not respond to the therapy. It is thought that this subset of patients may lack pre-existing T cell responses, which are required for the efficacy of checkpoint inhibition. Therefore, there is considerable interest in whether the use of vaccines that stimulate T cell activation can improve responses to checkpoint blockade and other immune modulating drugs. The survivin vaccine was combined with the immune checkpoint blockade inhibitors ɑ-PD-1, ɑ-CTLA-4 and ɑ-LAG-3, the co-stimulatory agent a-4-1BB, or administered with T regulatory cell (TREG) depletion, to reveal the immunogenicity of the vaccine.  This research revealed that combining the survivin vaccine with the immune checkpoint inhibitor ɑ-CTLA-4 improved overall survival of mice, compared to the vaccine alone. This finding suggests that this combined therapy may be a useful immunotherapeutic strategy for the treatment of GBM.</p>

Distinct Structural TCR Repertoires in Naturally Occurring Versus Vaccine-Induced CD8+ T-Cell Responses to the Tumor-Specific Antigen NY-ESO-1

2005 ◽  
Vol 28 (3) ◽  
pp. 252-257 ◽  
Author(s):  
Fr??d??rique-Anne Le Gal ◽  
Maha Ayyoub ◽  
Val??rie Dutoit ◽  
Val??rie Widmer ◽  
Elke J??ger ◽  
...  
Keyword(s):  
T Cell ◽  
Specific Antigen ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cell Responses ◽  
Naturally Occurring ◽  
Tumor Specific Antigen

scholarly journals Impact of checkpoint blockade on cancer vaccine–activated CD8+ T cell responses

2020 ◽  
Vol 217 (7) ◽  
Author(s):  
Patricia M. Santos ◽  
Juraj Adamik ◽  
Timothy R. Howes ◽  
Samuel Du ◽  
Lazar Vujanovic ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Responses ◽  
Positive Association ◽  
Cd8 T Cell ◽  
Checkpoint Blockade ◽  
Functional Responses ◽  
Cell Responses ◽  
Gene And Protein Expression ◽  
Clinical Responses

Immune and molecular profiling of CD8 T cells of patients receiving DC vaccines expressing three full-length melanoma antigens (MAs) was performed. Antigen expression levels in DCs had no significant impact on T cell or clinical responses. Patients who received checkpoint blockade before DC vaccination had higher baseline MA-specific CD8 T cell responses but no evidence for improved functional responses to the vaccine. Patients who showed the best clinical responses had low PD-1 expression on MA-specific T cells before and after DC vaccination; however, blockade of PD-1 during antigen presentation by DC had minimal functional impact on PD-1high MA-specific T cells. Gene and protein expression analyses in lymphocytes and tumor samples identified critical immunoregulatory pathways, including CTLA-4 and PD-1. High immune checkpoint gene expression networks correlated with inferior clinical outcomes. Soluble serum PD-L2 showed suggestive positive association with improved outcome. These findings show that checkpoint molecular pathways are critical for vaccine outcomes and suggest specific sequencing of vaccine combinations.

Development of an orthotopic HCC mouse model for analysis of tumor-specific CD8 T cell responses

2014 ◽  
Vol 52 (01) ◽  
Author(s):  
D Ostroumov ◽  
MP Manns ◽  
S Kubicka ◽  
F Kühnel ◽  
T Wirth
Keyword(s):  
T Cell ◽  
Mouse Model ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cell Responses

Analysis of Successful Virus-Specific CD8+ T Cell Responses in acute HBV infection

2006 ◽  
Vol 44 (01) ◽  
Author(s):  
E Panther ◽  
B Bengsch ◽  
T Böttler ◽  
N Nazarova ◽  
HC Spangenberg ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Hbv Infection ◽  
Cell Responses
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