Clinical implication of cellular vaccine in glioma: current advances and future prospects

AbstractGliomas, especially glioblastomas, represent one of the most aggressive and difficult-to-treat human brain tumors. In the last few decades, clinical immunotherapy has been developed and has provided exceptional achievements in checkpoint inhibitors and vaccines for cancer treatment. Immunization with cellular vaccines has the advantage of containing specific antigens and acceptable safety to potentially improve cancer therapy. Based on T cells, dendritic cells (DC), tumor cells and natural killer cells, the safety and feasibility of cellular vaccines have been validated in clinical trials for glioma treatment. For TAA engineered T cells, therapy mainly uses chimeric antigen receptors (IL13Rα2, EGFRvIII and HER2) and DNA methylation-induced technology (CT antigen) to activate the immune response. Autologous dendritic cells/tumor antigen vaccine (ADCTA) pulsed with tumor lysate and peptides elicit antigen-specific and cytotoxic T cell responses in patients with malignant gliomas, while its pro-survival effect is biased. Vaccinations using autologous tumor cells modified with TAAs or fusion with fibroblast cells are characterized by both effective humoral and cell-mediated immunity. Even though few therapeutic effects have been observed, most of this therapy showed safety and feasibility, asking for larger cohort studies and better guidelines to optimize cellular vaccine efficiency in anti-glioma therapy.

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Next-Generation Immunotherapies to Improve Anticancer Immunity

Frontiers in Pharmacology ◽

10.3389/fphar.2020.566401 ◽

2021 ◽

Vol 11 ◽

Author(s):

Yaoyao Shi ◽

Katarzyna Tomczak ◽

June Li ◽

Joshua K. Ochieng ◽

Younghee Lee ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Natural Killer Cells ◽

Natural Killer ◽

Tumor Cells ◽

Checkpoint Inhibitors ◽

Cytotoxic T Cells ◽

Cell Subset ◽

Cytotoxic T Cell ◽

Killer Cells

Checkpoint inhibitors are widely used immunotherapies for advanced cancer. Nonetheless, checkpoint inhibitors have a relatively low response rate, work in a limited range of cancers, and have some unignorable side effects. Checkpoint inhibitors aim to reinvigorate exhausted or suppressed T cells in the tumor microenvironment (TME). However, the TME contains various other immune cell subsets that interact to determine the fate of cytotoxic T cells. Activation of cytotoxic T cells is initiated by antigen cross-presentation of dendritic cells. Dendritic cells could also release chemokines and cytokines to recruit and foster T cells. B cells, another type of antigen-presenting cell, also foster T cells and can produce tumor-specific antibodies. Neutrophils, a granulocyte cell subset in the TME, impede the proliferation and activation of T cells. The TME also consists of cytotoxic innate natural killer cells, which kill tumor cells efficiently. Natural killer cells can eradicate major histocompatibility complex I-negative tumor cells, which escape cytotoxic T cell–mediated destruction. A thorough understanding of the immune mechanism of the TME, as reviewed here, will lead to further development of more powerful therapeutic strategies. We have also reviewed the clinical outcomes of patients treated with drugs targeting these immune cells to identify strategies for improvement and possible immunotherapy combinations.

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Dendritic Cells Reconstituted with a Human Heparanase Gene Induce Potent Cytotoxic T-Cell Responses against Gastric Tumor Cells in vitro

Tumor Biology ◽

10.1159/000107584 ◽

2007 ◽

Vol 28 (4) ◽

pp. 238-246 ◽

Cited By ~ 14

Author(s):

Yong-Guo Cai ◽

Dian-Chun Fang ◽

Ling Chen ◽

Xu-Dong Tang ◽

Ting Chen ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Tumor Cells ◽

T Cell Responses ◽

Gastric Tumor ◽

Cytotoxic T Cell ◽

Cell Responses ◽

Cytotoxic T Cell Responses

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Heat Shock Treatment of Tumor Lysate-Pulsed Dendritic Cells Enhances Their Capacity to Elicit Antitumor T Cell Responses against Medullary Thyroid Carcinoma

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2006-0971 ◽

2006 ◽

Vol 91 (11) ◽

pp. 4571-4577 ◽

Cited By ~ 13

Author(s):

Thomas Bachleitner-Hofmann ◽

Michaela Strohschneider ◽

Peter Krieger ◽

Monika Sachet ◽

Peter Dubsky ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Heat Shock ◽

Tumor Cells ◽

T Cell Responses ◽

Cytotoxic T Cell ◽

Tumor Lysate ◽

Cell Responses ◽

Cytotoxic T Cell Responses

Abstract Background: In vitro and in vivo studies have shown that dendritic cells (DCs) can stimulate antitumor T cell responses against medullary thyroid carcinoma (MTC). However, despite promising results in selected cases, the clinical efficacy of DC immunotherapy in patients with MTC has been limited. Recently, it has been demonstrated in mice that heat shock enhances the capacity of bone-marrow-derived DCs to stimulate antigen-specific T cells. The aim of our investigations was to evaluate whether heat shock also increases the capacity of human monocyte-derived DCs to stimulate antitumor T cell responses against MTC tumor cells. Methods: DCs from six patients with metastatic MTC were pulsed with tumor lysate derived from allogeneic MTC tumor cells and were heat shocked for 12 h at 40 C or kept at 37 C. Thereafter, the DCs were matured and cocultured with T cells. Finally, the cytotoxic activity of T cells against MTC tumor cells was measured in vitro. Results: In all patient samples, cytotoxic T cell responses against MTC tumor cells could be induced. Notably, heat-shocked DCs were more potent stimulators of cytotoxic T cell responses than control DCs, with T cells stimulated with heat-shocked DCs displaying a significantly increased cytotoxic activity against MTC tumor cells as compared with T cells stimulated with control DCs. In none of the experiments was a cytotoxic T cell response against unrelated pancreatic tumor cells (PANC-1) observed, using both control and heat-shocked DCs. Conclusions: Our study shows that heat-shocking DCs may be a valuable strategy to increase the immunostimulatory capacity of DCs used for immunotherapy of MTC.

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Stimulation of dendritic cells via the dectin-1/Syk pathway allows priming of cytotoxic T-cell responses

Blood ◽

10.1182/blood-2008-05-158469 ◽

2008 ◽

Vol 112 (13) ◽

pp. 4971-4980 ◽

Cited By ~ 122

Author(s):

Salomé LeibundGut-Landmann ◽

Fabiola Osorio ◽

Gordon D. Brown ◽

Caetano Reis e Sousa

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Cd8 T Cells ◽

Cytotoxic T Lymphocyte ◽

Cytotoxic T Cell ◽

Immune Recognition ◽

Cytotoxic T Cell Responses ◽

Ctl Responses

Abstract The C-type lectin receptor dectin-1 functions as a pattern recognition receptor for β-glucans and signals via Syk kinase but independently of the Toll-like receptor (TLR) pathway to regulate expression of innate response genes. Dectin-1 signaling can promote activation of dendritic cells (DCs), rendering them competent to prime Th1 and Th17 responses. Here we show that dectin-1–activated DCs can also prime cytotoxic T-lymphocyte (CTL) responses. DCs exposed to a dectin-1 agonist induced antigen-specific expansion of TCR transgenic CD8+ T cells and their differentiation into CTLs in vitro. Dectin-1 agonist also acted as an adjuvant for CTL crosspriming in vivo, eliciting potent CTL responses that protected mice from tumor challenge. In vitro but not in vivo, CTL crosspriming was dependent on IL-12 p70, which was produced by dectin-1–activated DCs in response to IFN-γ secreted by newly activated CD8+ T cells. The dectin-1/Syk pathway is thus able to couple innate immune recognition of β-glucans to all branches of the adaptive immune system, including CD4+ T-helper cells, B cells, and CD8+ cytotoxic T cells. These data highlight the ability of non-TLR receptors to bridge innate and adaptive immunity and suggest that dectin-1 agonists may constitute useful adjuvants for immunotherapy and vaccination.

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Human CD1c+ dendritic cells secrete high levels of IL-12 and potently prime cytotoxic T-cell responses

Blood ◽

10.1182/blood-2013-04-495424 ◽

2013 ◽

Vol 122 (6) ◽

pp. 932-942 ◽

Cited By ~ 185

Author(s):

Giulia Nizzoli ◽

Jana Krietsch ◽

Anja Weick ◽

Svenja Steinfelder ◽

Federica Facciotti ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cytotoxic T Cell ◽

Cell Responses ◽

Key Points ◽

Cytotoxic Molecules ◽

Cytotoxic T Cell Responses ◽

Antigen Presenting

Key Points CD1c+ DC but not BDCA-3+ DC or other antigen-presenting cells secrete high amounts of bioactive IL-12. CD1c+ DC efficiently cross-present antigens, prime CD8+ T cells, and induce the highest levels of cytotoxic molecules.

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Induction of Human Papillomavirus-Specific CD4+ and CD8+ Lymphocytes by E7-Pulsed Autologous Dendritic Cells in Patients with Human Papillomavirus Type 16- and 18-Positive Cervical Cancer

Journal of Virology ◽

10.1128/jvi.73.7.5402-5410.1999 ◽

1999 ◽

Vol 73 (7) ◽

pp. 5402-5410 ◽

Cited By ~ 106

Author(s):

Alessandro D. Santin ◽

Paul L. Hermonat ◽

Antonella Ravaggi ◽

Maurizio Chiriva-Internati ◽

Dejin Zhan ◽

...

Keyword(s):

Cervical Cancer ◽

T Cells ◽

Dendritic Cells ◽

Human Papillomavirus ◽

Tumor Cells ◽

Full Length ◽

Autologous Tumor ◽

Hpv 16 ◽

Pulsed Dc ◽

Hpv 18

ABSTRACT Human papillomavirus (HPV) type 16 (HPV 16) and HPV type 18 (HPV 18) are implicated in the induction and progression of the majority of cervical cancers. Since the E6 and E7 oncoproteins of these viruses are expressed in these lesions, such proteins might be potential tumor-specific targets for immunotherapy. In this report, we demonstrate that recombinant, full-length E7-pulsed autologous dendritic cells (DC) can elicit a specific CD8+ cytotoxic T-lymphocyte (CTL) response against autologous tumor target cells in three patients with HPV 16- or HPV 18-positive cervical cancer. E7-specific CTL populations expressed strong cytolytic activity against autologous tumor cells, did not lyse autologous concanavalin A-treated lymphoblasts or autologous Epstein-Barr virus-transformed lymphoblastoid cell lines (LCL), and showed low levels of cytotoxicity against natural killer cell-sensitive K562 cells. Cytotoxicity against autologous tumor cells could be significantly blocked by anti-HLA class I (W6/32) and anti-CD11a/LFA-1 antibodies. Phenotypically, all CTL populations were CD3+/CD8+, with variable levels of CD56 expression. CTL induced by E7-pulsed DC were also highly cytotoxic against an allogeneic HLA-A2+ HPV 16-positive matched cell line (CaSki). In addition, we show that specific lymphoproliferative responses by autologous CD4+ T cells can also be induced by E7-pulsed autologus DC. E7-specific CD4+ T cells proliferated in response to E7-pulsed LCL but not unpulsed LCL, and this response could be blocked by anti-HLA class II antibody. Finally, with two-color flow cytometric analysis of intracellular cytokine expression at the single-cell level, a marked Th1-like bias (as determined by the frequency of gamma interferon- and interleukin 4-expressing cells) was observable for both CD8+ and CD4+ E7-specific lymphocyte populations. Taken together, these data demonstrate that full-length E7-pulsed DC can induce both E7-specific CD4+ T-cell proliferative responses and strong CD8+ CTL responses capable of lysing autologous naturally HPV-infected cancer cells in patients with cervical cancer. These results may have important implications for the treatment of cervical cancer patients with active or adoptive immunotherapy.

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Evaluation of tumor immunity after administration of conditionally replicative adenoviral vector in canine osteosarcoma patients

10.21203/rs.2.16625/v1 ◽

2019 ◽

Author(s):

Payal Agarwal ◽

Elizabeth A Gammon ◽

Maninder Sandey ◽

Stephanie S Lindley ◽

Jey W Koehler ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Regulatory T Cells ◽

Tumor Cells ◽

Cell Activity ◽

Survival Duration ◽

Cytotoxic T Cell ◽

Cytokine Signaling ◽

Autologous Tumor ◽

Western Blots

Abstract Background: Osteosarcoma is one among the most common neoplasms in dogs. Current treatments include leg-amputation or limb-sparing techniques along with chemotherapy that show limited efficacy and fail to prevent metastasis. Conditionally replicative adenoviruses (CRAd) are gene therapy tools that replicate exclusively in targeted tumor cells, causing a cytopathic effect and in turn release of new virus particles to infect additional cells. We proposed that OC-CAVE1 (CAV2 with the E1A promoter replaced with the osteocalcin promotor) may also enhance existing immunity against tumors by overcoming immune tolerance via exposure of new epitopes and cytokine signaling. A previous study indicated administration of OC-CAVE1 was safe and showed specific replication in osteosarcoma cells. Results: We enrolled eleven client-owned dogs with spontaneously occurring osteosarcomas in a pilot clinical-trial. All dogs were injected with OC-CAVE1 following amputation of the affected limb or limb-sparing surgery. Dogs were monitored for viremia and viral shedding. There was minimal virus shedding in urine and feces by the 6th day and no virus was present in blood after 4 weeks. CAV-2 antibody-titers increased in all of the patients, post-CRAd injection. OC-CAVE1 injections did not result in a statistically significant increase in life span, although 2 dogs in the study achieved survival times in excess of 1 year. Immunological assays were performed to monitor 1) humoral response against tumors, 2) levels of circulatory CD11c+ cells, 3) levels of regulatory T cells, and 4) cytotoxic activity of tumor specific T cells against autologous tumor cells between pre-CRAd administration and 4 weeks post-CRAd administration samples. Western blots indicated an increased humoral immune response against pre-existing antigens in some dogs, but flow cytometry did not support this apparent increase. Cytotoxic T-cell activity did not increase in a consistent pattern. Levels of circulatory regulatory T-cells did decrease statistically in all patients. Conclusions: Administration of the CRAd OC-CAVE1 resulted in alteration of some immune response parameters but did not appear to result in increased survival duration. Weak replication of OC-CAVE1 in metastatic cells and delay of chemotherapy following CRAd treatment may contribute to the lack of improvement in survival time of the clinical patients.

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Polyanhydride nanovaccine platform enhances antigen-specific cytotoxic T cell responses

TECHNOLOGY ◽

10.1142/s2339547814500162 ◽

2014 ◽

Vol 02 (02) ◽

pp. 171-175 ◽

Cited By ~ 18

Author(s):

Lucas M. Huntimer ◽

Kathleen A. Ross ◽

Ross J. Darling ◽

Nicole E. Winterwood ◽

Paola Boggiatto ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Respiratory Infections ◽

Effector Memory ◽

Cytotoxic T Cell ◽

Transfer Model ◽

Cell Mediated Immunity ◽

Protein Antigens ◽

Specific Memory ◽

Cytotoxic T Cell Responses

Polyanhydride nanoparticle-based vaccines (or nanovaccines) stabilize protein antigens, provide sustained antigen release leading to prolonged antigen presence, enhance activation of antigen presenting cells, and elicit protective immunity against respiratory infections upon challenge. However, induction of cell-mediated immunity when mice are immunized with polyanhydride nanovaccines has not been evaluated. Using a transgenic ovalbumin-specific T cell adoptive transfer model, we report the induction of antigen-specific cytotoxic CD8+ T cells expressing an effector memory phenotype by seven days after immunization with nanovaccine formulations. Furthermore, mice immunized with polyanhydride nanovaccines demonstrated enhanced recall responses after antigen re-exposure 35 days post-immunization indicating the activation and recruitment of antigen-specific memory CD8+ T cells to the site of antigen deposition.

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Cellular cytotoxicity is a form of immunogenic cell death

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2019-000325 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000325 ◽

Cited By ~ 3

Author(s):

Luna Minute ◽

Alvaro Teijeira ◽

Alfonso R Sanchez-Paulete ◽

Maria C Ochoa ◽

Maite Alvarez ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

Dendritic Cells ◽

Tumor Cell ◽

Tumor Cells ◽

Cd8 T Cells ◽

Immunogenic Cell Death ◽

Cell Debris ◽

Tumor Cell Death ◽

Mhc Multimer

BackgroundThe immune response to cancer is often conceptualized with the cancer immunity cycle. An essential step in this interpretation is that antigens released by dying tumors are presented by dendritic cells to naive or memory T cells in the tumor-draining lymph nodes. Whether tumor cell death resulting from cytotoxicity, as mediated by T cells or natural killer (NK) lymphocytes, is actually immunogenic currently remains unknown.MethodsIn this study, tumor cells were killed by antigen-specific T-cell receptor (TCR) transgenic CD8 T cells or activated NK cells. Immunogenic cell death was studied analyzing the membrane exposure of calreticulin and the release of high mobility group box 1 (HMGB1) by the dying tumor cells. Furthermore, the potential immunogenicity of the tumor cell debris was evaluated in immunocompetent mice challenged with an unrelated tumor sharing only one tumor-associated antigen and by class I major histocompatibility complex (MHC)-multimer stainings. Mice deficient inBatf3,Ifnar1andSting1were used to study mechanistic requirements.ResultsWe observe in cocultures of tumor cells and effector cytotoxic cells, the presence of markers of immunogenic cell death such as calreticulin exposure and soluble HMGB1 protein. Ovalbumin (OVA)-transfected MC38 colon cancer cells, exogenously pulsed to present the gp100 epitope are killed in culture by mouse gp100-specific TCR transgenic CD8 T cells. Immunization of mice with the resulting destroyed cells induces epitope spreading as observed by detection of OVA-specific T cells by MHC multimer staining and rejection of OVA+EG7 lymphoma cells. Similar results were observed in mice immunized with cell debris generated by NK-cell mediated cytotoxicity. Mice deficient inBatf3-dependent dendritic cells (conventional dendritic cells type 1, cDC1) fail to develop an anti-OVA response when immunized with tumor cells killed by cytotoxic lymphocytes. In line with this, cultured cDC1 dendritic cells uptake and can readily cross-present antigen from cytotoxicity-killed tumor cells to cognate CD8+T lymphocytes.ConclusionThese results support that an ongoing cytotoxic antitumor immune response can lead to immunogenic tumor cell death.

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