scholarly journals 453 Novel combination immunotherapy for boosting and priming immune responses in pancreatic cancer: strong anti-tumour effects with interleukin-15 and CD40 agonist treatment

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A480-A480
Author(s):  
Jonas Van Audenaerde ◽  
Elly Marcq ◽  
Bianca von Scheidt ◽  
Ashleigh Davey ◽  
Amanda Oliver ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
T Cells ◽  
Dendritic Cells ◽  
Natural Killer ◽  
Mouse Models ◽  
Cd8 T Cells ◽  
Tumour Growth ◽  
Immune Memory ◽  
Combination Immunotherapy ◽  
Interleukin 15

BackgroundWith the poorest 5-year survival of all cancers, improving treatment for pancreatic cancer is one of the biggest challenges in cancer research. In this era of combination immunotherapies, we sought to explore the potential of combining both priming and activation of the immune system. To achieve this, we combined a CD40 agonist with interleukin-15 and tested its potential in pancreatic cancer.MethodsTwo different mouse models of pancreatic cancer were used to assess the potential of this combination regimen. Therefore, effects on tumour growth kinetics and survival were charted. Differential effects on immune signatures was investigated using RNA sequencing. Functional immune subset involvement was tested using different immune depletion experiments and multicolour flow cytometry in different relevant immune sites. Immune memory was checked using re-challenge experiments.ResultsWe demonstrated profound reduction in tumour growth and increased survival of mice with the majority of mice being cured when both agents were combined, including an unprecedented dose reduction of CD40 agonist without losing any efficacy (fig 1). RNA sequencing analysis showed involvement of natural killer cell and T cell mediated anti-tumour responses and the importance of antigen-presenting cell pathways. This combination resulted in enhanced infiltration of tumours by both cytotoxic T cells and natural killer cells, as well as a striking increase in the ratio of CD8+ T cells over T regulatory cells. We also observed a significant increase in numbers of dendritic cells in tumour draining lymph nodes, particularly CD103+ dendritic cells with cross-presentation potential. A critical role for CD8+ T cells and involvement of natural killer cells in the anti-tumour effect was highlighted. Importantly, strong immune memory was established, with an increase in memory CD8+ T cells only when both interleukin-15 and the CD40 agonist were combined.Abstract 453 Figure 1Tumour kinetics and survival in Panc02 (left) and KPC (right) pancreatic cancer mouse modelsConclusionsWe demonstrated profound synergistic anti-tumour effects upon combination of CD40 agonist and interleukin-15 treatment in mouse models of pancreatic cancer. This preclinical data supports initiation of a first-in-human clinical trial with this combination immunotherapy strategy in pancreatic cancer.

scholarly journals Immunization with dendritic cells can break immunological ignorance toward a persisting virus in the central nervous system and induce partial protection against intracerebral viral challenge

2004 ◽  
Vol 85 (8) ◽  
pp. 2379-2387 ◽  
Author(s):  
Ulrike Fassnacht ◽  
Andreas Ackermann ◽  
Peter Staeheli ◽  
Jürgen Hausmann
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
Dendritic Cells ◽  
Cd8 T Cells ◽  
Cytotoxic T Lymphocyte ◽  
Recombinant Vaccinia Virus ◽  
Immune Memory ◽  
Cervical Lymph Nodes ◽  
The Central Nervous System

Dendritic cells (DCs) have been used successfully to induce CD8 T cells that control virus infections and growth of tumours. The efficacy of DC-mediated immunization for the control of neurotropic Borna disease virus (BDV) in mice was evaluated. Certain strains of mice only rarely develop spontaneous neurological disease, despite massive BDV replication in the brain. Resistance to disease is due to immunological ignorance toward BDV antigen in the central nervous system. Ignorance in mice can be broken by immunization with DCs coated with TELEISSI, a peptide derived from the N protein of BDV, which represents the immunodominant cytotoxic T lymphocyte epitope in H-2k mice. Immunization with TELEISSI-coated DCs further induced solid protective immunity against intravenous challenge with a recombinant vaccinia virus expressing BDV-N. Interestingly, however, this immunization scheme induced only moderate protection against intracerebral challenge with BDV, suggesting that immune memory raised against a shared antigen may be sufficient to control a peripherally replicating virus, but not a highly neurotropic virus that is able to avoid activation of T cells. This difference might be due to the lack of BDV-specific CD4 T cells and/or inefficient reactivation of DC-primed, BDV-specific CD8 T cells by the locally restricted BDV infection. Thus, a successful vaccine against persistent viruses with strong neurotropism should probably induce antiviral CD8 (as well as CD4) T-cell responses and should favour the accumulation of virus-specific memory T cells in cervical lymph nodes.

Mechanism of activation of natural killer and CD8 T cells by interleukin 15 in the prostate cancer microenvironment

The Lancet ◽  
2014 ◽  
Vol 383 ◽  
pp. S47
Author(s):  
Oussama Elhage ◽  
Christina Sakellariou ◽  
Osamu Ukimura ◽  
Inderbir Gill ◽  
Richard A Smith ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
Natural Killer ◽  
Cd8 T Cells ◽  
Cancer Microenvironment ◽  
Interleukin 15

scholarly journals Vaccine Based on Dendritic Cells Electroporated with an Exogenous Ovalbumin Protein and Pulsed with Invariant Natural Killer T Cell Ligands Effectively Induces Antigen-Specific Antitumor Immunity

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 171
Author(s):  
Akihiro Watanabe ◽  
Kimihiro Yamashita ◽  
Mitsugu Fujita ◽  
Akira Arimoto ◽  
Masayasu Nishi ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Natural Killer ◽  
Cd8 T Cells ◽  
Antitumor Immunity ◽  
Tumor Antigens ◽  
Vaccine Strategy ◽  
Inkt Cells ◽  
Invariant Natural Killer ◽  
Natural Killer T

(1) Background: Cancer vaccines are administered to induce cytotoxic CD8+ T cells (CTLs) specific for tumor antigens. Invariant natural killer T (iNKT) cells, the specific T cells activated by α-galactosylceramide (α-GalCer), play important roles in this process as they are involved in both innate and adaptive immunity. We developed a new cancer vaccine strategy in which dendritic cells (DCs) were loaded with an exogenous ovalbumin (OVA) protein by electroporation (EP) and pulsed with α-GalCer. (2) Methods: We generated bone marrow-derived DCs from C57BL/6 mice, loaded full-length ovalbumin proteins to the DCs by EP, and pulsed them with α-GalCer (OVA-EP-galDCs). The OVA-EP-galDCs were intravenously administered to C57BL/6 mice as a vaccine. We then investigated subsequent immune responses, such as the induction of iNKT cells, NK cells, intrinsic DCs, and OVA-specific CD8+ T cells, including tissue-resident memory T (TRM) cells. (3) Results: The OVA-EP-galDC vaccine efficiently rejected subcutaneous tumors in a manner primarily dependent on CD8+ T cells. In addition to the OVA-specific CD8+ T cells both in early and late phases, we observed the induction of antigen-specific TRM cells in the skin. (4) Conclusions: The OVA-EP-galDC vaccine efficiently induced antigen-specific antitumor immunity, which was sustained over time, as shown by the TRM cells.

scholarly journals Redistribution, Hyperproliferation, Activation of Natural Killer Cells and CD8 T Cells, and Cytokine Production During First-in-Human Clinical Trial of Recombinant Human Interleukin-15 in Patients With Cancer

2015 ◽  
Vol 33 (1) ◽  
pp. 74-82 ◽  
Author(s):  
Kevin C. Conlon ◽  
Enrico Lugli ◽  
Hugh C. Welles ◽  
Steven A. Rosenberg ◽  
Antonio Tito Fojo ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Cd8 T Cells ◽  
Cell Cancer ◽  
Serum Levels ◽  
Metastatic Malignant Melanoma ◽  
Maximum Tolerated Dose ◽  
Peripheral Blood Lymphocytes ◽  
Interleukin 15

Purpose Interleukin-15 (IL-15) has significant potential in cancer immunotherapy as an activator of antitumor CD8 T and natural killer (NK) cells. The primary objectives of this trial were to determine safety, adverse event profile, dose-limiting toxicity, and maximum-tolerated dose of recombinant human IL-15 (rhIL-15) administered as a daily intravenous bolus infusion for 12 consecutive days in patients with metastatic malignancy. Patients and Methods We performed a first in-human trial of Escherichia coli–produced rhIL-15. Bolus infusions of 3.0, 1.0, and 0.3 μg/kg per day of IL-15 were administered for 12 consecutive days to patients with metastatic malignant melanoma or metastatic renal cell cancer. Results Flow cytometry of peripheral blood lymphocytes revealed dramatic efflux of NK and memory CD8 T cells from the circulating blood within minutes of IL-15 administration, followed by influx and hyperproliferation yielding 10-fold expansions of NK cells that ultimately returned to baseline. Up to 50-fold increases of serum levels of multiple inflammatory cytokines were observed. Dose-limiting toxicities observed in patients receiving 3.0 and 1.0 μg/kg per day were grade 3 hypotension, thrombocytopenia, and elevations of ALT and AST, resulting in 0.3 μg/kg per day being determined the maximum-tolerated dose. Indications of activity included clearance of lung lesions in two patients. Conclusion IL-15 could be safely administered to patients with metastatic malignancy. IL-15 administration markedly altered homeostasis of lymphocyte subsets in blood, with NK cells and γδ cells most dramatically affected, followed by CD8 memory T cells. To reduce toxicity and increase efficacy, alternative dosing strategies have been initiated, including continuous intravenous infusions and subcutaneous IL-15 administration.

scholarly journals The Role of Langerin⁺ CD8α⁺ Dendritic Cells in Tumour Immunotherapy

2021 ◽  
Author(s):  
◽  
John David Gibbins
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Natural Killer ◽  
Cd8 T Cells ◽  
Suppressor Cells ◽  
Invariant Natural Killer ◽  
Natural Killer T

<p>The immune system has the potential to selectively target and eliminate tumours cells. However, the induction of an immunosuppressive environment by factors released by tumours cells, or by the tumour stroma, in combination with difficulties in differentiating between healthy and malignant cells, contributes to inefficient or disabled anti-tumour immune responses. A variety of different immunotherapeutic approaches are being developed to tip the balance in favour of anti-tumour immunity. Many of these approaches are designed to stimulate improved activity of T cells with specificity for tumour-associated antigens.  This thesis explores how T cell-mediated responses are initiated and maintained in immunotherapy, with an emphasis on the role of antigen presentation by resident dendritic cells (DCs). An animal model was used in which a DC subset in the spleen that expresses the cell marker langerin could be selectively ablated during the course of therapy. As these DCs have been shown to be uniquely capable of acquiring circulating antigens and cellular debris, and have a heightened capacity for cross-priming CD8⁺ T cells, it was hypothesised that the function of these cells could play a significant role in determining the outcome of immunotherapies.  A model of adoptive T cell therapy was examined in mice challenged with an intravenously administered lymphoma that formed tumour foci in a variety of locations in the body. Treating established tumours by adoptively transferring in vitro activated effector CD8⁺ T cells significantly increased their symptom-free survival. The protection received by this therapy was dependent on a stimulus being provided by endogenous langerin⁺ CD8α⁺ DCs to the transferred T cells. In the absence of langerin⁺ CD8α⁺ DCs, the proportion and number of transferred anti-tumour CD8⁺ T cells was lower in the blood and spleen. However, no obvious differences in phenotype and function could be defined. Langerin⁺ CD8α⁺ DCs therefore contribute to the maintenance of an effective CD8⁺ T cell-based immunotherapy and the role of endogenous DCs should be taken into consideration during the design of immunotherapies.  To investigate the role of langerin⁺ CD8α⁺ DCs in initiating effector T cell responses, a novel whole-cell vaccine was developed for the treatment of acute myeloid leukaemia (AML). This vaccine exploited the stimulatory functions of invariant natural killer T cells, and was therefore administered intravenously to access the large invariant natural killer T cell compartment of the spleen. The vaccine completely protected mice from developing leukaemia when challenged with AML cells after vaccination, with CD4⁺ and CD8⁺ T cells mediating protection. The immune response generated by the vaccine was shown to be completely dependent on langerin⁺ CD8α⁺ DCs. In hosts with established tumours; however, the vaccine was ineffective. This may have been partially due to a reduced function of langerin⁺ CD8α⁺ DCs as their activation phenotype was significantly reduced in the presence of established AML; however, non-specific T cells could still be stimulated via these DCs. Reduced vaccine efficacy was associated with increased number and/or function of suppressor cells, including regulatory T cells and myeloid derived suppressor cells within the host. In addition, in leukemic hosts, the proportion of T cells in the spleen was reduced, and the function of AML-specific CD4⁺ T cells, but not CD8⁺ T cells, was impaired. Driving AML-bearing hosts into remission with chemotherapy prior to vaccination enabled the vaccine to protect the host from subsequent AML challenge. Langerin⁺ CD8α⁺ DCs are therefore responsible for initiating the vaccine-induced immune response in this model and their suppression may have contributed to the inefficacy of the vaccine in the presence of established tumours.</p>

scholarly journals cDC1 dysregulation in cancer: An opportunity for intervention

2020 ◽  
Vol 217 (8) ◽  
Author(s):  
Thomas F. Gajewski ◽  
Kyle R. Cron
Keyword(s):  
Pancreatic Cancer ◽  
T Cells ◽  
Dendritic Cells ◽  
Transcription Factor ◽  
Cd8 T Cells ◽  
Treatment Strategies ◽  
Checkpoint Blockade ◽  
Potential Treatment

Conventional dendritic cells driven by the transcription factor Batf3 (cDC1 cells) are critical for the activation and maintenance of tumor-specific CD8+ T cells. In this issue of JEM, Lin et al. (https://doi.org/10.1084/jem.20190673) demonstrate systemic dysfunction of cDC1 cells in pancreatic cancer, which offers potential treatment strategies to expand the benefit of checkpoint blockade immunotherapy.

scholarly journals The Role of Langerin⁺ CD8α⁺ Dendritic Cells in Tumour Immunotherapy

2021 ◽  
Author(s):  
◽  
John David Gibbins
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Natural Killer ◽  
Cd8 T Cells ◽  
Suppressor Cells ◽  
Invariant Natural Killer ◽  
Natural Killer T

<p>The immune system has the potential to selectively target and eliminate tumours cells. However, the induction of an immunosuppressive environment by factors released by tumours cells, or by the tumour stroma, in combination with difficulties in differentiating between healthy and malignant cells, contributes to inefficient or disabled anti-tumour immune responses. A variety of different immunotherapeutic approaches are being developed to tip the balance in favour of anti-tumour immunity. Many of these approaches are designed to stimulate improved activity of T cells with specificity for tumour-associated antigens.  This thesis explores how T cell-mediated responses are initiated and maintained in immunotherapy, with an emphasis on the role of antigen presentation by resident dendritic cells (DCs). An animal model was used in which a DC subset in the spleen that expresses the cell marker langerin could be selectively ablated during the course of therapy. As these DCs have been shown to be uniquely capable of acquiring circulating antigens and cellular debris, and have a heightened capacity for cross-priming CD8⁺ T cells, it was hypothesised that the function of these cells could play a significant role in determining the outcome of immunotherapies.  A model of adoptive T cell therapy was examined in mice challenged with an intravenously administered lymphoma that formed tumour foci in a variety of locations in the body. Treating established tumours by adoptively transferring in vitro activated effector CD8⁺ T cells significantly increased their symptom-free survival. The protection received by this therapy was dependent on a stimulus being provided by endogenous langerin⁺ CD8α⁺ DCs to the transferred T cells. In the absence of langerin⁺ CD8α⁺ DCs, the proportion and number of transferred anti-tumour CD8⁺ T cells was lower in the blood and spleen. However, no obvious differences in phenotype and function could be defined. Langerin⁺ CD8α⁺ DCs therefore contribute to the maintenance of an effective CD8⁺ T cell-based immunotherapy and the role of endogenous DCs should be taken into consideration during the design of immunotherapies.  To investigate the role of langerin⁺ CD8α⁺ DCs in initiating effector T cell responses, a novel whole-cell vaccine was developed for the treatment of acute myeloid leukaemia (AML). This vaccine exploited the stimulatory functions of invariant natural killer T cells, and was therefore administered intravenously to access the large invariant natural killer T cell compartment of the spleen. The vaccine completely protected mice from developing leukaemia when challenged with AML cells after vaccination, with CD4⁺ and CD8⁺ T cells mediating protection. The immune response generated by the vaccine was shown to be completely dependent on langerin⁺ CD8α⁺ DCs. In hosts with established tumours; however, the vaccine was ineffective. This may have been partially due to a reduced function of langerin⁺ CD8α⁺ DCs as their activation phenotype was significantly reduced in the presence of established AML; however, non-specific T cells could still be stimulated via these DCs. Reduced vaccine efficacy was associated with increased number and/or function of suppressor cells, including regulatory T cells and myeloid derived suppressor cells within the host. In addition, in leukemic hosts, the proportion of T cells in the spleen was reduced, and the function of AML-specific CD4⁺ T cells, but not CD8⁺ T cells, was impaired. Driving AML-bearing hosts into remission with chemotherapy prior to vaccination enabled the vaccine to protect the host from subsequent AML challenge. Langerin⁺ CD8α⁺ DCs are therefore responsible for initiating the vaccine-induced immune response in this model and their suppression may have contributed to the inefficacy of the vaccine in the presence of established tumours.</p>

scholarly journals Fatal Leukemia in Interleukin 15 Transgenic Mice Follows Early Expansions in Natural Killer and Memory Phenotype Cd8+ T Cells

2001 ◽  
Vol 193 (2) ◽  
pp. 219-232 ◽  
Author(s):  
Todd A. Fehniger ◽  
Kazuhiro Suzuki ◽  
Anand Ponnappan ◽  
Jeffrey B. VanDeusen ◽  
Megan A. Cooper ◽  
...  
Keyword(s):  
T Cells ◽  
Transgenic Mice ◽  
Natural Killer ◽  
Cd8 T Cells ◽  
Proinflammatory Cytokine ◽  
Lymphocytic Leukemia ◽  
Chronic Stimulation ◽  
Cd8 T Lymphocytes ◽  
Lymphocyte Homeostasis ◽  
Interleukin 15

Inflammation likely has a role in the early genesis of certain malignancies. Interleukin (IL)-15, a proinflammatory cytokine and growth factor, is required for lymphocyte homeostasis. Intriguingly, the expression of IL-15 protein is tightly controlled by multiple posttranscriptional mechanisms. Here, we engineered a transgenic mouse to overexpress IL-15 by eliminating these posttranscriptional checkpoints. IL-15 transgenic mice have early expansions in natural killer (NK) and CD8+ T lymphocytes. Later, these mice develop fatal lymphocytic leukemia with a T-NK phenotype. These data provide novel evidence that leukemia, like certain other cancers, can arise as the result of chronic stimulation by a proinflammatory cytokine.

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