scholarly journals Recent Advances and Future Perspective of DC-Based Therapy in NSCLC

2021 ◽  
Vol 12 ◽  
Author(s):  
Iris A. E. van der Hoorn ◽  
Georgina Flórez-Grau ◽  
Michel M. van den Heuvel ◽  
I. Jolanda M. de Vries ◽  
Berber Piet
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Clinical Benefit ◽  
Clinical Success ◽  
Cytotoxic T Cells ◽  
Treatment Options ◽  
Treatment Modalities ◽  
Future Perspective ◽  
Dc Function ◽  
Anti Cancer

Current treatment for patients with non-small-cell lung cancer (NSCLC) is suboptimal since therapy is only effective in a minority of patients and does not always induce a long-lasting response. This highlights the importance of exploring new treatment options. The clinical success of immunotherapy relies on the ability of the immune system to mount an adequate anti-tumor response. The activation of cytotoxic T cells, the effector immune cells responsible for tumor cell killing, is of paramount importance for the immunotherapy success. These cytotoxic T cells are primarily instructed by dendritic cells (DCs). DCs are the most potent antigen-presenting cells (APCs) and are capable of orchestrating a strong anti-cancer immune response. DC function is often suppressed in NSCLC. Therefore, resurrection of DC function is an interesting approach to enhance anti-cancer immune response. Recent data from DC-based treatment studies has given rise to the impression that DC-based treatment cannot induce clinical benefit in NSCLC by itself. However, these are all early-phase studies that were mainly designed to study safety and were not powered to study clinical benefit. The fact that these studies do show that DC-based therapies were well-tolerated and could induce the desired immune responses, indicates that DC-based therapy is still a promising option. Especially combination with other treatment modalities might enhance immunological response and clinical outcome. In this review, we will identify the possibilities from current DC-based treatment trials that could open up new venues to improve future treatment.

scholarly journals Heterologous vaccination regimens with self-amplifying RNA and adenoviral COVID vaccines induce robust immune responses in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Alexandra J. Spencer ◽  
Paul F. McKay ◽  
Sandra Belij-Rammerstorfer ◽  
Marta Ulaszewska ◽  
Cameron D. Bissett ◽  
...  
Keyword(s):  
Immune Response ◽  
Clinical Trials ◽  
T Cells ◽  
Immune Responses ◽  
Viral Vectors ◽  
Cytotoxic T Cells ◽  
Antibody Responses ◽  
Limited Data ◽  
Vectored Vaccine ◽  
Cellular Immune

AbstractSeveral vaccines have demonstrated efficacy against SARS-CoV-2 mediated disease, yet there is limited data on the immune response induced by heterologous vaccination regimens using alternate vaccine modalities. Here, we present a detailed description of the immune response, in mice, following vaccination with a self-amplifying RNA (saRNA) vaccine and an adenoviral vectored vaccine (ChAdOx1 nCoV-19/AZD1222) against SARS-CoV-2. We demonstrate that antibody responses are higher in two-dose heterologous vaccination regimens than single-dose regimens. Neutralising titres after heterologous prime-boost were at least comparable or higher than the titres measured after homologous prime boost vaccination with viral vectors. Importantly, the cellular immune response after a heterologous regimen is dominated by cytotoxic T cells and Th1+ CD4 T cells, which is superior to the response induced in homologous vaccination regimens in mice. These results underpin the need for clinical trials to investigate the immunogenicity of heterologous regimens with alternate vaccine technologies.

443 An immunotherapy trio in advanced HNSCC for coordinated B and T cell antigen response

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A469-A469
Author(s):  
Bernard Fox ◽  
Tarsem Moudgil ◽  
Traci Hilton ◽  
Noriko Iwamoto ◽  
Christopher Paustian ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Cell Responses ◽  
Data Sets ◽  
Cell Responses ◽  
Anti Cancer ◽  
Bead Arrays ◽  
Hnscc Cell

BackgroundOutcomes for recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) are dismal and responses to anti-PD-1 appear best in tumors with PD-1+ T cells in proximity to PD-L1+ cells, arguing that improved outcome is associated with a pre-existing anti-cancer immune response. Based on this, we hypothesize that vaccines which prime and/or expand T cells to a spectrum of antigens overexpressed by HNSCC combined with T cell agonists, like anti-GITR, that provide costimulatory signals will improve the anti-PD-1 response rates. We have developed a cancer vaccine, DPV-001, that contains more than 300 proteins for genes overexpressed by HNSCC, encapsulated in a CLEC9A-targeted microvesicle and containing TLR/NOD agonists and DAMPs. Recently, we reported that combining anti-GITR + vaccine + anti-PD-1 augmented therapeutic efficacy in a preclinical model and now plan a phase 1b trial of this combination in patients with advanced HNSCC.MethodsSera from patients receiving DPV-001 as adjuvant therapy for definitively treated NSCLC, were analyzed for IgG responses to human proteins by MAP bead arrays and results compared to TCGA gene expression data sets for HNSCC. HNSCC cell lines were evaluated by RNASeq and peptides were eluted from HLA, analyzed by mass spectroscopy and correlated against MAP bead arrays and TCGA data sets. Tumor-reactive T cells from a vaccinated patient were enriched and expanded, and used in cytokine release assay (CRA) against autologous NSCLC and partially HLA matched allogeneic HNSCC cell lines.ResultsPatients receiving DPV-001 (N=13) made 147 IgG responses to at least 70 proteins for genes overexpressed by HNSCC. Preliminary evaluation of the HNSCC peptidome against the results of MAP bead array identify antigens that are target of a humoral immune response. Additionally, tumor-reactive T cells from DPV-001 vaccinated patient recognize two partially HLA-matched HNSCC targets, but not a mis-matched target.ConclusionsRecent observations from our lab and others have correlated IgG Ab responses with T cell responses to epitopes of the same protein. Based on the data summarized above, we hypothesize that we have induced T cell responses against a broad spectrum of shared cancer antigens that are common among adenocarcinomas and squamous cell cancers. Our planned clinical trial will vaccinate and boost the induced responses by costimulation with anti-GITR and then sequence in delayed anti-PD-1 to relieve checkpoint inhibition. MAP bead arrays and the peptidome library generated above will be used to assess anti-cancer B and T cell responses.Trial RegistrationNCT04470024Ethics ApprovalThe original clinical trial was approved by the Providence Portland Medical Center IRB, approval # 13-046. The proposed clinical trial has not yet been reviewed by the IRB.

scholarly journals COVID-19, T Cells, Cytokines and Immunotherapy: Review

2021 ◽  
pp. 70-82
Author(s):  
Nesrin I. Tarbiah
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Viral Infections ◽  
Cytotoxic T Cells ◽  
Clinical Findings ◽  
Global Pandemic ◽  
Significant Step ◽  
Novel Coronavirus ◽  
Cellular Immune ◽  
Cell Expression

In December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus (COVID-19), materialized in the city of Wuhan and quickly spread to form a global pandemic. An essential role in the immune system is undertaken by lymphocytes, which defend against bacteria, viruses, fungi, and parasites. Previous study found that very severe COVID-19 patients had suppression of the immune response enabling the virus to spread and cause more damage. This was evident by the changes in their white blood cell and lymphocyte count. Early clinical findings suggest that those suffering from severe COVID-19 have reduced numbers of lymphocytes, monocytes, and other granulocytes. One of the most efficient responses for a variety of viral infections is cellular immune response activation, especially via T cells. Viruses can be eliminated by T cytotoxic (CD8+) (Tc) in the host body, these secrete a variety of molecules, including interferons (IFNs), granzyme, and perforin. T helper (CD4+) (Th) cells help by assisting cytotoxic T cells and B cells to eliminate viral infection. CD8+ and CD4+ work together in a coordinated immune response with other constituents to primarily resolve acute viral infections, and after to produce protection against any reinfection. Also, COVID-19 causes dramatic changes in cytokine profiles and serological markers. Therefore, the subsets of immune cells and the level of the pro-inflammatory cytokines are crucial evidence to determine the severity of COVID-19. The disease severity has already been proved to be associated with the disruption in the proinflammatory chemokine response, this eventually leads to a cytokine storm and progression of cytokines release syndrome (CRS). This review aimed to demonstrate a full understanding of the alterations to the immune response by determining the T-cell expression and cytokine levels against the pathological processes of COVID-19, which can be a significant step in early treatment and diagnosis of this disease, in reduction of COVID-19 mortality cases, and to emphasize the most recent and current studies to try to identify new immuno-therapeutics for COVID-19.  

scholarly journals Activating a collaborative innate-adaptive immune response to control breast and ovarian cancer metastasis

2020 ◽  
Author(s):  
Lijuan Sun ◽  
Tim Kees ◽  
Ana Santos Almeida ◽  
Bodu Liu ◽  
Xue-Yan He ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Cancer Metastasis ◽  
Cytotoxic T Cells ◽  
Interleukin 12 ◽  
Type I ◽  
Monophosphoryl Lipid A ◽  
Response To Chemotherapy

AbstractMany cancers recruit monocytes/macrophages and polarize them into tumor-associated macrophages (TAMs). TAMs promote tumor growth and metastasis and inhibit cytotoxic T cells. Yet, macrophages can also kill cancer cells after polarization by e.g., lipopolysaccharide (LPS, a bacteria-derived toll-like receptor 4 [TLR4] agonist) and interferon gamma (IFNγ). They do so via nitric oxide (NO), generated by inducible NO synthase (iNOS). Altering the polarization of macrophages could therefore be a strategy for controlling cancer. Here, we show that monophosphoryl lipid A (MPLA, a derivative of LPS) with IFNγ activated macrophages isolated from metastatic pleural effusions of breast cancer patients to kill the corresponding patients’ cancer cells in vitro. Importantly, intratumoral injection of MPLA with IFNγ not only controlled local tumor growth but also reduced metastasis in mouse models of luminal and triple negative breast cancers. Furthermore, intraperitoneal administration of MPLA with IFNγ reprogrammed peritoneal macrophages, suppressed metastasis, and enhanced the response to chemotherapy in the ID8-p53−/− ovarian carcinoma mouse model. The combined MPLA+IFNγ treatment reprogrammed the immunosuppressive microenvironment to be immunostimulatory by recruiting leukocytes, stimulating type I interferon signaling, decreasing tumor-associated (CD206+) macrophages, increasing tumoricidal (iNOS+) macrophages, and activating cytotoxic T cells through macrophage-secreted interleukin 12 (IL-12) and tumor necrosis factor α (TNFα). Both macrophages and T cells were critical for the anti-metastatic effects of MPLA+IFNγ. MPLA and IFNγ are already used individually in clinical practice, so our strategy to engage the anti-tumor immune response, which requires no knowledge of unique tumor antigens, may be ready for near-future clinical testing.

scholarly journals Heterologous vaccination regimens with self-amplifying RNA and Adenoviral COVID vaccines induce superior immune responses than single dose vaccine regimens in mice

2021 ◽  
Author(s):  
Alexandra J Spencer ◽  
Paul F McKay ◽  
Sandra Belij-Rammerstorfer ◽  
Marta Ulaszewska ◽  
Cameron D Bissett ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Single Dose ◽  
Cytotoxic T Cells ◽  
High Titre ◽  
Limited Data ◽  
Neutralising Antibodies ◽  
Vectored Vaccine ◽  
Cellular Immune ◽  
Dose Vaccine

AbstractSeveral vaccines have demonstrated efficacy against SARS-CoV-2 mediated disease, yet there is limited data on the immune response induced by heterologous vaccination regimens using alternate vaccine modalities. Here, we present a detailed description of the immune response, in mice, following vaccination with a self-amplifying RNA (saRNA) vaccine and an adenoviral vectored vaccine (ChAdOx1 nCoV-19/AZD1222) against SARS-CoV-2. We demonstrate that antibody responses are higher in two dose heterologous vaccination regimens than single dose regimens, with high titre neutralising antibodies induced. Importantly, the cellular immune response after a heterologous regimen is dominated by cytotoxic T cells and Th1+ CD4 T cells which is superior to the response induced in homologous vaccination regimens in mice.

Clinical and Immunological responses in patients with malignant melanoma treated with a dendritic cell-based vaccine. Preliminary report from a multi-institutional phase II clinical trial

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3004-3004
Author(s):  
M. Ross ◽  
L. H. Camacho ◽  
E. M. Hersh ◽  
C. K. Brown ◽  
J. Richards ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Immune Response ◽  
T Cells ◽  
Metastatic Melanoma ◽  
Phase Ii ◽  
Clinical Benefit ◽  
Therapeutic Vaccine ◽  
Phase Ii Clinical Trial ◽  
Age Related Macular Degeneration ◽  
Ifn Γ

3004 Background: We have previously reported that vaccination with IDM therapeutic vaccine (IDD-3/Uvidem [Uvidem is co-developed with SANOFI-AVENTIS]) composed of dendritic cells (DC) loaded with three allogeneic lysates from tumor cell lines can elicit immune and anti-tumor responses. We describe here the preliminary results from a phase II clinical trial in metastatic melanoma patients. Methods: DC-MEL-202 is a single arm, two-stage phase II trial designed to evaluate clinical and immunological activities and the safety of a multivalent DC vaccine in patients with in-transit or low volume metastatic melanoma. There was no HLA restriction. Autologous DC were generated, under GMP conditions, from monocytes cultured in GM-CSF and IL-13, loaded with three allogeneic melanoma tumor lysates (M44, SK-MEL 28 and COLO 829) and matured with a combination of bacterial extract (FMKP) and IFN-γ, generating up to 15 doses of the vaccine containing 25x106 DC. Patients received six bi-weekly and two 6-weekly injections (id and sc). Clinical responders were eligible to receive additional doses. Immune response against tumor-associated antigens (TAA) peptides was assessed, at several time points, by detection of IFN-γ producing cells by flow cytometry Results: 33 patients were treated. To date: Vaccination is well tolerated with toxicity limited to mild events (only one possibly related SAE, age-related macular degeneration, was reported). Clinical response (RECIST): 6 patients showed evidence of clinical benefit (1CR, 1PR and 4 SD) with duration of response ranging from 7.5 to 22 months. Assessment of pathological response in target sites in 2 pts (1 PR, 1 SD) showed no residual disease.. 23/33 patients are still alive with a mean follow-up of 11mo (range 3–22mo). Mature data of PFS and OS will be presented. Immune response: 21 (84 %) out of 25 evaluated patients showed detectable TAA-specific CD8+ T cells with ten showing boosted or appearance of anti-TAA specific CD8+ T cells. Conclusions: Vaccination with IDD-3/Uvidem is safe and can elicit tumor specific CD8+ T cells not limited to HLA-A2+ patients. Substantial clinical benefit warrants further development of IDD3. No significant financial relationships to disclose.

Correlation between Platelet to Lymphocyte Ratio with C-Reactive Protein in COVID-19 Patients

2021 ◽  
Vol 28 (1) ◽  
pp. 17
Author(s):  
Novianti Anggie Lestari ◽  
Dwi Retnoningrum
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cytotoxic T Cells ◽  
The Body ◽  
Cross Sectional ◽  
Reactive Protein ◽  
A Value ◽  
Infected Cells ◽  
Spearman Test ◽  
Moderate Positive Correlation

Coronavirus 2019 (COVID-19) is an infectious disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Inflammation occurs when the body is infected with the virus. Platelets play a role in immune response and immunomodulation by activating P-Selectin Glycoprotein (PSGL) to the site of inflammation. Lymphocytes play a role through CD4 T-cells, B-cells producing specific viral antibodies, and CD8 cytotoxic T-cells by directly killing the virus in infected cells. This study aimed to prove the correlation between PLR and CRP as inflammation markers in COVID-19 patients. This study was a retrospective observational study with the cross-sectional approach at Dr. Kariadi Hospital, Semarang, for the period March-August 2020. Spearman test performed for analyzing data with p<0.05 was significant. Thirty-three confirmed COVID-19 patients with median value of PLR 218 (103-1609) and CRP 15.94 (1.24-200) mg/L were tested for correlation with a value of p=0.013 and r=0.427. The increase of PLR and CRP in COVID-19 patients was caused by an inflammatory process mediated by the immune response. High values in the blood were associated with disease severity and poor prognosis. There was a statistically significant moderate positive correlation between PLR and CRP in COVID-19 patients.

Frequency and Stimulation of NPM1-Specific Immune Responses By Anti-PD1 Antibodies in NPM1-Mutated AML

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 15-15
Author(s):  
Jochen Greiner ◽  
Vanessa Schneider ◽  
Hubert Schrezenmeier ◽  
Markus Wiesneth ◽  
Susanne Hofmann ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Research Funding ◽  
Wilms Tumor ◽  
Cytotoxic T Cells ◽  
Treatment Options ◽  
Npm1 Mutation ◽  
Immunogenic Epitope ◽  
Programmed Death ◽  
Programmed Death 1

Nucelophosmin1 (NPM1) is one of the most commonly mutated genes in AML, represents a distinct entity according to the WHO and is commonly associated with a favorable prognosis. We described specific immune responses against immunogenic epitopes derived from the mutational region of NPM1 in AML and specific immune responses against leukemic progenitor and stem cells (LPC/LSC). Immune responses play an increasing role in AML treatment options. However, the role of Immuncheckpoint inhibition is still controversially discussed in AML. In this work, we investigated NPM1 specific immune responses but also responses against other leukemia associated antigens (LAA) like PRAME (P300), Wilms' Tumor 1 (WT1) and RHAMM (R3) in an extended cohort. We investigated these immune responses in LSC/LPC using colony-forming immunoassays (CFI) and ELISpots. We examine whether immuncheckpoint inhibition using the anti-programmed death 1 (anti-PD-1) antibody might increase immune responses against stem cell like cells, comparing NPM1-mutated (NPM1mut) to NPM1 wildtype (NPM1wt) patients. In AML NPM1mut patients, specific immune responses of cytotoxic T cells against the epitope NPM1 showed a mean reduction of colonies in CFI of 27%, for P300 of 38%, for WT1 of 32% and for R3 of 42%. NPM1wt patients showed a mean reduction of colonies in CFI of for P300 of 28%, for WT1 of 28% and for R3 of 41%. Results are comparable, for NPM1mut and NPM1wt patients, there were immune responses seen in all epitopes. When adding the anti-PD-1 antibody to CFI, in NPM1mut patients the mean additional inhibition using NPM1 as target was 47%, and for the other epitopes: P300 23%, WT1 27% and R3 26%. For NPM1WT patients, the additional inhibition with the addition of anti-PD-1 to CFI was for P300 25%, for WT1 34% and for R3 23%. For the NPM1 epitope, 8 of 10 NPM1mut patients showed an immune response and 3/10 showed reduction in CFI of &gt; 50%. The NPM1 epitope displayed an additional reduction with anit-PD-1 in all 10 NPM1mut Patients and in 6 of 10 a reduction of &gt; 50%. Thus, especially the NPM1 specific immune responses are strong in NPM1mut patients by adding anti-PD-1. Taken together, the anti-PD-1 antibody increases specific T cell responses of LAA-stimulated CTL and the cytotoxic effect of T cells against LPC/LSC. The effect was strongest in NPM1mut patients against the immunogenic epitope derived from the mutational region of NPM1 and even stronger when adding anti-PD-1. These data suggest there could be a NPM1 mutation directed immunotherapeutic approach using LAA-directed vaccination strategies in NPM1-mutated AML and combination with anti-PD-1 antibodies might open new application possibilities. Disclosures Greiner: BMS: Research Funding. Schrezenmeier:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding.

Increased Cytotoxic T-Cell Infiltrates in the Bone Marrow Is an Independent Adverse Prognostic Factor in Patients with Newly Diagnosed Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1492-1492
Author(s):  
Grzegorz S. Nowakowski ◽  
Chin-Yang Li ◽  
David Dingli ◽  
Shaji Kumar ◽  
Morie A. Gertz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Immune Response ◽  
Overall Survival ◽  
T Cells ◽  
T Cell ◽  
Prognostic Factor ◽  
Cytotoxic T Cells ◽  
Cytotoxic T Cell ◽  
Newly Diagnosed

Abstract Background: Cytotoxic T-cell infiltrates are a nearly universal finding in the bone marrow of patients with multiple myeloma. It has been postulated that presence of T-cells in the bone marrow of multiple myeloma (MM) patients represents an immune response against the tumor and therefore, might be associated with an improved prognosis. However, the impact of bone marrow T-cells on the prognosis of multiple myeloma patients has not been studied systematically. Methods: Bone marrow biopsies of patients with newly diagnosed multiple myeloma were stained by immnohistochemistry for the CD8 antigen and reviewed by a blinded hematopathologist. Three high power fields are reviewed for each biopsy and the total number of CD8 positive cells counted and reported. For patients with more than 300 cells per 3 fields, results were reported as &gt;300. The number of bone marrow CD8 positive cells was then correlated with patients’ clinical data, including other prognostic factors and overall survival. Results: Bone marrow biopsy specimens from 100 patients, performed within the week of a diagnosis of multiple myeloma and collected between May 1998 and January 2001 were evaluated. The median number of CD8 positive cells was 270 (33 – &gt;300). Patients’ characteristics are shown in Table 1. Median follow up was 30 months (0–80). The number of cytotoxic T-cells as a continuous variable was a risk factor for shortened overall survival, HR 1.86 (95% CI 1.11–3.35). Using minimal p value approach, the cutoff of 270 cells (the median) risk stratified patients into two groups: the median survival of patients with &gt; 270 CD8 positive cells was 16 months vs. 48 months in patients with ≤270 cells, p=0.005 (Figure). In multivariate analysis including age, B2M, albumin, CRP, bone marrow plasma cell percentage and plasma cell labeling index, the number of cytotoxic T-cells was an independent predictor of overall survival was HR 3.1, p=0.0017. Conclusion: We show that the number of cytotoxic T-cells in the bone marrow is a strong and independent prognostic factor in patients with newly diagnosed multiple myeloma. Our observation does not contradict the hypothesis that cytotoxic T-cells participate in an immune response against the tumor since our findings may represent a higher level of immune response associated with baseline aggressive disease biology. However, our study suggests for the first time that increased marrow cytotoxic T-cells have an adverse effect on outcome in myeloma, and suggest that these cells may have a direct facilitating effect on tumor growth and on the marrow microenvironment. Further studies of the biology of behind this observation are warranted. Characteristic N Median (range) Gender male 61 CRP 81 0.4mg/L (0.01–11.2) Albumin 99 3.6 g/dL (2.6–5.4) B2microglobulin 94 4.0 (0.9–28) μg/mL Marrow PC% 90 45% (11–99) PC labeling index 90 high (&gt;1%) 36 BM CD8 cells 100 270 (33 – &gt;300) ISS 94 1 19 2 41 3 34 Figure Figure

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