A phase II, open-label, randomized trial of durvalumab (D) with olaparib (O) or cediranib (C) in patients (pts) with leiomyosarcoma (LMS).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11522-11522
Author(s):  
Olubukola Ayodele ◽  
Ben X Wang ◽  
Thomas D Pfister ◽  
Esmail Mutahar Al-Ezzi ◽  
Hal Berman ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Stable Disease ◽  
Immune Cells ◽  
Immune Cell ◽  
Tumor Infiltrating Lymphocytes ◽  
Fold Increase ◽  
Immune Checkpoint Blockade ◽  
Tumor Growth Rate ◽  
Open Label ◽  
Fluorescent Immunohistochemistry

11522 Background: The use of immune checkpoint blockade (ICB) in non-inflamed (cold) tumors is associated with limited clinical efficacy. Combination of ICB with certain molecularly targeted agents (MTA) is hypothesized to increase tumor immunogenicity by recruiting tumor infiltrating lymphocytes in cold tumors, such as LMS. Here, we present the results of LMS cohort treated on the DAPPER study (NCT03851614). Methods: LMS pts with ECOG 0-1 were randomized to either D+O (arm A), or D+C (arm B). In a 28-day cycle, D 1500mg i.v. q4w with either O 300mg bid po qd or C 20mg po qd 5d/week were administered. Overall response rates (ORR) were determined using RECISTv1.1. Evaluation of tumor kinetics (TK) was performed by calculating tumor growth rate (TGR) of target lesions on CT images at baseline and on-treatment, adjusted to account for the time difference between scans. TGR is expressed as % tumor growth/week (Ferte C et al. CCR, 2014). Additionally, paired FFPE samples (from baseline and on-treatment biopsies) were assessed using multispectral fluorescent immunohistochemistry (IHC) panel: CD3, CD8, CD20, CD68, FOXP3 and cytokeratin. Tumor areas were identified by a pathologist and immune cells were quantified using InForm image analysis software. Results: 25 metastatic LMS pts were randomized to arm A (n = 11) or B (n = 14) over 21 months. Median age was 53 years, 96% were females and 60% of pts had ≥3 lines of therapy. In 23 evaluable pts, no responses were seen, 7 pts had stable disease (SD) while 16 has progressive disease (PD). TK analysis was evaluable for 18 pts (arm A = 8, B = 10). 5/8 pts (62.5%) in arm A and 6/10 pts (60%) in arm B showed decreased TK (defined as TGRbaseline > TGRon-treatment). In 4/5 (80%) pts who had deceleration of TK in arm A, SD was maintained for ≥6 months. The reduction in TGR on treatment, compared to baseline was significant in arm A but not in arm B (measured as median % tumor growth/week of 0.5 vs 5.1, 95% CI 0.2-4.3, p = 0.035 in arm A; and 1.3 vs 2.9, 95% CI 0.2-2.7, p = 0.088 in arm B). The median PFS of arm A and B were 9 (95% CI 3-12.8) and 4 (95% CI 2.2-4.6) months respectively. There were no statistically significant differences in tumor-infiltrating immune cells when comparing baseline and on-treatment biopsies from arm A or B. In arm A, one pt with SD > 6 months had a 2.5-fold increase in CD8 (CD3+CD8+) T cells and a 7.6-fold increase in macrophages (CD68+). Conclusions: D+O or D+C resulted in stable disease in 30% of pts, mostly on arm A (D+O). TK analysis may identify pts with prolonged SD on treatment. Although a cold-to-hot immunophenotype change was not generally seen, changes in tumor infiltrating immune cell subsets were observed in one patient with prolonged stable disease. These findings support further molecular and immunophenotype characterization in LMS patients treated with D+O or D+C. Clinical trial information: NCT03851614.

Evaluation of pharmacodynamic (PD) biomarkers in patients with metastatic pancreatic cancer treated with BL-8040, a novel CXCR4 antagonist.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 88-88 ◽  
Author(s):  
Manuel M. Hidalgo ◽  
Ron Epelbaum ◽  
Valeriya Semenisty ◽  
Ravit Geva ◽  
Talia Golan ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Flow Cytometry ◽  
Immune Cells ◽  
Immune Cell ◽  
Cell Subset ◽  
Fold Increase ◽  
Cell Infiltration ◽  
Metastatic Pancreatic Cancer ◽  
Cxcr4 Antagonist ◽  
Open Label

88 Background: BL-8040 is a novel CXCR4 antagonist being developed for multiple oncology indications. Preclinical studies demonstrated that BL-8040 increases the number of immune cells in peripheral blood and promotes CD8+ T cell infiltration into orthotropic pancreatic mouse tumors, reducing tumor load. BL-8040 is being evaluated in a Phase 2a, multicenter, open label trial in patients with metastatic pancreatic cancer (the COMBAT study). Patients are undergoing a 5-day period of monotherapy in which they receive daily doses of BL-8040, followed by 21-day cycles in which patients receive one dose of pembrolizumab and 3 doses/week of BL-8040 until disease progression or discontinuation. To date, 32 patients have been enrolled. Methods: On Day 1 and Day 5, blood samples were taken at pre- and post-dosing, to evaluate peripheral immune cell subset frequency by flow cytometry. In addition, core biopsies were taken from liver metastases, where possible, to assess immune cell infiltration into tumors and the tumor microenvironment (TME). Results: Here we present interim PD biomarker data from the BL-8040 monotherapy portion of the trial. Flow cytometry shows that BL-8040 monotherapy caused an approximately two-fold reduction in frequency of peripheral T regulatory cells, but had no effect on the frequency of T cells, NKT cells or cell populations that contain B cells (CD3- CD56-). Additionally, BL-8040 remained bound to CXCR4 on peripheral immune cells throughout the period of monotherapy. Analysis of available biopsies (N = 7) shows an up to 15-fold increase in the CD3+ population, and up to two-fold increase of CD8+ cells, in the tumor periphery and TME of 43% (3/7) of the patients after five days of BL-8040 monotherapy compared to baseline. Conclusions: In summary, the PD biomarker results in humans support the proposed mechanism of action for BL-8040 that was based on preclinical mouse models. Analysis of tumor biopsies is ongoing, with an emphasis on investigating the effects of BL-8040 on tumor-resident immune cells and the TME. Clinical trial information: NCT02826486.

scholarly journals Synergy between Toxoplasma gondii type I ΔGRA17 immunotherapy and PD-L1 checkpoint inhibition triggers the regression of targeted and distal tumors

2021 ◽  
Vol 9 (11) ◽  
pp. e002970
Author(s):  
Yu-Chao Zhu ◽  
Hany M Elsheikha ◽  
Jian-Hua Wang ◽  
Shuai Fang ◽  
Jun-Jun He ◽  
...  
Keyword(s):  
Immune Response ◽  
Toxoplasma Gondii ◽  
Tumor Growth ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Immune Cell ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Complete Regression ◽  
Type I

BackgroundIn this study, we hypothesize that the ability of the protozoan Toxoplasma gondii to modulate immune response within the tumor might improve the therapeutic effect of immune checkpoint blockade. We examined the synergetic therapeutic activity of attenuated T. gondii RH ΔGRA17 strain and programmed death ligand-1 (PD-L1) treatment on both targeted and distal tumors in mice.MethodsThe effects of administration of T. gondii RH ΔGRA17 strain on the tumor volume and survival rate of mice bearing flank B16-F10, MC38, or LLC tumors were studied. We characterized the effects of ΔGRA17 on tumor biomarkers’ expression, PD-L1 expression, immune cells infiltrating the tumors, and expression of immune-related genes by using immunohistochemistry, immunofluorescence, flow cytometry, NanoString platform, and real-time quantitative PCR, respectively. The role of immune cells in the efficacy of ΔGRA17 plus PD-L1 blockade therapy was determined via depletion of immune cell subtypes.ResultsTreatment with T. gondii ΔGRA17 tachyzoites and anti-PD-L1 therapy significantly extended the survival of mice and suppressed tumor growth in preclinical mouse models of melanoma, Lewis lung carcinoma, and colon adenocarcinoma. Attenuation of the tumor growth was detected in the injected and distant tumors, which was associated with upregulation of innate and adaptive immune pathways. Complete regression of tumors was underpinned by late interferon-gamma-producing CD8+ cytotoxic T cells.ConclusionThe results from these models indicate that intratumoral injection of ΔGRA17 induced a systemic effect, improved mouse immune response, and sensitized immunologically ‘cold’ tumors and rendered them sensitive to immune checkpoint blockade therapy.

Evaluation of pharmacodynamic (PD) biomarkers in patients with metastatic pancreatic cancer treated with BL-8040, a novel CXCR4 antagonist.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 276-276 ◽  
Author(s):  
Manuel M. Hidalgo ◽  
Ron Epelbaum ◽  
Valeriya Semenisty ◽  
Ravit Geva ◽  
Talia Golan ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Flow Cytometry ◽  
Immune Cells ◽  
Immune Cell ◽  
Cell Subset ◽  
Fold Increase ◽  
Cell Infiltration ◽  
Metastatic Pancreatic Cancer ◽  
Cxcr4 Antagonist ◽  
Open Label

276 Background: BL-8040 is a novel CXCR4 antagonist being developed for multiple oncology indications. Preclinical studies demonstrated that BL-8040 increases the number of immune cells in peripheral blood and promotes CD8+ T cell infiltration into orthotropic pancreatic mouse tumors, reducing tumor load. BL-8040 is being evaluated in a Phase 2a, multicenter, open label trial in patients with metastatic pancreatic cancer (the COMBAT study). Patients are undergoing a 5-day period of monotherapy in which they receive daily doses of BL-8040, followed by 21-day cycles in which patients receive one dose of pembrolizumab and 3 doses/week of BL-8040 until disease progression or discontinuation. To date, 32 patients have been enrolled. Methods: On Day 1 and Day 5, blood samples were taken at pre- and post-dosing, to evaluate peripheral immune cell subset frequency by flow cytometry. In addition, core biopsies were taken from liver metastases, where possible, to assess immune cell infiltration into tumors and the tumor microenvironment (TME). Results: Here we present interim PD biomarker data from the BL-8040 monotherapy portion of the trial. Flow cytometry shows that BL-8040 monotherapy caused an approximately two-fold reduction in frequency of peripheral T regulatory cells, but had no effect on the frequency of T cells, NKT cells or cell populations that contain B cells (CD3- CD56-). Additionally, BL-8040 remained bound to CXCR4 on peripheral immune cells throughout the period of monotherapy. Analysis of available biopsies (N = 7) shows an up to 15-fold increase in the CD3+ population, and up to two-fold increase of CD8+ cells, in the tumor periphery and TME of 43% (3/7) of the patients after five days of BL-8040 monotherapy compared to baseline. Conclusions: In summary, the PD biomarker results in humans support the proposed mechanism of action for BL-8040 that was based on preclinical mouse models. Analysis of tumor biopsies is ongoing, with an emphasis on investigating the effects of BL-8040 on tumor-resident immune cells and the TME. Clinical trial information: NCT02826486.

scholarly journals A TLR4 agonist improves immune checkpoint blockade treatment by increasing the ratio of effector to regulatory cells within the tumor microenvironment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
A. Farias ◽  
A. Soto ◽  
F. Puttur ◽  
C. J. Goldin ◽  
S. Sosa ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Therapeutic Effect ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Combined Treatment ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Regulatory Cells ◽  
Ifn Γ

AbstractBrucella lumazine synthase (BLS) is a homodecameric protein that activates dendritic cells via toll like receptor 4, inducing the secretion of pro-inflammatory cytokines and chemokines. We have previously shown that BLS has a therapeutic effect in B16 melanoma-bearing mice only when administered at early stages of tumor growth. In this work, we study the mechanisms underlying the therapeutic effect of BLS, by analyzing the tumor microenvironment. Administration of BLS at early stages of tumor growth induces high levels of serum IFN-γ, as well as an increment of hematopoietic immune cells within the tumor. Moreover, BLS-treatment increases the ratio of effector to regulatory cells. However, all treated mice eventually succumb to the tumors. Therefore, we combined BLS administration with anti-PD-1 treatment. Combined treatment increases the outcome of both monotherapies. In conclusion, we show that the absence of the therapeutic effect at late stages of tumor growth correlates with low levels of serum IFN-γ and lower infiltration of immune cells in the tumor, both of which are essential to delay tumor growth. Furthermore, the combined treatment of BLS and PD-1 blockade shows that BLS could be exploited as an essential immunomodulator in combination therapy with an immune checkpoint blockade to treat skin cancer.

scholarly journals The Crosstalk Between Malignant Cells and Tumor-Promoting Immune Cells Relevant to Immunotherapy in Pancreatic Ductal Adenocarcinoma

2022 ◽  
Vol 9 ◽  
Author(s):  
Xuefei Liu ◽  
Ziwei Luo ◽  
Xuechen Ren ◽  
Zhihang Chen ◽  
Xiaoqiong Bao ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Rna Sequencing ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Immune Cell ◽  
Immune Checkpoint Blockade ◽  
Ductal Adenocarcinoma ◽  
Malignant Cells ◽  
Sequencing Data ◽  
Immunosuppressive Microenvironment

Background: Pancreatic ductal adenocarcinoma (PDAC) is dominated by an immunosuppressive microenvironment, which makes immune checkpoint blockade (ICB) often non-responsive. Understanding the mechanisms by which PDAC forms an immunosuppressive microenvironment is important for the development of new effective immunotherapy strategies.Methods: This study comprehensively evaluated the cell-cell communications between malignant cells and immune cells by integrative analyses of single-cell RNA sequencing data and bulk RNA sequencing data of PDAC. A Malignant-Immune cell crosstalk (MIT) score was constructed to predict survival and therapy response in PDAC patients. Immunological characteristics, enriched pathways, and mutations were evaluated in high- and low MIT groups.Results: We found that PDAC had high level of immune cell infiltrations, mainly were tumor-promoting immune cells. Frequent communication between malignant cells and tumor-promoting immune cells were observed. 15 ligand-receptor pairs between malignant cells and tumor-promoting immune cells were identified. We selected genes highly expressed on malignant cells to construct a Malignant-Immune Crosstalk (MIT) score. MIT score was positively correlated with tumor-promoting immune infiltrations. PDAC patients with high MIT score usually had a worse response to immune checkpoint blockade (ICB) immunotherapy.Conclusion: The ligand-receptor pairs identified in this study may provide potential targets for the development of new immunotherapy strategy. MIT score was established to measure tumor-promoting immunocyte infiltration. It can serve as a prognostic indicator for long-term survival of PDAC, and a predictor to ICB immunotherapy response.

scholarly journals IL-35 Regulates the Function of Immune Cells in Tumor Microenvironment

2021 ◽  
Vol 12 ◽  
Author(s):  
Kewei Liu ◽  
Ai Huang ◽  
Jun Nie ◽  
Jun Tan ◽  
Shijie Xing ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Immune Cells ◽  
Immune Checkpoint Blockade ◽  
Future Research ◽  
Barr Virus ◽  
Promote Tumor Growth ◽  
Epstein Barr ◽  
Mechanistic Basis ◽  
Tumor Growth And Metastasis

Interleukin-35 (IL-35) is a heterodimeric cytokine composed of Epstein-Barr virus-induced gene 3 (EBI3) and IL-12p35 that has recently been shown to play diverse and important roles in the tumor microenvironment (TME). Owing to its immunosuppressive activity and ability to promote tumor growth and progression, IL-35 is widely recognized as a key mediator of TME status. Immune cells are key mediators of diverse tumor-related phenotypes, and immunosuppressive cytokines such as IL-35 can promote tumor growth and metastasis in TME. These influences should be considered together. Since tumor immunotherapy based on immune checkpoint blockade remains ineffective in many patients due to tumoral resistance, a new target or efficacy enhancing factor is urgently needed. Suppressing IL-35 production and activity has been demonstrated as an effective factor that inhibits tumor cells viability, and further investigation of this cytokine is warranted. However, the mechanistic basis for IL-35-mediated regulation of immune cells in the TME remains to be fully clarified. In the present review, we explore the roles of IL-35 in regulating immune cells within the TME. In addition, we highlight IL-35 as a specific immunological target and discuss its possible relevance in the context of immunotherapy. Lastly, we sought to summarize potential future research directions that may guide the advancement of current understanding regarding the role of this important cytokine as a regulator of oncogenesis.

scholarly journals Applications of Single-Cell Omics to Dissect Tumor Microenvironment

2020 ◽  
Vol 11 ◽  
Author(s):  
Tingting Guo ◽  
Weimin Li ◽  
Xuyu Cai
Keyword(s):  
Tumor Microenvironment ◽  
Single Cell ◽  
Immune Cells ◽  
Immune Cell ◽  
Cell Types ◽  
Immune Checkpoint Blockade ◽  
Lineage Tracing ◽  
Great Success ◽  
Novel Technologies ◽  
Single Cell Sequencing

The recent technical and computational advances in single-cell sequencing technologies have significantly broaden our toolkit to study tumor microenvironment (TME) directly from human specimens. The TME is the complex and dynamic ecosystem composed of multiple cell types, including tumor cells, immune cells, stromal cells, endothelial cells, and other non-cellular components such as the extracellular matrix and secreted signaling molecules. The great success on immune checkpoint blockade therapy has highlighted the importance of TME on anti-tumor immunity and has made it a prime target for further immunotherapy strategies. Applications of single-cell transcriptomics on studying TME has yielded unprecedented resolution of the cellular and molecular complexity of the TME, accelerating our understanding of the heterogeneity, plasticity, and complex cross-interaction between different cell types within the TME. In this review, we discuss the recent advances by single-cell sequencing on understanding the diversity of TME and its functional impact on tumor progression and immunotherapy response driven by single-cell sequencing. We primarily focus on the major immune cell types infiltrated in the human TME, including T cells, dendritic cells, and macrophages. We further discuss the limitations of the existing methodologies and the prospects on future studies utilizing single-cell multi-omics technologies. Since immune cells undergo continuous activation and differentiation within the TME in response to various environmental cues, we highlight the importance of integrating multimodal datasets to enable retrospective lineage tracing and epigenetic profiling of the tumor infiltrating immune cells. These novel technologies enable better characterization of the developmental lineages and differentiation states that are critical for the understanding of the underlying mechanisms driving the functional diversity of immune cells within the TME. We envision that with the continued accumulation of single-cell omics datasets, single-cell sequencing will become an indispensable aspect of the immune-oncology experimental toolkit. It will continue to drive the scientific innovations in precision immunotherapy and will be ultimately adopted by routine clinical practice in the foreseeable future.

Effect of MMP9 inhibition on effector T-cell responses in a PD1-axis refractory model.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 104-104
Author(s):  
Victoria Smith ◽  
Vladi Juric ◽  
Amanda Mikels-Vigdal ◽  
Chris O'Sullivan ◽  
Maria Kovalenko ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Cell Activation ◽  
Immune Cell ◽  
Single Agent ◽  
Fold Increase ◽  
Cytotoxic T Cell

104 Background: Matrix metalloproteinase 9 (MMP9) acts via diverse mechanisms to promote tumor growth and metastasis, and is a key component of the immune-suppressive myeloid inflammatory milieu. We developed a monoclonal antibody (AB0046) that inhibits murine MMP9 and assessed its mechanism of action in immunocompetent mice as a single agent, or in combination with a murine anti-PDL1 antibody. Methods: An orthotopic, syngeneic tumor model (NeuT), which models MMP9-positive myeloid infiltrate, was utilized for efficacy and pharmacodynamic studies involving RNA and T cell receptor (TCR) sequencing, and flow cytometry. Enzymatic analyses were performed on T cell chemoattractant CXCR3 ligands (CXCL9, CXCL10, and CXCL11) which were subsequently evaluated in chemotaxis assays. Results: Anti-MMP9 treatment alone or in combination with an anti-PDL1 antibody decreased primary tumor growth as compared to IgG control-treated animals (56% vs 335% tumor growth increase, p = 0.0005) or anti-PDL1 alone. Profiling of tumors by RNA sequencing revealed that inhibition of MMP9 resulted in elevated expression of genes associated with immune cell activation pathways (Hallmark Interferon Gamma Response, FDR p < 0.001). Treatment with anti-MMP9 and anti-PDL1 antibodies decreased TCR clonality, with evidence of a more diverse TCR repertoire (p = 0.005). Immunophenotyping of tumor-associated T cells by flow cytometry showed that anti-MMP9 and anti-PDL1 co-treatment promoted a 2.8-fold increase in CD3+ cells in tumors (p = 0.01), which was associated with an increase in CD4+ T cells (3.2-fold increase; p = 0.006) and CD8+ T cells (2.8-fold increase; p = 0.013). In contrast, anti-MMP9 and combination treatment resulted in a decrease in tumor-associated regulatory T cells (CD25+ FoxP3+ cells, p = 0.04). MMP9 cleavage of T cell chemoattractant ligands in vitro rendered them functionally inactive for recruitment of activated primary human effector T cells. Conclusions: Inhibition of MMP9 reduces tumor burden and promotes cytotoxic T cell infiltration in a PD1-axis refractory mouse model. The combination of nivolumab and GS-5745, a humanized anti-MMP9 inhibitory antibody, is currently being evaluated in gastric cancer (NCT02864381).

An exploratory study of metformin (Met) with or without rapamycin (Rapa) as maintenance therapy after induction chemotherapy in patients (Pts) with metastatic pancreatic adenocarcinoma (PDA).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 700-700
Author(s):  
Katherine M. Bever ◽  
Erkut Hasan Borazanci ◽  
Elizabeth Thompson ◽  
Annie Wu ◽  
Jennifer N. Durham ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Stable Disease ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Open Label ◽  
Peripheral Blood Mononuclear ◽  
Mtor Inhibition ◽  
Oncogenic Pathways ◽  
Line Of Therapy ◽  
Ecog Ps

700 Background: Few studies have examined maintenance therapy in unselected pts with metastatic PDA (mPDA). mTOR signaling is central to several oncogenic pathways in PDA and also has a role in T cell differentiation and activation, and we hypothesized a role for mTOR inhibition (mTORi) in the maintenance setting. Methods: This was a randomized open-label study conducted at 2 sites. Eligible pts had mPDA with stable disease for ≥6 months on chemotherapy and ECOG PS 0/1. Pts were randomized 1:1 to Met 850mg BID alone (Arm A) or with Rapa 4mg daily (Arm B), stratified by prior FOLFIRINOX. Baseline and on-treatment PET scans and peripheral blood mononuclear cells were obtained for exploratory analyses. Results: 23 pts were randomized. Median age was 64 (range 34-77) and 82% had ECOG PS 1. 12 of 23 received prior FOLFIRINOX; 8 received >1 prior line of therapy. 22 subjects (11 per arm) were treated per protocol. Treatment related adverse events of Grade ≥3 were seen in 0% vs 27% of pts in Arm A vs B and were all asymptomatic hematologic or electrolyte abnormalities that were not clinically significant. Median PFS/OS were 3.5 (95% CI: 2.9-9.2)/13.2 mos (95% CI: 7.8 to not reached) respectively, with 2 yr OS rate of 37% (95% CI: 21-66%); there were no differences between treatment arms. As expected in the maximally debulked setting, no responses were observed by RECIST; however, decreases in FDG avidity and/or CA199 were observed in several long-term survivors. Better survival was associated with low baseline neutrophil to lymphocyte ratio, baseline lack of assessable disease by PET, and with expansion of dendritic cells following treatment. Compared to Met alone, Met + Rapa was associated with decreased mTOR activity on some immune cell subsets and decreased metabolic fitness, but this was not correlated with outcome. Conclusions: Met +/- rapa maintenance for mPDA was well-tolerated and several pts achieved stable disease associated with exceptionally long survival. Further prospective studies are needed to clarify the role of mTORi in the maintenance setting and to enhance pt selection for such approaches. Clinical trial information: NCT02048384.

scholarly journals Co-dimension two bifurcations analysis of a delayed tumor model with Allee effect

2021 ◽  
Vol 2021 (1) ◽  
Author(s):  
Qinrui Dai
Keyword(s):  
Growth Rate ◽  
Hopf Bifurcation ◽  
Tumor Growth ◽  
Allee Effect ◽  
Immune Cell ◽  
Functional Differential Equations ◽  
Tumor Model ◽  
Point Of View ◽  
Tumor Growth Rate ◽  
Tumor Models

AbstractThe mathematical model has become an important means to study tumor treatment and has developed with the discovery of medical phenomena. In this paper, we establish a delayed tumor model, in which the Allee effect is considered. Different from the previous similar tumor models, this model is mainly studied from the point of view of stability and co-dimension two bifurcations, and some nontrivial phenomena and conclusions are obtained. By calculation, there are at most two positive equilibria in the system, and their stability is investigated. Based on these, we find that the system undergoes Bautin bifurcation, zero-Hopf bifurcation, and Hopf–Hopf bifurcation with time delay and tumor growth rate as bifurcation parameters. The interesting thing is that there is a Zero-Hopf bifurcation, which is not common in tumor models, making abundant dynamic phenomena appear in the system. By using the bifurcation theory of functional differential equations, we calculate the normal form of these Co-dimension two bifurcations. Finally, with the aid of MATLAB package DDE-BIFTOOL, some numerical simulations have been performed to support our theoretical results. In particular, we obtain the bifurcation diagram of the system in the two parameter plane and divide its regions according to the bifurcation curves. Meanwhile, the phenomena of multistability and periodic coexistence of some regions can be also demonstrated. Combined with the simulation results, we can know that when the tumor growth rate and the delay of immune cell apoptosis are small, the tumor may tend to be stable, and vice versa.

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