scholarly journals Submicron particle docetaxel intratumoral injection in combination with anti-mCTLA-4 into 4T1-Luc orthotopic implants reduces primary tumor and metastatic pulmonary lesions

2021 ◽  
Vol 38 (9) ◽  
Author(s):  
Holly Maulhardt ◽  
Alyson Marin ◽  
Holly Hesseltine ◽  
Gere diZerega
Keyword(s):  
Combination Treatment ◽  
Immune Cell ◽  
Group Versus ◽  
Suppressor Cells ◽  
Tumor Model ◽  
Intratumoral Injection ◽  
Combination Group ◽  
Submicron Particle ◽  
Breast Cancer Model ◽  
Treatment Tolerance

AbstractWe describe here characterization of the response of local and metastatic disease and immunomodulation following intratumoral (IT) injection of submicron particle docetaxel (SPD) administered alone or in combination with systemic antibody anti-mCTLA-4 (anti-mCTLA-4) in the metastatic 4T1-Luc2-1A4 (4T1) murine breast cancer model. In-life assessments of treatment tolerance, tumor volume (TV), and metastasis were performed (n = 10 animals/group). At study end, immune cell populations in tumor-site tissues and peripheral blood were analyzed using flow cytometry. Signs of distress typical of this aggressive tumor model occurred across all animals except for the combination treated which were asymptomatic and gained weight. TV at study end was significantly reduced in the combination group versus untreated [43% reduced (p < 0.05)] and vehicle controls [54% reduced (p < 0.0001)]. No evidence of thoracic metastasis was found in 40% of combination group animals and thoracic bioluminescence imaging (BLI) was reduced vs. untreated controls (p < 0.01). Significant elevations (p < 0.05) in CD4 + T, CD4 + helper T, Treg, and NKT cells were found in tumor and blood in SPD or combination treatment compared to controls or anti-mCTLA-4. Combination treatment increased tumor-associated CD8 + T cells (p < 0.01), peripheral B cells (p < 0.01), and tumor associated and circulating dendritic cells (DC) (p < 0.05). Tumor-associated NK cells were significantly increased in SPD ± anti-mCTLA-4 treatments (p < 0.01). Myeloid-derived suppressor cells (MDSC) were reduced in bloods in SPD ± anti-mCTLA-4 groups (p < 0.05). These data demonstrate that both SPD and anti-mCTLA-4 produce local anti-tumor effects as well as reductions in metastasis which are significantly enhanced when administered in combination.

scholarly journals High potency STING agonists engage unique myeloid pathways to reverse pancreatic cancer immune privilege

2021 ◽  
Vol 9 (8) ◽  
pp. e003246
Author(s):  
Casey R Ager ◽  
Akash Boda ◽  
Kimal Rajapakshe ◽  
Spencer Thomas Lea ◽  
Maria Emilia Di Francesco ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Pancreatic Adenocarcinoma ◽  
T Cell Activation ◽  
Cell Activation ◽  
Suppressor Cells ◽  
Intratumoral Injection ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
High Potency

BackgroundIntratumoral injection of cyclic dinucleotide (CDN) agonists of the stimulator of interferon genes (STING) pathway engages innate immune activation and priming of adaptive immune effectors to foster local and distal tumor clearance. Despite proven therapeutic efficacy in preclinical models, a thorough understanding of how CDNs reprogram suppressive myeloid stroma in mouse and man is lacking.MethodsHere, we perform deep transcript-level and protein-level profiling of myeloid-derived suppressor cells and M2 macrophages following stimulation with CDNs of ascending potency. Additionally, we leverage orthotopic Kras+/G12DTP53+/R172HPdx1-Cre (KPC) derived models of pancreatic adenocarcinoma (PDAC) to determine the capacity for locally administered CDNs to sensitize PDAC to immune checkpoint blockade. We use bioluminescent in vivo imaging and 30-parameter flow cytometry to profile growth kinetics and remodeling of the tumor stroma post-therapy.ResultsHighly potent synthetic STING agonists repolarize suppressive myeloid populations of human and murine origin in part through inhibition of Myc signaling, metabolic modulation, and antagonism of cell cycle. Surprisingly, high-potency synthetic agonists engage qualitatively unique pathways as compared with natural CDNs. Consistent with our mechanistic observations, we find that intratumoral injection of the highest activity STING agonist, IACS-8803, into orthotopic pancreatic adenocarcinoma lesions unmasks sensitivity to checkpoint blockade immunotherapy. Dimensionality reduction analyses of high parameter flow cytometry data reveals substantial contributions of both myeloid repolarization and T cell activation underlying the in vivo therapeutic benefit of this approach.ConclusionsThis study defines the molecular basis of STING-mediated myeloid reprogramming, revealing previously unappreciated and qualitatively unique pathways engaged by CDNs of ascending potency during functional repolarization. Furthermore, we demonstrate the potential for high potency CDNs to overcome immunotherapy resistance in an orthotopic, multifocal model of PDAC.

scholarly journals The impact of adding solifenacin to tamsulosin therapy for treatment of storage lower urinary tract symptoms owing to benign prostatic hyperplasia

2020 ◽  
Vol 26 (1) ◽  
Author(s):  
Mohamed Elbadry ◽  
Ahmed Issam Ali ◽  
Eman Saleh ◽  
Amal Kamal ◽  
Ahmed H. Gabr
Keyword(s):  
Quality Of Life ◽  
Lower Urinary Tract ◽  
Group Versus ◽  
Prostatic Hyperplasia ◽  
Combination Group ◽  
Urinary Tract Symptoms ◽  
Bladder Symptoms ◽  
Group 1 ◽  
Lower Urinary

Abstract Background Benign prostatic hyperplasia (BPH) is a common problem in aging males which has a potential impact on patients’ health-related quality of life. In the present prospective study, we evaluated the effect of adding solifenacin to tamsulosin, compared to tamsulosin alone on overactive bladder symptoms scores (OABSS) and patients’ quality of life (QoL) in patients with filling lower urinary tract symptoms due to BPH. Methods Patients included in our study were randomly assigned into 2 groups: group 1 included patients with BPH who received tamsulosin alone and group 2 included patients with BPH who received a combination of tamsulosin and sofinacin. Treatment period was 12 weeks in both groups. Quality of life and overactive bladder symptoms score questionnaires were obtained and compared in both groups before and after treatment. Results No significant differences were found between both groups before treatment. At the end of treatment period, The QoL score for Group 1 patients was significantly greater than the other group (mean rank was 138.98 in tamsulosin group versus 62.02 in the combination group, P-value < 0.01). Similarly, OABSS for tamsulosin only group was significantly higher than combined treatment patients (mean rank was 145.03 in tamsulin group versus 55.98 in the combination group, P-value < 0.01). Conclusion Adding solifenacin to tamsulosin was associated with an improvement of QoL and OABSS in patients with irritative urinary symptoms due to BPH when compared with tamsulosin monotherapy.

scholarly journals THER-09. ONCOLYTIC ADENOVIRUS, DNX-2401, FOR NAIVE DIFFUSE INTRINSIC PONTINE GLIOMAS: A PHASE I CLINICAL TRIAL

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii473-iii473
Author(s):  
Ignacio Iñigo-Marco ◽  
Marisol Gonzalez-Huarriz ◽  
Marc García-Moure ◽  
Ibon Tamayo ◽  
Sandra Hervas ◽  
...  
Keyword(s):  
T Cell ◽  
Neutralizing Antibodies ◽  
Immune Cell ◽  
Combined Treatment ◽  
Intratumoral Injection ◽  
Post Treatment ◽  
Virus Infectivity ◽  
Tumor Biopsy ◽  
Functional Studies ◽  
Cell Diversity

Abstract The objective of this trial is to determine the safety, tolerability, and toxicity of DNX-2401 in newly diagnosed DIPG patients (NCT03178032) followed by radiotherapy. Secondary endpoints are overall survival at 12 months, percentage of responses and induced immune response against tumor. Tumor biopsy was performed through the cerebellar peduncle, followed by intratumoral injection of DNX-2401 (N=12). Three patients were treated with 1x1010vp and given the lack of toxicity we escalated to 5x1010vp. The procedure was well tolerated and reduced tumor volume was demonstrated in all patients after combined treatment (virus + radiotherapy). We performed molecular studies (RNAseq and the Oncomine Childhood Research Panel from Thermo Fisher). The immune cell composition of the biopsies pre-virus injection was assessed using multiplexed quantitative immunofluorescence. T cells were hardly detectable in these tumors while macrophages were abundant. Using a multiplexed TCR-sequencing mRNA-based assay to analyze 18 available paired pre- and post-treatment samples from the trial, we detected increased clonal T cell diversity following treatment with the virus. We also measured pre and post treatment neutralizing antibodies and their relationship with survival. Finally, we performed functional studies using 2 cell lines isolated from patients included in this trial to assess the response to the virus (infectivity, viability, T-cell recognition). In summary, the virus has shown safety and efficacy in some patients. The information obtained in this clinical study would aid understanding the response of DIPG patients to viral therapies and, therefore, to better tailor this strategy to improve the survival of these patients.

scholarly journals Temporal Changes in Immune Responses within the Tumor Microenvironment in the 4T1.2-HER2 Mammary Tumor Model

2021 ◽  
Author(s):  
Yitong Xu ◽  
Connie Rogers
Keyword(s):  
Immune Responses ◽  
Tumor Growth ◽  
Immune Cells ◽  
Tumor Regression ◽  
Tumor Model ◽  
Second Phase ◽  
Tumor Inoculation ◽  
Cancer Model ◽  
Breast Cancer Model ◽  
Initial Tumor

Abstract Background: The murine 4T1.2 triple-negative breast cancer model is widely used, but is poorly immunogenic with no defined tumor-associated antigens. A modified 4T1.2 model has been developed that stably expresses a surrogate tumor antigen, human epidermal growth factor receptor-2 (HER2). The goal of the current study was to characterize host immune responses in the 4T1.2-HER2 tumor model, focusing on the tumor microenvironment (TME) during the early stage of tumor development. Methods: Female BALB/c mice were orthotopically inoculated with 4T1.2-HER2 tumor cells and sacrificed at day (D) 6, 9, 12, 15 and 18 post tumor inoculation. The phenotype and function of tumor-infiltrating immune cells were assessed. Results: 4T1.2 and 4T1.2-HER2 tumor cells had similar proliferation rates in vitro. In contrast to the rapid progression of the parental 4T1.2 model, the 4T1.2-HER2 model demonstrated initial tumor growth followed by spontaneous tumor regression by D18 post tumor inoculation, which was not observed in scid mice. Following tumor regression, mice demonstrated either a second phase of tumor outgrowth or complete tumor rejection. Within the TME, the percentage of T cells was reduced at D9 and increased during tumor regression through D18 (p<0.05), whereas the percentage of myeloid-derived suppressor cells (MDSCs) increased during the initial tumor growth and was reduced by D18 (p<0.01). There was a stepwise increase in the percentage of IFNg+, IL-2+ and perforin+ T cells and NK cells peaking at D12-15. Furthermore, tumor regression occurred concurrently with HER2-specific IFNg production from tumor-infiltrating immune cells at D12 and D15 (p<0.05). During the second phase of 4T1.2-HER2 tumor growth, tumor volume was negatively correlated with immune infiltration (r=0.662, p=0.052). Conclusions: These results suggest that the integration of a surrogate tumor antigen, human HER2, into the clinically relevant, yet poorly immunogenic 4T1.2 breast cancer model enhanced its immunogenicity and induced HER2-specific immune responses.

scholarly journals EXTH-32. TARGETED STAT3 INHIBITION IMPAIRS MDSC MOBILIZATION AND RECRUITMENT IN GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii93-ii94
Author(s):  
Christina von Roemeling ◽  
Chenglong Li ◽  
Duane Mitchell
Keyword(s):  
Immune Cell ◽  
Large Fraction ◽  
Single Agent ◽  
Suppressor Cells ◽  
Peripheral Circulation ◽  
Immune Checkpoint Blockade ◽  
Tumor Burden ◽  
Checkpoint Blockade ◽  
Specific Marker ◽  
Stat3 Phosphorylation

Abstract BACKGROUND Glioblastoma tumors (GBM) are comprised upwards of 30 percent by glioma-associated myeloid cells (GAMs). A large fraction of GAMs are myeloid-derived suppressor cells (MDSC) thought to traffic in from peripheral circulation. MDSCs foster a hospitable environment for cancer cells by regulating immune suppression and driving resistance to immunotherapy. While signal transducer and activator of transcription 3 (STAT3) is considered to be a specific marker for MDSCs and is a known player in their phenotypic polarization in cancer, we sought to closely examine its specific role in MDSC trafficking and tumor recruitment. HYPOTHESIS Targeted inhibition of STAT3 blocks MDSC from the bone marrow, mitigating their accumulation within GBM tumors. METHODS Human and murine GBM samples were analyzed for immune-specific STAT3 phosphorylation (P-STAT3). Immune cell characterization and quantification in peripheral and GBM tissue from syngeneic murine models treated with a novel STAT3 inhibitor (LLL12B) was done. Therapeutic responses to LLL12B alone and in combination with immune checkpoint blockade were evaluated. RESULTS We found P-STAT3 to be predominantly expressed by tumor-associated immune cells in both human and murine GBM, particularly MDSCs. Circulating numbers of MDSCs dramatically increase in response to tumor burden. P-STAT3 is elevated in these cells, indicating that its activation occurs prior to tumor infiltration. LLL12B blockade of STAT3 significantly reduced the number of circulating and tumor-infiltrating MDSCs. As a single agent LLL12B reduced tumor volume and extended the survival of murine GBM models. When combined with anti-PD-1 checkpoint blockade, we observed durable survival in a significant fraction of treated mice. CONCLUSIONS These findings advocate a critically important role for STAT3 in regulating MDSC mobilization and trafficking to GBM tumors. It additionally reveals a new therapeutic mechanism of action for LLL12B that may be relevant for other direct inhibitors of STAT3, influencing their clinical applicability to treat GBM.

scholarly journals Mouse Breast Carcinoma Monocytic/Macrophagic Myeloid-Derived Suppressor Cell Infiltration as a Consequence of Endothelial Dysfunction in Shb-Deficient Endothelial Cells Increases Tumor Lung Metastasis

2021 ◽  
Vol 22 (21) ◽  
pp. 11478
Author(s):  
Qi He ◽  
Maria Jamalpour ◽  
Eric Bergquist ◽  
Robin L. Anderson ◽  
Karin Gustafsson ◽  
...  
Keyword(s):  
Breast Carcinoma ◽  
Lung Metastasis ◽  
Immune Cells ◽  
Tyrosine Kinases ◽  
Immune Cell ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Suppressor Cells ◽  
Suppressor Cell ◽  
Barrier Properties

Metastasis reflects both the inherent properties of tumor cells and the response of the stroma to the presence of the tumor. Vascular barrier properties, either due to endothelial cell (EC) or pericyte function, play an important role in metastasis in addition to the contribution of the immune system. The Shb gene encodes the Src homology-2 domain protein B that operates downstream of tyrosine kinases in both vascular and immune cells. We have investigated E0771.lmb breast carcinoma metastasis in mice with conditional deletion of the Shb gene using the Cdh5-CreERt2 transgene, resulting in inactivation of the Shb-gene in EC and some hematopoietic cell populations. Lung metastasis from orthotopic tumors, tumor vascular and immune cell characteristics, and immune cell gene expression profiles were determined. We found no increase in vascular leakage that could explain the observed increase in metastasis upon the loss of Shb expression. Instead, Shb deficiency in EC promoted the recruitment of monocytic/macrophagic myeloid-derived suppressor cells (mMDSC), an immune cell type that confers a suppressive immune response, thus enhancing lung metastasis. An MDSC-promoting cytokine/chemokine profile was simultaneously observed in tumors grown in mice with EC-specific Shb deficiency, providing an explanation for the expanded mMDSC population. The results demonstrate an intricate interplay between tumor EC and immune cells that pivots between pro-tumoral and anti-tumoral properties, depending on relevant genetic and/or environmental factors operating in the microenvironment.

scholarly journals Early Myeloid Derived Suppressor Cells (eMDSCs) Are Associated With High Donor Myeloid Chimerism Following Haploidentical HSCT for Sickle Cell Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Deepali K. Bhat ◽  
Purevdorj B. Olkhanud ◽  
Arunakumar Gangaplara ◽  
Fayaz Seifuddin ◽  
Mehdi Pirooznia ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Graft Rejection ◽  
Immune Cell ◽  
Plasma Concentrations ◽  
Suppressor Cells ◽  
Suppressor Cell ◽  
Cell Disease ◽  
Hematopoietic Stem ◽  
Post Transplant

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is a widely available curative option for patients with sickle cell disease (SCD). Our original non-myeloablative haplo-HSCT trial employing post-transplant (PT) cyclophosphamide had a low incidence of GVHD but had high rejection rates. Here, we aimed to evaluate immune reconstitution following haplo-HSCT and identify cytokines and cells associated with graft rejection/engraftment. 50 cytokines and 10 immune cell subsets were screened using multiplex-ELISA and flow cytometry, respectively, at baseline and PT-Days 30, 60, 100, and 180. We observed the most significant differences in cytokine levels between the engrafted and rejected groups at PT-Day 60, corresponding with clinical findings of secondary graft rejection. Of the 44 cytokines evaluated, plasma concentrations of 19 cytokines were different between the two groups at PT-Day 60. Factor analysis suggested two independent factors. The first factor (IL-17A, IL-10, IL-7, G-CSF, IL-2, MIP-1a, VEGF, and TGFb1 contributed significantly) was strongly associated with engraftment with OR = 2.7 (95%CI of 1.4 to 5.4), whereas the second factor (GROa and IL-18 contributed significantly) was not significantly associated with engraftment. Sufficient donor myeloid chimerism (DMC) is critical for the success of HSCT; here, we evaluated immune cells among high (H) DMC (DMC≥20%) and low (L) DMC (DMC&lt;20%) groups along with engrafted and rejected groups. We found that early myeloid-derived suppressor cell (eMDSC) frequencies were elevated in engrafted patients and patients with HDMC at PT-Day 30 (P&lt; 0.04 &amp; P&lt; 0.003, respectively). 9 of 20 patients were evaluated for the source of eMDSCs. The HDMC group had high mixed chimeric eMDSCs as compared to the LDMC group (P&lt; 0.00001). We found a positive correlation between the frequencies of eMDSCs and Tregs at PT-Day 100 (r=0.72, P &lt;0.0007); eMDSCs at BSL and Tregs at PT-Day 100 (r=0.63, P &lt;0.004). Of 10 immune regulatory cells and 50 cytokines, we observed mixed chimeric eMDSCs and IL-17A, IL-10, IL-7, G-CSF, IL-2, MIP-1a, VEGF, TGFb1 as potential hits which could serve as prognostic markers in predicting allograft outcome towards engraftment following haploidentical HSCT employing post-transplant cyclophosphamide. The current findings need to be replicated and further explored in a larger cohort.

When will it be better? Lenvatinib combined with TACE for unresectable hepatocellular carcinoma: A retrospective analysis of real-world evidence in China.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 281-281
Author(s):  
Lan Zhang ◽  
Yanhong Wang ◽  
Ningling Ge ◽  
Yu-Hong Gan ◽  
ZhengGang Ren ◽  
...  
Keyword(s):  
Combination Treatment ◽  
Real World ◽  
Response Rate ◽  
Objective Response ◽  
Progression Free Survival ◽  
Combination Group ◽  
Optimal Timing ◽  
Real World Data ◽  
Combination Strategy ◽  
Significant Difference

281 Background: TACE and lenvatinib has each shown to prolong overall survival in patients with unresectable HCC, combination of which may also improve clinical outcomes and have been widely used in the real world accordingly. However, the optimal timing of adding on lenvatinb to TACE remains unclear. We are aiming to evaluate the efficacy and safety between two combination strategies. Methods: From Nov 2018 to Jun 2020, 79 consecutive patients had received a combination treatment of lenvatinib and TACE. Patients followed up for more than 2 months were included in this analysis. They were classified as early-combination group(add on lenvatinib before or after the first TACE ) and late-combination group(add on lenvatinib after at least two procedures of TACE ). Tumor response and progression-free survival (PFS,time from the first day of prescribing lenvatinib to progression or death) were assessed according to RECIST1.1 criteria. Liver function were also evaluated at baseline and every 2 months later. AEs were recorded during the combination treatment period according to CTCAE 5.0. Results: A total of 48 u-HCC patients was finally enrolled. Median follow-up in all patients was 9.3(5.3-14.3)months. Patients’ baseline characteristics were similar in two groups. For early-combination group(n=22)and late-combination group(n=26), the mean age was 65±9.7 and 61±11.6years(p=0.2);BCLC stage C HCC was 59% and 54%(p=0.89);and Child-Pugh A proportion was 81.8% and 77%(p=0.73) respectively. The objective response rate(ORR) was 22.9% in total 48 cases. There was no significant difference in response rate (18.2% vs 26.9%, P=0.51) or disease control rate (90.9% vs 92.3%, P=1.00). Median PFS was significantly longer in the early-combination group than that in late-combination group (14.5 vs 8.9 months; p=0.048). The safety profile was similar between two groups. Grade 3/4 adverse events were 3 (13.6%) and 2 cases(7.7%) respectively (P=0.65). Conclusions: This is to date the first real-world data of the combination timing of lenvatinib with TACE in u-HCC patients. Early-combination strategy may be a better option for the u-HCC patients with a longer mPFS.

Sign in / Sign up

Export Citation Format

Share Document