scholarly journals Activity of tumor-associated macrophage depletion by CSF1R blockade is highly dependent on the tumor model and timing of treatment

2021 ◽  
Author(s):  
Sarah A. O’Brien ◽  
Jessica Orf ◽  
Katarzyna M. Skrzypczynska ◽  
Hong Tan ◽  
Jennie Kim ◽  
...  
Keyword(s):  
Immune Response ◽  
Tumor Growth ◽  
Landscape Heterogeneity ◽  
Tumor Model ◽  
Tumor Growth Inhibition ◽  
Murine Models ◽  
Tumor Implantation ◽  
Tumor Associated Macrophage ◽  
Macrophage Depletion ◽  
Inflammatory State

AbstractTumor-associated macrophages (TAMs) are abundant in solid tumors where they exhibit immunosuppressive and pro-tumorigenic functions. Inhibition of TAM proliferation and survival through CSF1R blockade has been widely explored as a cancer immunotherapy. To further define mechanisms regulating CSF1R-targeted therapies, we systematically evaluated the effect of anti-CSF1R treatment on tumor growth and tumor microenvironment (TME) inflammation across multiple murine models. Despite substantial macrophage depletion, anti-CSF1R had minimal effects on the anti-tumor immune response in mice bearing established tumors. In contrast, anti-CSF1R treatment concurrent with tumor implantation resulted in more robust tumor growth inhibition and evidence of enhanced anti-tumor immunity. Our findings suggest only minor contributions of CSF1R-dependent TAMs to the inflammatory state of the TME in established tumors, that immune landscape heterogeneity across different tumor models can influence anti-CSF1R activity, and that alternative treatment schedules and/or TAM depletion strategies may be needed to maximize the clinical benefit of this approach.

Anti-Tumor Activity of the Aurora a Inhibitor MLN8237 in Diffuse Large B-Cell Lymphoma Preclinical Models.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1592-1592 ◽  
Author(s):  
Jessica J Huck ◽  
Mengkun Zhang ◽  
Marc L Hyer ◽  
Mark G Manfredi
Keyword(s):  
Tumor Growth ◽  
Growth Inhibition ◽  
Tumor Model ◽  
B Cell Lymphoma ◽  
Tumor Growth Inhibition ◽  
Aurora A ◽  
Hct 116 ◽  
Xenograft Models

Abstract Aurora A kinase is a serine/threonine protein kinase that is essential for normal transit of cells through mitosis. In many tumor types the Aurora A gene is amplified and/or the protein is over-expressed. The Aurora A small-molecule inhibitor MLN8237 demonstrated robust tumor growth inhibition in xenograft models of solid tumors grown subcutaneously (S.C.) in immunocompromised mice. Here we explored the antitumor activity of MLN8237 in models of diffuse large B-cell lymphoma (DLBCL) both in vitro and in vivo. In vivo three established DLBCL xenograft models (OCI-Ly7, OCI-Ly19, and WSU-DLCL2; all cells expressing luciferase) and a primary DLBCL tumor model PHTX-22-06 were tested using MLN8237 at different doses. Rituximab, an anti-CD20 monoclonal antibody that is active against CD20+ malignant B cells and is a standard of care agent was used for comparison. Using these model systems, tumor cells were injected either I.V. (to evaluate disseminated disease), or S.C. in severe combined immunodeficient mice (SCID). Animals were dosed orally for 21 days with MLN8237 (QD or BID) at various doses, or Rituximab dosed at 10mg/kg IV (once/week) and tumor growth inhibition was monitored using either bioluminescent imaging for the disseminated models or vernier calipers for the S.C. models. Tumor growth inhibition by MLN8237 was dose dependent with 20 mg/kg bid being the most efficacious dose (TGI>100% in both disseminated OCI-Ly19 and WSU models). All animals in the OCI-Ly19 disseminated model 20 mg/kg BID treatment group demonstrated regressions and remained disease free until the end of the study, day 65. In this study the Rituximab treated animals were euthanized on day 31 due to a high level of tumor burden. In the primary tumor model, PHTX-22-06, MLN8237 dosed at 20 mg/kg BID was also the most efficacious with a TGI of 95%. Moreover, tumor growth inhibition was durable as determined by prolonged tumor growth delay (>50 days). Significant efficacy was achieved in all models tested, whether grown as disseminated or subcutaneous models. A noted increase in durability of response was observed with MLN8237 treatment when compared with previous data from solid tumor models. In vitro, MLN8237 treatment increased levels of apoptosis in the OCI-Ly19 cells in comparison to the solid tumor cell line HCT-116 (colon). Greater Annexin V positive cells and greater cleaved PARP and Caspase-3 signals were detected in the MLN8237 treated OCI-Ly19 cells when compared to HCT-116 cells. The demonstration of robust and durable anti-tumor activity in preclinical models treated with MLN8237 provides the basis for its clinical evaluation as a treatment option for DLBCL. MLN8237 is currently in multiple Phase I clinical trials.

Combination of TLR9 agonists EnanDIM with checkpoint inhibitors for cancer immunotherapy.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 134-134
Author(s):  
Manuel Schmidt ◽  
Kerstin Kapp ◽  
Detlef Oswald ◽  
Burghardt Wittig ◽  
Barbara Volz
Keyword(s):  
Immune System ◽  
Tumor Growth ◽  
Colon Carcinoma ◽  
Mononuclear Cells ◽  
Checkpoint Inhibitors ◽  
Tumor Model ◽  
Tumor Growth Inhibition ◽  
Mouse Tumor ◽  
New Family ◽  
Ifn Alpha

134 Background: TLR9 agonists have shown anti-tumor effects by modulating the innate and adaptive immune system. Ongoing clinical studies support the use of TLR9 agonists for immunotherapeutic approaches. The new family of TLR9 agonists, EnanDIM, consists of linear single-stranded ODN synthesized using L-deoxyribonucleotides (natural enantiomers of D-deoxyribonucleotides) at their 3’-ends to prevent degradation. Therefore, EnanDIM does not own the off-target effects of PTO-modified CpG-ODN. Methods: EnanDIM with varying nucleotid sequences were compared for IFN-alpha response from human peripheral blood mononuclear cells and those molecules inducing the stronges response were selected. A maximum feasible dose (MFD) approach was employed to evaluate their acute toxicity and immunomodulatory properties. In addition, a combinatory approach with aPD-1 was evaluated in an syngeneic colon carcinoma CT26 mouse tumor model. Results: EnanDIM581 and EnanDIM532 were selected due to their pronounced activation of the IFN-alpha pathway in vitro. Safety assessments throughout and a gross necropsy at the end of the study revealed no signs of toxicity despite extremely high doses (300 - 1700 mg/kg). Dose-dependent increase of IP-10 levels in serum was observed between 6 and 24 hours after injection. In the colon carcinoma CT26 model subcutaneous injection of EnanDIM532 and intraperitoneal injection of aPD-1 had a moderate effect on the tumor growth when used in monotherapy (28.3% and 57.0% tumor growth inhibition, TGI). Notably, a combination of EnanDIM532 and aPD-1 further reduced tumor growth (74.7% TGI) and thus prolonged survival of the mice. Conclusions: In conclusion, EnanDIM, a new family of TLR9 agonists and immune surveillance reactivators (ISR), broadly activates the immune system, shows no toxicity in an MFD study and enhances the anti-tumor effects of the aPD-1 checkpoint inhibitor in a pilot study of a murine colon carcinoma tumor model. These data show the promising potential of EnanDIM not only for monotherapeutic but also combinatory approaches.

scholarly journals Vascular disrupting agent induced aggregation of gold nanoparticles for photothermally enhanced tumor vascular disruption

2020 ◽  
Vol 6 (23) ◽  
pp. eabb0020 ◽  
Author(s):  
Sheng Hong ◽  
Di-Wei Zheng ◽  
Cheng Zhang ◽  
Qian-Xiao Huang ◽  
Si-Xue Cheng ◽  
...  
Keyword(s):  
Gold Nanoparticles ◽  
Tumor Growth ◽  
Tumor Therapy ◽  
Tumor Model ◽  
Vascular Damage ◽  
Photothermal Effect ◽  
Tumor Growth Inhibition ◽  
Vascular Disrupting Agent ◽  
Induced Aggregation ◽  
Vascular Disrupting

Although vascular disrupting agents (VDAs) have been extensively implemented in current clinical tumor therapy, the notable adverse events caused by long-term dosing severely limit the therapeutic efficacy. To improve this therapy, we report a strategy for VDA-induced aggregation of gold nanoparticles to further destroy tumor vascular by photothermal effect. This strategy could effectively disrupt tumor vascular and cut off the nutrition supply after just one treatment. In the murine tumor model, this strategy results in notable tumor growth inhibition and gives rise to a 92.7% suppression of tumor growth. Besides, enhanced vascular damage could also prevent cancer cells from distant metastasis. Moreover, compared with clinical therapies, this strategy still exhibits preferable tumor suppression and metastasis inhibition ability. These results indicate that this strategy has great potential in tumor treatment and could effectively enhance tumor vascular damage and avoid the side effects caused by frequent administration.

Polarization of tumor-associated macrophage phenotype via porous hollow iron nanoparticles for tumor immunotherapy in vivo

Nanoscale ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 130-144 ◽  
Author(s):  
Ke Li ◽  
Lu Lu ◽  
Chencheng Xue ◽  
Ju Liu ◽  
Ye He ◽  
...  
Keyword(s):  
Immune Response ◽  
Tumor Growth ◽  
Iron Nanoparticles ◽  
Tumor Immunotherapy ◽  
Macrophage Phenotype ◽  
Tumor Associated Macrophage ◽  
Immunosuppressive Microenvironment ◽  
M1 Type

PHNPs and 3-MA re-polarize TAMs to M1-type by activating the protein of NF-κB p65 and then remodelling the immunosuppressive microenvironment, thus activating immune response and inhibiting tumor growth.

Transgenic expression of CD40 ligand produces an in vivo antitumor immune response against both CD40+ and CD40− plasmacytoma cells

Blood ◽  
2002 ◽  
Vol 100 (1) ◽  
pp. 200-207 ◽  
Author(s):  
Gianpietro Dotti ◽  
Barbara Savoldo ◽  
Patricia Yotnda ◽  
Donna Rill ◽  
Malcolm K. Brenner
Keyword(s):  
Immune Response ◽  
Tumor Growth ◽  
Cell Lines ◽  
Cd40 Ligand ◽  
Additional Treatment ◽  
Antitumor Immune Response ◽  
Tumor Growth Inhibition ◽  
Protective Effects ◽  
Transgenic Expression

Abstract Because tumor-specific antigens have been identified in multiple myeloma (MM), immunotherapy might provide an additional treatment modality for the disease. Expression of CD40 ligand (CD40L) proximate to the MM cells might serve this purpose, either by increasing their capacity to present self-antigens by activation through their CD40 receptor or by the recruitment of professional antigen-presenting cells (APCs) able to take up and present tumor-associated antigens. To distinguish between these possibilities and predict whether human CD40− myeloma might respond to this approach, we examined 3 murine plasmacytoma cell lines, 2 (MPC-11 and S107) expressing the CD40 molecule and 1 (X-24) lacking such expression. Syngeneic BALB/CBYJ mice were inoculated subcutaneously with tumor cells mixed with CL7.1 fibroblasts, retrovirally transduced to express either the mCD40L or the neo gene. For all 3 plasmacytoma cell lines, coinjection with CL7.1/mCD40L significantly reduced local tumor growth compared with controls. This effect was mediated by a systemic antitumor immune response, since mice immunized with tumor and CL7.1/mCD40L were resistant to subsequent challenge with tumor, and tumor growth inhibition was abolished when CD8+or CD4+ lymphocytes were depleted. Because expression of CD40L gave equivalent protection from CD40+ and CD40− tumors and transgenic-CD40L failed to up-regulate costimulatory molecules in either tumor, the protective effects of CD40L probably resulted from recruitment/activation of professional APCs rather than from CD40 activation of plasmacytoma cells. As further support of this concept, we found that mice were also well protected if CL7.1 and CD40L were injected together with apoptotic plasmacytoma cells from these tumors. Hence, transgenic CD40L expression may produce an antimyeloma immune response against either CD40+ or CD40− tumors and may be of therapeutic value for both types of myeloma in humans.

scholarly journals Antitumor efficiency of contact radiotherapy in combination with a chlorin-based photosensitizer in experiment

2021 ◽  
Vol 10 (2) ◽  
pp. 25-33
Author(s):  
D. A. Tzerkovsky ◽  
Ya. L. Protopovich ◽  
D. I. Kozlovsky ◽  
V. A. Suslova
Keyword(s):  
Radiation Therapy ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Tumor Model ◽  
Growth Patterns ◽  
Antitumor Efficacy ◽  
Laboratory Animals ◽  
Tumor Growth Inhibition ◽  
Histological Structure ◽  
Complete Tumor

Authors have studied the antitumor efficacy of contact radiation therapy (CRT) in combination with a chlorin-based photosensitizer (PS) in an experiment on laboratory animals with transplanted tumors. The experimental study was performed in 50 white outbred rats weighing 250±50 g. Subcutaneously transplanted Pliss lymphosarcoma (PLS) and alveolar liver cancer RS1 (RS1) were used as tumor models. Chlorinbased PS photolon (RUE «Belmedpreparaty», Republic Belarus) was injected intravenously at a dose of 2.5 mg/kg. The radiation sessions were carried out 2.5–4 hours (depending on the tumor model) after the administration of the PS using the device «microSelectron HDR V3 Digital» («Nucletron», Netherlands) with a 192-Ir radiation source in single focal doses 5 and 10 Gy. All laboratory animals (for PLS and RS1) were subdivided into 5 groups of 5 animals each: intact control, CRT 5 Gy, CRT 10 Gy, PS + CRT 5 Gy, PS + CRT 10 Gy. For the PLS tumor model – on the 14th day from the beginning of the experiment Vav. in groups were 26.31±5.81; 22.45±6.97; 18.99±4.86; 10.75±5.18 and 28.06±2.85 cm3, respectively (p˂0.05). The coefficients of tumor growth inhibition in the experimental groups were 14.67%, 27.82%, 59.14% and 6.65%, respectively. The frequency of complete tumor regressions 60 days after the start of the experiment was 0%, 20%, 20%, 60%, and 20%, respectively. On RS1 tumor model – on the 14th day from the beginning of the experiment Vav. in groups were 4.48±1.03; 0.80±0.21; 0.29±0.09; 0.19±0.07 and 0.32±0.08 cm3, respectively (p=0.009). The coefficients of tumor growth inhibition in the experimental groups were 82.14%, 93.53%, 95.76% and 92.86%, respectively. The frequency of complete tumor regressions 60 days after the start of the experiment was 0%, 0%, 20%, 0%, and 0%, respectively. Systemic administration of chlorin-based PS before the CRT session increases the antitumor efficacy of radiation therapy in animals with transplantable tumors of different histological structure and growth patterns. The data obtained indicate that further studies of the radiosensitizing properties of PS are promising.

Characterization of an antitumor immune response after light-activated drug therapy using talaporfin sodium in a spontaneously metastasizing mammary tumor model

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3052-3052
Author(s):  
E. Bromley ◽  
B. Owczarczak ◽  
L. Keltner ◽  
S. Wang ◽  
S. O. Gollnick
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Drug Therapy ◽  
Tumor Growth ◽  
Mammary Tumor ◽  
Tumor Model ◽  
Primary Tumors ◽  
Talaporfin Sodium ◽  
Secondary Tumor ◽  
Mammary Tumor Model

3052 Background: An innovative light-activated drug therapy (Litx) is a cytoreductive treatment that uses light-emitting diodes to activate talaporfin sodium (LS11), a water-soluble drug, resulting in the production of singlet oxygen. Tumor destruction involves direct and indirect tumor kill through apoptosis, vascular occlusion, and potentially antitumor immunologic effects. To provide evidence for the potential antitumor immunologic effects, we have used the therapy to treat primary tumors and examine prevention of metastases in the 4T1 tumor model, an aggressive, spontaneously metastasizing murine mammary tumor model that mirrors human breast cancer. When grown in the mammary fat pad of BALB/c mice, untreated 4T1 tumors rapidly metastasize to lung, liver, lymph nodes, and brain. Methods: To confirm tumor kill by this therapy, the primary 4T1 tumors grown in mice were treated and animal survival was followed. To determine whether the therapy could enhance antitumor immunity and reduce metastases, the lymph node (LN) cells from treated and control mice were transferred to naïve recipient mice. Recipients were challenged with a tumorigenic dose of 4T1 cells 3 days after adoptive transfer and primary and secondary tumor growth in the recipients was examined. Results: Treatment of primary tumors significantly increased survival (p≤0.01) when compared to animals treated with either light or drug alone. LN cells isolated from treated mice, but not control mice, significantly inhibited primary tumor growth in recipients (p≤0.0001) and dramatically reduced the number of lung metastases present 40d after tumor challenge (p≤0.02). The ability to inhibit primary and secondary tumor growth in recipients depended on the presence of CD8+ T cells; depletion of CD8+ T cells from the LN abolished the effect. Preliminary evidence for such effect on untreated tumors has been observed in human trials of this therapy. Conclusions: These results indicated that this light-activated drug therapy not only destroyed the treated tumors directly but also controlled growth of untreated tumors through induction of a specific host antitumor immune response mediated by CD8+ T cells. [Table: see text]

scholarly journals Metabolites Profiling of Melanoma Interstitial Fluids Reveals Uridine Diphosphate as Potent Immune Modulator Capable of Limiting Tumor Growth

2021 ◽  
Vol 9 ◽  
Author(s):  
Eleonora Vecchio ◽  
Carmen Caiazza ◽  
Selena Mimmi ◽  
Angelica Avagliano ◽  
Enrico Iaccino ◽  
...  
Keyword(s):  
Immune Response ◽  
Tumor Growth ◽  
Gene Expression Analysis ◽  
Uridine Diphosphate ◽  
Additional Tool ◽  
Tumor Associated Macrophage ◽  
Guanosine Diphosphate ◽  
Expression Of Genes ◽  
Tumor Interstitial Fluid ◽  
Metabolomic Approach

Tumor interstitial fluid (TIF) surrounds and perfuses tumors and collects ions, metabolites, proteins, and extracellular vesicles secreted by tumor and stromal cells. Specific metabolites, accumulated within the TIF, could induce metabolic alterations of immune cells and shape the tumor microenvironment. We deployed a metabolomic approach to analyze the composition of melanoma TIF and compared it to the plasma of C57BL6 mice, engrafted or not with B16-melanoma cells. Among the classes of metabolites analyzed, monophosphate and diphosphate nucleotides resulted enriched in TIF compared to plasma samples. The analysis of the effects exerted by guanosine diphosphate (GDP) and uridine diphosphate (UDP) on immune response revealed that GDP and UDP increased the percentage of CD4+CD25+FoxP3– and, on isolated CD4+ T-cells, induced the phosphorylation of ERK, STAT1, and STAT3; increased the activity of NF-κB subunits p65, p50, RelB, and p52; increased the expression of Th1/Th17 markers including IFNγ, IL17, T-bet, and RORγt; and reduced the expression of IL13, a Th2 marker. Finally, we observed that local administrations of UDP in B16-engrafted C57BL6 mice reduced tumor growth and necrotic areas. In addition, UDP-treated tumors showed a higher presence of MHCIIhi tumor-associated macrophage (TAM) and of CD3+CD8+ and CD3+CD4+ tumor-infiltrating T-lymphocytes (TILs), both markers of anti-tumor immune response. Consistent with this, intra-tumoral gene expression analysis revealed in UDP-treated tumors an increase in the expression of genes functionally linked to anti-tumor immune response. Our analysis revealed an important metabolite acting as mediator of immune response, which could potentially represent an additional tool to be used as an adjuvant in cancer immunotherapy.

scholarly journals 848 Novel small molecule HPK1 inhibitor PCC-1 induces strong anti-tumor activity

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A889-A889
Author(s):  
Sanjib Das ◽  
Sravan Mandadi ◽  
Jagmohan Saini ◽  
Sachin Chaudhari ◽  
Ameya Deshpande ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Small Molecule ◽  
Tumor Model ◽  
Tumor Growth Inhibition ◽  
Target Engagement ◽  
Ct26 Tumor ◽  
Syngeneic Model

BackgroundHematopoietic progenitor kinase 1 (HPK1, MAP4K1), is a negative regulator of T and B cell receptor signaling.1 2 3 A strong anti-tumor immunogenic response and tumor rejection was observed in mice with HPK1 gene knocked out.3 Treatment of HPK1 kinase dead mice with immune check-point blockers (ICBs) demonstrated enhanced tumor growth inhibition.3 Hence, HPK1 is an attractive therapeutic strategy for immuno-oncology based treatment in cancers. In comparison to our previous HPK1 small molecule inhibitor, PCC,4 we present here a differentiated novel HPK1 inhibitor, PCC-1 with good anti-T cell kinases selectivity and stronger anti-tumor efficacy in CT26 tumor model. In addition, using the syngeneic model of MC38 expressing human PD-L1, we present for the first time, the combination efficacy of a HPK1 inhibitor with the clinical ICB, Atezolizumab.MethodsIntuitive medicinal chemistry complemented by structure-based drug design was used to identify & develop potent inhibitors of HPK1 with optimal kinase selectivity, PK and in vivo efficacy profile. The SAR efforts were guided by biochemical assays, functional read-outs and primary human in vitro T-cell activation assays. In vivo target engagement and pharmacodynamic data was generated using CT26 and MC38-hPD-L1 tumor models.ResultsPCC-1 has sub-nanomolar HPK1 inhibition potency and strong target engagement resulting in pSLP76 inhibition, enhanced anti-tumor cytokine production of IL-2 and/or IFNgamma in Jurkat cells, human PBMCs and human whole blood. PCC-1 also demonstrated nanomolar potency in inducing a complete reversal of PGE2 or adenosine mediated immunosuppression. Oral dosing of PCC-1 as a single agent, induced strong tumor growth inhibition (TGI) in the syngeneic model of CT26 and MC38-hPD-L1 tumor models. Combination of PCC-1 with anti-CTLA4 in CT26 tumor model induced significantly greater TGI than anti-CTLA4 alone. Moreover, as a first, the combination of PCC-1 with clinical ICB, Atezolizumab in MC38-hPD-L1 induced enhanced rejection of tumors. These results strongly suggest PCC-1 as a promising candidate for HPK1 inhibition and as a combination partner with ICBs in clinic.ConclusionsPCC-1 is a novel, orally active HPK1 inhibitor that demonstrates excellent stand-alone efficacy and enhances current immunotherapy efficacy. Further evaluation of PCC-1 is ongoing to advance towards clinic.AcknowledgementsWe thank Dnyaneshwar Dahale, Sanjay Patale, Sandip Patil, Vidya Kattige, Jiju Mani, Namrata Singh, Ekta Kashyap, Sandeep Thorat, Pankaj Jain and Pramod Sagar for their contributions to the projectTrial RegistrationN/AReferencesKiefer F, et al. The EMBO Journal 1996.Hu, et al. Genes and Development 1996.Sawasdikosol, Burakoff. eLife 2020;9:e55122.Sachin S Chaudhari, et al. Poster#1709, AACR Annual Meeting April-May 2021.Ethics ApprovalThe studies involving animals have obtained ethics approval from Institutional Animal Ethics Committee (IAEC), The Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), New Delhi, India, GRC/IAEC/472/2020-1. Participants of the studies have given informed consent before taking part.

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