NAP1051, a Lipoxin A4 Biomimetic Analog, Demonstrates Antitumor Activity Against the Tumor Microenvironment

A versatile polyion complex was fabricated which could response to tumor microenvironment and possess remarkable tumor penetrating capability with elevated antitumor activity for LCSCs elimination in vivo.

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In Vivo Evaluation of Immunomodulating Effects of Lenalidomide (L) on Tumor Cell Microenvironment as a Possible Underlying Mechanism of the Antitumor Effects Observed in Patients (pts) with Chronic Lymphocytic Leukemia (CLL).

Blood ◽

10.1182/blood.v106.11.2975.2975 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2975-2975 ◽

Cited By ~ 2

Author(s):

Asher Alban Chanan-Khan ◽

Swaminathan Padmanabhan ◽

Kena C. Miller ◽

Paula Pera ◽

Laurie DiMiceli ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Study ◽

Tumor Microenvironment ◽

Antitumor Activity ◽

Immune Cell ◽

Underlying Mechanism ◽

Antitumor Effects ◽

Absolute Increase

Abstract Introduction: L is a more potent analogue of thalidomide with antitumor activity reported in MDS and multiple myeloma. Clinical anti-leukemic activity of L is reported for the first time by our group in pts with CLL. The underlying mechanism of its antitumor activity remains undetermined. We investigated the effect of L on the tumor microenvironment and studied the modulation of soluble cytokines and immune cells (T and NK cells) in pts receiving L. Patients and Methods: CLL pts enrolled on the clinical study with L were eligible. Pre and post (day 7) samples were obtained for evaluation of changes in serum cytokine and immune cell environment. Malignant cells were also obtained to investigate the in vitro antitumor activity of L prior to initiating treatment on clinical trial. Results: With Anexin V staining for evaluation of apoptosis induction, in vitro testing of pts samples (n=10) showed only a modest increase in apoptosis at 200mg of L - levels clinically not achievable. Yet same pts treated with L on clinical study showed significant antitumor response, suggesting the mechanism to be possibly related to modulation of the tumor microenvironment. In evaluation of the tumor cytokine microenvironment (n= 10) we noted significant L induced increase in IL-10 (n=6), IL-8 (n=8), IP-10 (n=10), IL-8 (n=8), TNF-alpha (n=4) and decrease in PDGF (n=5) and RANTES (n=5). While evaluation of the immune cell repertoire we observed an absolute increase in T-cell as well as NK-cell after treatment with L. Conclusion: Our in vitro evaluation does not suggest a direct apoptotic effect of L on the malignant CLL cells and thus support the hypothesis that the anti-leukemic effect noted in the clinical trial (reported separately) is most likely from in vivo modulation of the tumor microenvironment as is demonstrated from changes in the cytokine milieu and the cellular immune response. Collectively these changes may be responsible for the immune modulating properties of L and the resultant anti-CLL activity in pts.

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Targeting the immunosuppressive tumor microenvironment: Synergistic effect of low-dose IL12 in combination with dual immune checkpoint inhibition in a preclinical model of ovarian cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.5_suppl.7 ◽

2020 ◽

Vol 38 (5_suppl) ◽

pp. 7-7

Author(s):

Paul G. Pavicic ◽

Patricia A. Rayman ◽

Hussein Al-Sudani ◽

C. Marcela Diaz-Montero ◽

Haider Mahdi

Keyword(s):

Ovarian Cancer ◽

T Cells ◽

Tumor Microenvironment ◽

Antitumor Activity ◽

Synergistic Effect ◽

Immune Checkpoint ◽

Low Dose ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition ◽

Activated T Cells

7 Background: Epithelial ovarian cancer (OC) is the most lethal gynecologic cancer with ~22,000 women diagnosed annually in the US. The impact of immune checkpoint inhibition (ICI) in the treatment of solid tumors has been significant. However, the response rates for OC are low ranging from 11-15%. It is critical to explore strategies to enhance the efficacy of ICI immunotherapy in OC. Targeting immunosuppressive factors and cells within the tumor microenvironment (TME) represents a feasible approach. The use of IL12 is attractive because induces potent antitumor activity by targeting myeloid cells and lymphocytes. However its clinical application has been hindered by its potential systemic toxicity. Here we explore the use of low dose intraperitoneal IL12 to enhance the antitumor activity of dual ICI in OC. Methods: Mice bearing ID8-VEGF tumors implanted intraperitoneally received either anti-PD1 alone or dual ICI treatment of anti-PD1 plus anti-CTLA4 with or without low dose IL12. Ascites accumulation was used as surrogate for tumor progression and determined by assessing weight increase. Blood and ascites were analyzed by flow cytometry for frequency of PMN-MDSC, M-MDSC, and activated T cells. Results: Low dose IL12 alone induced a significant delay in ascites accumulation when compared to untreated controls or mice treated with PD1 monotherapy or dual ICI. Addition of IL12 to dual ICI resulted in significant tumor regression and extended survival benefit compared to dual ICI alone. A synergistic effect of IL12 was not observed when combined with PD1 monotherapy. Antitumor responses associated with a marked decrease in the frequency of M-MDSC in blood and a decrease in both PMN- and M-MDSC in ascites. Decrease in MDSC associated with elevated levels of activated T cells. Conclusions: Low dose IL12 can induce regression of ID8-VEGF tumors. However, durable responses were only observed when IL12 was added to dual ICI. This suggests that IL12 can induce changes in the TME, particularly on MDSC, that can potentiate the antitumor activity of dual ICI. Our findings also suggest a crucial role of CTLA4 blockade perhaps via Treg targeting.

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Identification of an immune gene expression signature associated with favorable clinical features in Treg-enriched patient tumor samples

10.1101/246603 ◽

2018 ◽

Author(s):

Kevin B. Givechian ◽

Kamil Wnuk ◽

Chad Garner ◽

Stephen Benz ◽

Hermes Garban ◽

...

Keyword(s):

T Cells ◽

Tumor Microenvironment ◽

Antitumor Activity ◽

Adaptive Immune Response ◽

Gene Expression Signature ◽

Gene Signature ◽

Clinical Feature ◽

Immune Gene ◽

M1 Macrophage ◽

Patient Prognosis

AbstractImmune heterogeneity within the tumor microenvironment undoubtedly adds several layers of complexity to our understanding of drug sensitivity and patient prognosis across various cancer types. Within the tumor microenvironment, immunogenicity is a favorable clinical feature in part driven by the antitumor activity of CD8+ T cells. However, tumors often inhibit this antitumor activity by exploiting the suppressive function of Regulatory T cells (Tregs), thus suppressing the adaptive immune response. Despite the seemingly intuitive immunosuppressive biology of Tregs, prognostic studies have produced contradictory results regarding the relationship between Treg enrichment and survival. We therefore analyzed RNA-seq data of Treg-enriched tumor samples to derive a pan-cancer gene signature able to help reconcile the inconsistent results of Treg studies, by better understanding the variable clinical association of Tregs across alternative tumor contexts. We show that increased expression of a 32-gene signature in Treg-enriched tumor samples (n=135) is able to distinguish a cohort of patients associated with chemosensitivity and overall survival This cohort is also enriched for CD8+ T cell abundance, as well as the antitumor M1 macrophage subtype. With a subsequent validation in a larger TCGA pool of Treg-enriched patients (n = 626), our results reveal a gene signature able to produce unsupervised clusters of Treg-enriched patients, with one cluster of patients uniquely representative of an immunogenic tumor microenvironment. Ultimately, these results support the proposed gene signature as a putative biomarker to identify certain Treg-enriched patients with immunogenic tumors that are more likely to be associated with features of favorable clinical outcome.

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Landscape of innate lymphoid cells in human head and neck cancer reveals divergent NK cell states in the tumor microenvironment

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2101169118 ◽

2021 ◽

Vol 118 (28) ◽

pp. e2101169118

Author(s):

Uriel Y. Moreno-Nieves ◽

Joshua K. Tay ◽

Saumyaa Saumyaa ◽

Nina B. Horowitz ◽

June Ho Shin ◽

...

Keyword(s):

Tumor Microenvironment ◽

Antitumor Activity ◽

Nk Cells ◽

Nk Cell ◽

Human Head ◽

Lymphoid Cells ◽

Cell Phenotype ◽

Tumor Control ◽

Novel Therapy

Natural killer (NK) cells comprise one subset of the innate lymphoid cell (ILC) family. Despite reported antitumor functions of NK cells, their tangible contribution to tumor control in humans remains controversial. This is due to incomplete understanding of the NK cell states within the tumor microenvironment (TME). Here, we demonstrate that peripheral circulating NK cells differentiate down two divergent pathways within the TME, resulting in different end states. One resembles intraepithelial ILC1s (ieILC1) and possesses potent in vivo antitumor activity. The other expresses genes associated with immune hyporesponsiveness and has poor antitumor functional capacity. Interleukin-15 (IL-15) and direct contact between the tumor cells and NK cells are required for the differentiation into CD49a+CD103+ cells, resembling ieILC1s. These data explain the similarity between ieILC1s and tissue-resident NK cells, provide insight into the origin of ieILC1s, and identify the ieILC1-like cell state within the TME to be the NK cell phenotype with the greatest antitumor activity. Because the proportions of the different ILC states vary between tumors, these findings provide a resource for the clinical study of innate immune responses against tumors and the design of novel therapy.

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MAP Kinase inhibition reshapes tumor microenvironment of mouse pancreatic cancer by depleting anti-inflammatory macrophages

10.1101/759779 ◽

2019 ◽

Author(s):

Pietro Delfino ◽

Christian Neander ◽

Dea Filippini ◽

Sabrina L. D’Agosto ◽

Caterina Vicentini ◽

...

Keyword(s):

Tumor Microenvironment ◽

Antitumor Activity ◽

Map Kinase ◽

Ductal Adenocarcinoma ◽

Oncogenic Signaling ◽

Kinase Activation ◽

Immune Contexture ◽

Inflammatory Macrophages

ABSTRACTThe RAF/MEK/ERK (MAP Kinase) pathway is the index oncogenic signaling towards which many compounds have been developed and tested for the treatment of KRAS-driven cancers, including pancreatic ductal adenocarcinoma (PDA). Here, we explored the immunological changes induced by targeted MEK1/2 inhibition (MEKi) using trametinib in preclinical mouse models of PDA. We evaluated the dynamic changes in the immune contexture of mouse PDA upon MEKi using a multidimensional approach (mRNA analyses, flow cytometry, and immunophenotyping). Effect of MEKi on the viability and metabolism of macrophages was investigated in vitro. We showed that transcriptional signatures of MAP Kinase activation are enriched in aggressive human PDA subtype (squamous/basal-like/quasimesenchymal), while short term MEKi treatment in mouse PDA induced subtype switching. Integrative mRNA expression and immunophenotypic analyses showed that MEKi reshapes the immune landscape of PDA by depleting rather than reprogramming macrophages, while augmenting infiltration by neutrophils. Depletion of macrophages is observed early in the course of in vivo treatment and is at least partially due to their higher sensitivity to MEKi. Tumor-associated macrophages were consistently reported to interfere with gemcitabine uptake by PDA cells. Here, our in vivo studies show a superior antitumor activity upon combination of MEKi and gemcitabine using a sequential rather than simultaneous dosing protocol. Our results show that MEK inhibition induces a dramatic remodeling of the tumor microenvironment of mouse PDA through depletion of macrophages, which substantially improves the antitumor activity of gemcitabine.

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Antiangiogenic antibody BD0801 combined with immune checkpoint inhibitors achieves synergistic antitumor activity and affects the tumor microenvironment

BMC Cancer ◽

10.1186/s12885-021-08859-5 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Liting Xue ◽

Xingyuan Gao ◽

Haoyu Zhang ◽

Jianxing Tang ◽

Qian Wang ◽

...

Keyword(s):

T Cells ◽

Tumor Microenvironment ◽

Antitumor Activity ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Clinical Development ◽

Cell Mediated Immunity ◽

Tumor Models ◽

Anti Vegf

Abstract Background Signaling through VEGF/VEGFR induces cancer angiogenesis and affects immune cells. An increasing number of studies have recently focused on combining anti-VEGF/VEGFR agents and immune checkpoint inhibitors (ICIs) to treat cancer in preclinical and clinical settings. BD0801 is a humanized rabbit anti-VEGF monoclonal antibody in the clinical development stage. Methods In this study, the anti-cancer activities of BD0801 and its potential synergistic anti-tumor effects when combined with different immunotherapies were assessed by using in vitro assays and in vivo tumor models. Ex vivo studies were conducted to reveal the possible mechanisms of actions (MOA) underlying the tumor microenvironment modification. Results BD0801 showed more potent antitumor activity than bevacizumab, reflected by stronger blockade of VEGF/VEGFR binding and enhanced inhibitory effects on human umbilical vein endothelial cells (HUVECs). BD0801 exhibited dose-dependent tumor growth inhibitory activities in xenograft and murine syngeneic tumor models. Notably, combining BD0801 with either anti-PD-1 or anti-PD-L1 antibodies showed synergistic antitumor efficacy in both lung and colorectal cancer mouse models. Furthermore, the mechanistic studies suggested that the MOA of the antitumor synergy involves improved tumor vasculature normalization and enhanced T-cell mediated immunity, including increased tumor infiltration of CD8+ and CD4+ T cells and reduced double-positive CD8+PD-1+ T cells. Conclusions These data provide a solid rationale for combining antiangiogenic agents with immunotherapy for cancer treatment and support further clinical development of BD0801 in combination with ICIs.

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