scholarly journals IMMU-09. MODULATING THE MYELOID POPULATION IN DIPG MODELS WITH ONCOLYTIC VIRUS AND COMPLEMENT INHIBITORS SHOWS THERAPEUTIC EFFICACY

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i28-i29
Author(s):  
Montserrat Puigdelloses ◽  
Virginia Laspidea ◽  
Dolores Hambardzumyan ◽  
Zhihong Chen ◽  
Sumit Gupta ◽  
...  
Keyword(s):  
Immune Response ◽  
Tumor Microenvironment ◽  
Oncolytic Virus ◽  
Continuous Production ◽  
Therapeutic Benefit ◽  
Antitumor Immune Response ◽  
In Vivo Studies ◽  
Immune Memory ◽  
Inflammatory Microenvironment

Abstract Diffuse intrinsic pontine glioma (DIPG) is the leading cause of brain tumor-related death in children. It is characterised for having a non-inflammatory microenvironment and be immunologically inert. Therefore, strategies aiming to break the microenvironment status-quo in this disease could provide therapeutic benefit. The complement system promotes tumor progression due to the continuous production of anaphylatoxins leading to the infiltration of myeloid cells, which express high levels of complement receptors (C3aR and C5aR1). We have in silico data showing the high expression of C5aR1 in DIPGs. Thus, we wanted to assess first whether complement C5aR1 could constitute an actionable target, and second whether combining C5aR1 inhibitors with oncolytic virus could result in a superior antitumor immune response than either agent alone in DIPG. In this study, we used two different peptide inhibitors of C5aR1, PMX53 and PMX205 combined with the virus Delta-24-ACT (an oncolytic virus armed with 4-1BBL). We performed in vivo studies to evaluate the efficacy of this combination in immunocompetent DIPG models. Our data showed that the combination Delta-24-ACT/PMX53 significantly extended the median survival of the animals when compared with either agent alone, and led to long-term survivors that generated immune memory. The combination treatment modulated the tumor microenvironment promoting an increase in lymphocytes, mainly CD8+ cells presenting an active phenotype, and a reduction in C5aR1 expression in the myeloid compartment. We are currently evaluating in vivo whether PMX205, which has an improved ability to cross the blood brain barrier, leads to better therapeutic response. In summary, the combination of Delta-24-ACT with a C5aR1 inhibitor showed the capacity to shake the DIPG tumor microenvironment and unleashed an antitumor immune response. These data underscore the possibilities to combine oncolytic virus with targets of the tumor microenvironment to improve their therapeutic benefit in DIPGs.

scholarly journals Angiostatic activity of the antitumor cytokine interleukin-21

Blood ◽  
2008 ◽  
Vol 112 (13) ◽  
pp. 4940-4947 ◽  
Author(s):  
Karolien Castermans ◽  
Sebastien P. Tabruyn ◽  
Rong Zeng ◽  
Judy R. van Beijnum ◽  
Cheryl Eppolito ◽  
...  
Keyword(s):  
Immune Response ◽  
Tumor Angiogenesis ◽  
Chorioallantoic Membrane ◽  
Antitumor Immune Response ◽  
In Vivo Studies ◽  
Type I ◽  
Stat3 Phosphorylation ◽  
Interleukin 21

Abstract Interleukin-21 (IL-21) is a recently described immunoregulatory cytokine. It has been identified as a very potent immunotherapeutic agent in several cancer types in animal models, and clinical studies are ongoing. IL-21 belongs to the type I cytokine family of which other members, ie, IL-2, IL-15, and IL-4, have been shown to exert activities on vascular endothelial cells (ECs). We hypothesized that IL-21, in addition to inducing the antitumor immune response, also inhibits tumor angiogenesis. In vitro experiments showed a decrease of proliferation and sprouting of activated ECs after IL-21 treatment. We found that the IL-21 receptor is expressed on vascular ECs. Furthermore, in vivo studies in the chorioallantoic membrane of the chick embryo and in mouse tumors demonstrated that IL-21 treatment disturbs vessel architecture and negatively affects vessel outgrowth. Our results also confirm the earlier suggested angiostatic potential of IL-2 in vitro and in vivo. The angiostatic effect of IL-21 is confirmed by the decrease in expression of angiogenesis-related genes. Interestingly, IL-21 treatment of ECs leads to a decrease of Stat3 phosphorylation. Our research shows that IL-21 is a very powerful antitumor compound that combines the induction of an effective antitumor immune response with inhibition of tumor angiogenesis.

scholarly journals Characterization of Weissella viridescens UCO-SMC3 as a Potential Probiotic for the Skin: Its Beneficial Role in the Pathogenesis of Acne Vulgaris

2021 ◽  
Vol 9 (7) ◽  
pp. 1486
Author(s):  
Marcela Espinoza-Monje ◽  
Jorge Campos ◽  
Eduardo Alvarez Villamil ◽  
Alonso Jerez ◽  
Stefania Dentice Maidana ◽  
...  
Keyword(s):  
Immune Response ◽  
Oral Treatment ◽  
Acne Vulgaris ◽  
Topical Administration ◽  
In Vivo Studies ◽  
Mice Model ◽  
Cutibacterium Acnes ◽  
Snail Helix Aspersa

Previously, we isolated lactic acid bacteria from the slime of the garden snail Helix aspersa Müller and selected Weissella viridescens UCO-SMC3 because of its ability to inhibit in vitro the growth of the skin-associated pathogen Cutibacterium acnes. The present study aimed to characterize the antimicrobial and immunomodulatory properties of W. viridescens UCO-SMC3 and to demonstrate its beneficial effect in the treatment of acne vulgaris. Our in vitro studies showed that the UCO-SMC3 strain resists adverse gastrointestinal conditions, inhibits the growth of clinical isolates of C. acnes, and reduces the adhesion of the pathogen to keratinocytes. Furthermore, in vivo studies in a mice model of C. acnes infection demonstrated that W. viridescens UCO-SMC3 beneficially modulates the immune response against the skin pathogen. Both the oral and topical administration of the UCO-SCM3 strain was capable of reducing the replication of C. acnes in skin lesions and beneficially modulating the inflammatory response. Of note, orally administered W. viridescens UCO-SMC3 induced more remarkable changes in the immune response to C. acnes than the topical treatment. However, the topical administration of W. viridescens UCO-SMC3 was more efficient than the oral treatment to reduce pathogen bacterial loads in the skin, and effects probably related to its ability to inhibit and antagonize the adhesion of C. acnes. Furthermore, a pilot study in acne volunteers demonstrated the capacity of a facial cream containing the UCO-SMC3 strain to reduce acne lesions. The results presented here encourage further mechanistic and clinical investigations to characterize W. viridescens UCO-SMC3 as a probiotic for acne vulgaris treatment.

scholarly journals IMMU-14. ONCOLYTIC VIRUS EXPRESSING A POSITIVE IMMUNE CHECKPOINT MODULATOR AS A THERAPEUTIC APPROACH FOR DIPG

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi122-vi122
Author(s):  
Virginia Laspidea ◽  
Montse Puigdelloses ◽  
Ignacio Iñigo-Marco ◽  
Marc Garcia-Moure ◽  
Iker Ausejo ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cell Death ◽  
Cell Lines ◽  
Oncolytic Virus ◽  
Murine Models ◽  
Antitumoral Effect ◽  
Infected Cells

Abstract Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain tumor, being the leading cause of pediatric death caused by cancer. We previously showed that administration of the oncolytic virus Delta-24-RGD to DIPG murine models was safe and led to an increase in the median survival of these animals. However, not all the animals responded, underscoring the need to improve this therapy. In order to increase the antitumoral effect of the virus, we have engineered Delta-24-RGD with the costimulatory ligand 4-1BBL (Delta24-ACT). 4-1BB is a costimulatory receptor that promotes the survival and expansion of activated T cells, and the generation and maintenance of memory CD8+ T cells. In this project, we evaluated the oncolytic effect of Delta24-ACT and the antitumor immune response in DIPG murine models. In vitro, Delta24-ACT was able to infect and induce cell death in a dose-dependent manner in murine DIPG cell lines. In addition, Delta24-ACT was able to replicate in these tumor cells and to express viral proteins. Moreover, infected cells expressed 41BBL in their membranes. Delta24-ACT could induce immunogenic cell death due to an increased secretion of ATP and calreticulin translocation to the membrane of infected cells (in no-infected cells it located in the ER), DAMPs that can trigger the immune response activation. In vivo, Delta24-ACT demonstrated to be safe in all the tested doses and was able to induce a significant increase in the median survival of the treated animals. Moreover, long-term survivors display immunological memory. Delta24-ACT treatment led to antitumoral effect in DIPG murine cell lines in vitro. Of significance, we have demonstrated that in vivo administration of Delta24-ACT is safe and results in an enhanced antitumor effect. Future in vivo studies will explore the underlying immune mechanism of the virus.

In vivo resistance of secondary antitumor immune response to cyclophosphamide: effects on T cell subsets

1987 ◽  
Vol 24 (1) ◽  
Author(s):  
Samuele Peppoloni ◽  
BonnieJ. Mathieson ◽  
RonaldB. Herberman ◽  
RoyW. Overton ◽  
Eliezer Gorelik
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Antitumor Immune Response ◽  
T Cell Subsets

scholarly journals IMMU-08. MICROENVIRONMENT MODULATION BY TIM-3 BLOCKADE IMPROVES THE OUTCOME OF PRECLINICAL DIPG MODELS

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i28-i28
Author(s):  
Iker Ausejo-Mauleon ◽  
Sara Labiano ◽  
Virginia Laspidea ◽  
Marc Garcia-Moure ◽  
Daniel de la Nava ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Nk Cells ◽  
Immune Cell ◽  
Cell Types ◽  
Pediatric Brain Tumors ◽  
Immune Memory ◽  
Cd8 Cells ◽  
Functional Studies

Abstract Diffuse Midline Gliomas (DMGs), encompassing Diffuse Intrinsic Pontine Gliomas (DIPGs), are the most aggressive pediatric brain tumors. Their meagre survival has not changed despite the combination of radiotherapy with targeted therapies emphasizing the urgent need for effective treatments. Recent research suggested that the DIPG tumor microenvironment is neither highly immunosuppressive nor inflammatory. These analyses showed the lack of infiltrating lymphocytes and the abundance of CD11b+ cells. TIM-3 (HAVCR2) is a member of the T-cell immunoglobulin and mucin domain protein family which is expressed on multiple immune cell types including T cells, Tregs, NK cells, monocytes, dendritic cells and microglia, where it potently regulates not only adaptive immunity but also innate immunity. Therefore, the central hypothesis of this study is that TIM-3 inhibitors could stimulate a cytotoxic immune effect and challenge several components in the tumor microenvironment including microglia, thereby providing a potential effective treatment for DMGs. In silico assessment of TIM-3 expression in a DIPG datasets showed a robust expression of this gene. Moreover, single-cell sequencing analyses of DIPG biopsies uncover its expression on tumor cells, especially in the OPCs compartment. In vivo efficacy studies showed that treatment with anti-TIM-3 antibody significantly increase the overall survival in two DIPG immunocompetent orthotopic animal models (doubling the median), lead to long-term survivors (50%) and showed immune memory. Analyses of CD45+ populations in the tumor microenvironment showed a significant increase in B, NK and CD8+ cells corresponding with a T-cell activate phenotype in treated-mice. The potential therapeutic involvement of NK cells was certified using nude mice and functional studies. Involvement of microglia in currently being analysed. In summary, these data underscore TIM-3 as a potential target DIPGs and uncover the potential involvement of NKs and other immune mechanisms in the efficacy of anti-TIM-3 therapy.

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