Abstract P074: MB097: A therapeutic consortium of bacteria clinically-defined by precision microbiome profiling of immune checkpoint inhibitor patients with potent anti-tumor efficacy in vitro and in vivo

2022 ◽  
Author(s):  
Matthew J. Robinson ◽  
Kevin Vervier ◽  
Simon Harris ◽  
Amy Popple ◽  
Dominika Klisko ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Microbiome Profiling

scholarly journals Nanoparticle delivery of immunostimulatory oligonucleotides enhances response to checkpoint inhibitor therapeutics

2020 ◽  
Vol 117 (24) ◽  
pp. 13428-13436 ◽  
Author(s):  
Colin G. Buss ◽  
Sangeeta N. Bhatia
Keyword(s):  
Animal Models ◽  
Tumor Growth ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Engineered Nanoparticles ◽  
Therapeutic Effects

The recent advent of immune checkpoint inhibitor (CPI) antibodies has revolutionized many aspects of cancer therapy, but the efficacy of these breakthrough therapeutics remains limited, as many patients fail to respond for reasons that still largely evade understanding. An array of studies in human patients and animal models has demonstrated that local signaling can generate strongly immunosuppressive microenvironments within tumors, and emerging evidence suggests that delivery of immunostimulatory molecules into tumors can have therapeutic effects. Nanoparticle formulations of these cargoes offer a promising way to maximize their delivery and to enhance the efficacy of checkpoint inhibitors. We developed a modular nanoparticle system capable of encapsulating an array of immunostimulatory oligonucleotides that, in some cases, greatly increase their potency to activate inflammatory signaling within immune cells in vitro. We hypothesized that these immunostimulatory nanoparticles could suppress tumor growth by activating similar signaling in vivo, and thereby also improve responsiveness to immune checkpoint inhibitor antibody therapies. We found that our engineered nanoparticles carrying a CpG DNA ligand of TLR9 can suppress tumor growth in several animal models of various cancers, resulting in an abscopal effect on distant tumors, and improving responsiveness to anti-CTLA4 treatment with combinatorial effects after intratumoral administration. Moreover, by incorporating tumor-homing peptides, immunostimulatory nucleotide-bearing nanoparticles facilitate antitumor efficacy after systemic intravenous (i.v.) administration.

scholarly journals A Small Molecule Antagonist of PD-1/PD-L1 Interactions Acts as an Immune Checkpoint Inhibitor for NSCLC and Melanoma Immunotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuanyuan Wang ◽  
Tingxuan Gu ◽  
Xueli Tian ◽  
Wenwen Li ◽  
Ran Zhao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Monoclonal Antibodies ◽  
Small Molecule ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Small Molecule Antagonist ◽  
Programmed Death

Immune checkpoint inhibitors, such as monoclonal antibodies targeting programmed death 1 (PD-1) and programmed death ligand-1 (PD-L1), have achieved enormous success in the treatment of several cancers. However, monoclonal antibodies are expensive to produce, have poor tumor penetration, and may induce autoimmune side effects, all of which limit their application. Here, we demonstrate that PDI-1 (also name PD1/PD-L1 inhibitor 1), a small molecule antagonist of PD-1/PD-L1 interactions, shows potent anti-tumor activity in vitro and in vivo and acts by relieving PD-1/PD-L1-induced T cell exhaustion. We show that PDI-1 binds with high affinity to purified human and mouse PD-1 and PD-L1 proteins and is a competitive inhibitor of human PD-1/PD-L1 binding in vitro. Incubation of ex vivo activated human T cells with PDI-1 enhanced their cytotoxicity towards human lung cancer and melanoma cells, and concomitantly increased the production of granzyme B, perforin, and inflammatory cytokines. Luciferase reporter assays showed that PDI-1 directly increases TCR-mediated activation of NFAT in a PD-1/PD-L1-dependent manner. In two syngeneic mouse tumor models, the intraperitoneal administration of PDI-1 reduced the growth of tumors derived from human PD-L1-transfected mouse lung cancer and melanoma cells; increased and decreased the abundance of tumor-infiltrating CD8+ and FoxP3+ CD4+ T cells, respectively; decreased the abundance of PD-L1-expressing tumor cells, and increased the production of inflammatory cytokines. The anti-tumor effect of PDI-1 in vivo was comparable to that of the anti-PD-L1 antibody atezolizumab. These results suggest that the small molecule inhibitors of PD-1/PD-L1 may be effective as an alternative or complementary immune checkpoint inhibitor to monoclonal antibodies.

scholarly journals Phytochemicals in Cancer Immune Checkpoint Inhibitor Therapy

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1107
Author(s):  
Juwon Lee ◽  
Youngjin Han ◽  
Wenyu Wang ◽  
HyunA Jo ◽  
Heeyeon Kim ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Therapeutic Option ◽  
In Vitro Models ◽  
Immune Checkpoints ◽  
Checkpoint Inhibitor Therapy ◽  
Cancer Types

The interaction of immune checkpoint molecules in the tumor microenvironment reduces the anti-tumor immune response by suppressing the recognition of T cells to tumor cells. Immune checkpoint inhibitor (ICI) therapy is emerging as a promising therapeutic option for cancer treatment. However, modulating the immune system with ICIs still faces obstacles with severe immunogenic side effects and a lack of response against many cancer types. Plant-derived natural compounds offer regulation on various signaling cascades and have been applied for the treatment of multiple diseases, including cancer. Accumulated evidence provides the possibility of efficacy of phytochemicals in combinational with other therapeutic agents of ICIs, effectively modulating immune checkpoint-related signaling molecules. Recently, several phytochemicals have been reported to show the modulatory effects of immune checkpoints in various cancers in in vivo or in vitro models. This review summarizes druggable immune checkpoints and their regulatory factors. In addition, phytochemicals that are capable of suppressing PD-1/PD-L1 binding, the best-studied target of ICI therapy, were comprehensively summarized and classified according to chemical structure subgroups. It may help extend further research on phytochemicals as candidates of combinational adjuvants. Future clinical trials may validate the synergetic effects of preclinically investigated phytochemicals with ICI therapy.

Using precision microbiome profiling to develop a biomarker for immune checkpoint inhibitor response and a novel therapeutic.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21546-e21546
Author(s):  
Mat Robinson ◽  
Kevin Vervier ◽  
Amy Popple ◽  
Simon Harris ◽  
Robyne Hudson ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Advanced Melanoma ◽  
Metagenomic Sequencing ◽  
Genome Database ◽  
Syngeneic Mouse Model ◽  
Melanoma Patients

e21546 Background: Four independent groups have demonstrated that the pre-treatment gut microbiome of cancer patients impacts the subsequent response to Immune Checkpoint Inhibitor (ICIs) therapy [1-4]. However, the patient’s outcome was linked to different bacteria in each study, which has limited the development of drug response biomarkers and clinic-first design of novel microbiome-based therapeutics. Methods: The Cambridge (UK) MELRESIST study includes a cohort of advanced melanoma patients receiving approved ICIs. Pretreatment stool samples from MELRESIST were analysed by Microbiotica using shotgun metagenomic sequencing. Microbiotica’s platform comprises the world’s leading Reference Genome Database to give the most comprehensive and precise mapping of the gut microbiome. Results: MELRESIST samples showed an overall difference in the microbiome composition between advanced melanoma patients and healthy donors, but not between patients who did or did not respond to ICIs. However, we did identify a discrete microbiome signature that differentiated responders and non-responders with an accuracy of 93%. We extended this signature by reanalysing three published melanoma cohorts [1-3] using the Microbiotica platform, and a propriety bioinformatic model. The resultant bacterial signature was very accurate at predicting response in all 4 published studies combined (91%), and each cohort individually (82-100%). We validated the model using independent validation cohorts and the signature using lung and renal cancer studies [4]. At the core of our microbiome signature was 9 bacteria most significantly associated with ICI efficacy. All 9 were overrepresented in patients who responded to immunotherapy suggesting high abundance of these bacteria is a central driver of ICI response. A consortium comprised of all 9 strains had very potent anti-tumor efficacy in a cancer syngeneic mouse model. The bacteria also demonstrate multiple interactions with primary human immune cells in vitro leading to dendritic cells activation, Cytotoxic T lymphocyte activation and tumor cell killing. These validate the potential of this consortium as a novel therapy for use in combination with ICIs. Conclusions: We have identified a unique microbiome signature predictive of ICI response in 4 independent melanoma cancer cohorts. This removes a major challenge to the field, and could represent a new highly accurate biomarker with clinical application. Nine core bacteria appear to be driving response, and demonstrate anti-tumor activity in vivo and in vitro. This consortium holds great potential as a co-therapy with ICIs. References:1 Matson V et al, Science (2018) 359:104; 2 Gopalakrishnan V et al, Science (2018) 359:97; 3 Frankel AE et al, Neoplasia (2017) 19:848; 4 Routy B et al, Science (2018) 359:91.

scholarly journals IMMU-21. THE COMBINATION OF DELTA-24-ACT WITH AN IMMUNE CHECKPOINT INHIBITOR RESULTS IN ANTI-GLIOMA EFFECT AND IMMUNE MEMORY

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii109-ii109
Author(s):  
Montserrat Puigdelloses ◽  
Virginia Laspidea ◽  
Marc Garcia-Moure ◽  
Daniel De la Nava ◽  
Dolores Hambardzumyan ◽  
...  
Keyword(s):  
Immune Checkpoint Inhibitor ◽  
Immune Cell ◽  
Checkpoint Inhibitor ◽  
Immune Memory ◽  
Long Term Survivors ◽  
Anti Tumour Effect ◽  
Murine Glioma

Abstract Oncolytic viruses have become promising therapeutic candidates to treat gliomas. Our group has developed Delta-24-ACT, an oncolytic adenovirus armed with the positive costimulatory ligand 4-1BBL which is capable to trigger the activation of T cells and thereby increase their antitumor immune response. Here we evaluate the anti-glioma effect of Delta-24-ACT alone or in combination with an immune checkpoint inhibitor. We observed that Delta-24-ACT was able to infect and kill murine glioma (GL261-5 and CT-2A) and also human glioma cell lines (U87-MG and U251-MG), while maintaining its replication in the latter. Of importance, Delta-24-ACT infection resulted in 4-1BBL expression on the membrane of glioma cells. Moreover, this ligand was functional and was able to stimulate CD8 lymphocytes in vitro, suggesting the potential of Delta-24-ACT to trigger an effective immune response. Furthermore, in vivo Delta-24-ACT showed anti-tumour effect in two murine glioma models by significantly increasing the median survival time and leading to long-term survivors. Mechanistic studies demonstrated an increase of the T cell infiltration and the activation of different immune cell populations by flow cytometry and a decrease of proliferative cells and tumour vessels by immunohistochemistry on FFPE brain samples. Importantly, the infiltrating lymphocytes also showed signs of exhaustion increasing the amount of IL-10 and the expression of PD-1. To overcome this exhaustion we combined Delta-24-ACT with an anti-PD-1 antibody. Evaluation of this combination in vivo further increased the median survival time of treated tumor-bearing mice and resulted in 50% long-term survivors. Rechallenge studies with the same cell line showed that combination treatment effectively protected these animals of developing tumors and therefore, the acquisition of immune memory. In summary, our data demonstrated that Delta-24-ACT induces a potent anti-tumour effect in vitro and in vivo as a result of the recruitment of immune cell populations modulating the immunosuppressive tumour microenvironment of glioma.

scholarly journals Adaptive Antitumor Immune Response Stimulated by Bio-nanoparticle Based Vaccine and Checkpoint Blockade

2021 ◽  
Author(s):  
Xuewei Bai ◽  
Yanmei Zhou ◽  
Yuki Yokota ◽  
Yoshihiro Matsumoto ◽  
Bo Zhai ◽  
...  
Keyword(s):  
Immune Response ◽  
Cancer Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Adaptive Immune Response ◽  
Control Group ◽  
Lymphoid Structures

Abstract Background: Interactions between tumor and microenvironment determines the response to immunotherapy. Triple negative breast cancer (TNBC) and hepatocellular carcinoma (HCC) have exhibited suboptimal responses to immune checkpoint inhibitors. Aspartate beta-hydroxylase (ASPH), an oncofetal protein and tumor associated antigen (TAA), is a potential target for immunotherapy. Methods: Orthotopic TNBC and subcutaneous HCC murine models were established. Immunohistochemistry, flow cytometry, ELISA and in vitro cytotoxicity assays were performed. Results: The ASPH-MYC signaling cascade upregulates PD-L1 expression on breast and liver tumor cells. A bio-nanoparticle based vaccine targeting ASPH was administrated to BALB/c mice harboring syngeneic HCC or TNBC tumors, either alone or in combination with PD-1 blockade. In the control group, autocrine CXCL13-CXCR5 axis promoted cancer development and progression. Inhibition between PD-L1+ cancer cells and PD-1+ T cells resulted in T cell exhaustion and apoptosis. In contrast, combination therapy significantly suppressed primary hepatic or mammary tumor growth with distant pulmonary metastases in TNBC. An adaptive immune response was attributed to expansion of activated CD4+ Th1/CD8+ CTLs with enhanced effector function and high titers of ASPH-specific antibody. When the PD-1/PD-L1 signal was inhibited, CXCL13 produced by ASPH+ cancer cells recruited CXCR5+/CD8+ T lymphocytes to tertiary lymphoid structures (TLSs), which secreted CXCL13 to recruit more CXCR5+ immune cells and to lyse CXCR5+ cancer cells. Upon combination treatment, the presence of TLSs predicts sensitivity to immune checkpoint inhibitor blockade. Conclusions: Synergistic antitumor efficacy attributable to a λ phage vaccine specifically targeting ASPH combined with an immune checkpoint inhibitor represents a new approach for TNBC and HCC.

scholarly journals Intergraft Variability in Nonhematopoietic Immunoregulatory Cell Number and Expression of Immune Checkpoint Inhibitor Receptors and Ligands in Both Allo- and Autografts: Potential Target for Intervention

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3382-3382
Author(s):  
Qingdong Guan ◽  
Scott Gilpin ◽  
James Doerksen ◽  
Lauren Bath ◽  
Tracey Lam ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Cell Number ◽  
Cell Dose ◽  
Cd34 Cells ◽  
Ifn Γ

Abstract Intergraft variability in nonhematopoietic immunoregulatory cell number and expression of immune checkpoint inhibitor receptors and ligands in both allo- and autografts: potential target for intervention Qingdong Guan,1-3 Scott Gilpin,3 James Doerksen,3 Lauren Bath,3 Tracey Lam,3 Kristjan Paulson,4 Pascal Lambert,4 Yun Li,1,3 Donna A.Wall1-4 1, Department of Pediatrics and Child Health, 2, Immunology, University of Manitoba; 3, Manitoba Center for Advanced Cell and Tissue Therapy; 4, CancerCare Manitoba The number of CD34+ hematopoietic stem/progenitor cells (HSC) in HSC products is the main and often sole characterization of the graft used in HSCT. However CD34+ cells make up only 0.3-5% of the graft with the rest of the cells being lymphocytes and immature myeloid and granulocytic cells, including myeloid-derived suppressor cells (MDSC). We examined a cohort of HSC products collected from 2010-2014. Filgrastim and chemotherapy was used to mobilize 60 multiple myeloma and 34 lymphoma patients. Filgrastim-mobilized healthy donor products used in allografts (N=68) was a comparator. Aliquots stored in liquid nitrogen were analyzed for cell phenotype with a focus on immunoregulatory populations. We found CD33+CD15-CD14+HLA-DR-/low monocytic (M-MDSC) ranged from 0-59% in the infused graft. Similarly CD3+T lymphocyte ranged from 2-80% in the graft. There were 10-50 fold more M-MDSC than CD34+ cells with the infused M-MDSC cell dose ranging from 0-600×106/kg (Fig 1). Similarly CD3+T cell dose ranged from 4-670×106/kg (Fig1). M-MDSC were functional as they could suppress T cell proliferation and IFN-γ secretion, but promote regulatory T cell development in vitro. We examined receptor-ligand relations between M-MDSC and T cells and markers of T exhaustion. M-MDSC expressed variable PD-L1 (19.3±13.9% for MM, 10.4±4.4% for lymphoma and 7.0±4.8% for allografts), and CD86 (48.3±17.1% for MM, 59.9±15.4% for lymphoma and 57.8±17.0% for allografts), the ligands for PD-1 and CTLA-4, respectively. Blocking PD-L1-PD-1 signaling pathway using anti-PD-L1 or anti-PD1 partially reversed the suppressive functions of M-MDSC. Compared to allografts, CD4+T and CD8+T cells in the autografts showed poor proliferation, decreased the secretion of IFN-γ and/or granzyme B, and increased inhibitory receptors PD-1 and CTLA-4 on their surface - markers of T cell exhaustion. Levels of PD-L1 and CD86 on M-MDSC were correlated with expression of inhibitory receptors PD-1 and CTLA-4 on T cells, respectively. Taken together, our pilot data showed variable numbers of M-MDSC are infused with HSC grafts. These cells have strong immune regulatory function in vitro. T cells in autografts have high levels of T cell exhaustion markers and are less functional. It indicated immune function may be enhanced by interfering with PD1/PDL1 or CTLA-4. The numbers of M-MDSC and T cells are in the range of a cellular therapy product and may be targeted for enhance/inactivation pre- or peri-transplant immune function. Figure 1. The infusion cell dose of CD34+ stem cells, M-MDSC and CD3+T. Disclosures No relevant conflicts of interest to declare.

Low-dose photodynamic therapy promotes a cytotoxic immunological response in a murine model of pleural mesothelioma

2020 ◽  
Vol 58 (4) ◽  
pp. 783-791
Author(s):  
Sabrina Cavin ◽  
Aspasia Gkasti ◽  
Julien Faget ◽  
Yameng Hao ◽  
Igor Letovanec ◽  
...  
Keyword(s):  
Photodynamic Therapy ◽  
Immune Checkpoint ◽  
Tumour Growth ◽  
Low Dose ◽  
Immune Checkpoint Inhibitor ◽  
Immune Cell ◽  
Checkpoint Inhibitor ◽  
Pleural Mesothelioma ◽  
Tumour Control

Abstract OBJECTIVES Malignant pleural mesothelioma (MPM) is a deadly disease with limited treatment options. Approaches to enhance patient immunity against MPM have been tested but shown variable results. Previously, we have demonstrated interesting vascular modulating properties of low-dose photodynamic therapy (L-PDT) on MPM. Here, we hypothesized that L-PDT vascular modulation could favour immune cell extravasation in MPM and improve tumour control in combination with immune checkpoint inhibitors. METHODS First, we assessed the impact of L-PDT on vascular endothelial E-selectin expression, a key molecule for immune cell extravasation, in vitro and in a syngeneic murine model of MPM. Second, we characterized the tumour immune cell infiltrate by 15-colour flow cytometry analysis 2 and 7 days after L-PDT treatment of the murine MPM model. Third, we determined how L-PDT combined with immune checkpoint inhibitor anti-CTLA4 affected tumour growth in a murine MPM model. RESULTS L-PDT significantly enhanced E-selectin expression by endothelial cells in vitro and in vivo. This correlated with increased CD8+ T cells and activated antigen-presenting cells (CD11b+ dendritic cells and macrophages) infiltration in MPM. Also, compared to anti-CTLA4 that only affects tumour growth, the combination of L-PDT with anti-CTLA4 caused complete MPM regression in 37.5% of animals. CONCLUSIONS L-PDT enhances E-selectin expression in the MPM endothelium, which favours immune infiltration of tumours. The combination of L-PDT with immune checkpoint inhibitor anti-CTLA4 allows best tumour control and regression.

645 Preclinical development of a novel colon-targeted therapeutic for the treatment of immune checkpoint inhibitor (ICI)-colitis

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A682-A682
Author(s):  
Nazli Dizman ◽  
Milton L Greenberg ◽  
Andrew C Newman ◽  
Jonathan Skupsky ◽  
JoAnn Hsu ◽  
...  
Keyword(s):  
T Cells ◽  
Side Effects ◽  
Systemic Inflammation ◽  
Adoptive Transfer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Transfer Model ◽  
Next Generation

BackgroundImmune Checkpoint Inhibitor (ICI) therapies have significantly improved overall survival in numerous cancers, but colitis has emerged as the most frequent dose-limiting toxicity associated with these therapies. Patients experiencing colitis side effects have to discontinue their cancer therapy to treat the colitis, which repositions life-threatening cancer. An ideal therapeutic would offer a colon-restricted approach to treating colitis side effects, while allowing patients to stay on their ICI therapy, an approach unavailable with currently approved therapies.MethodsTo test this localized approach for the treatment of ICI-mediated colitis, we have developed a new chemical entity as a next-generation candidate therapeutic designed for oral administration. Permeability was tested in predictive epithelial monolayers and confirmed in rodent pharmacokinetic studies. We tested the drug in the preclinical adoptive transfer model for colitis. In this model, immunodeficient mice are hosts for adoptive transfer of naïve CD4+ T cells. In the absence of regulatory T cells, the transferred cells drive systemic inflammation and migrate to the colon, causing disease. Without treatment, these mice develop signs of colitis including weight loss, altered crypt architecture and infiltration of the lamina propria by week four. Furthermore, we developed a live biopsy culture system to test drug effects on ICI-colitis patient biopsies obtained via colonoscopy.ResultsIn-vitro studies demonstrate that the drug has minimal toxicity and that it potently suppresses T cell proliferation and cytokine secretion. Permeability studies show a limited ability to cross the colonic mucosa restricting anti-inflammatory effects to sites of ulceration and active colitis. When colitis mice were given drug by oral gavage after colitis had developed, treated mice showed a significant increase in weight over controls and improved histological scores. Importantly, markers of systemic inflammation remained unchained, and the cancer-killing ability of the primary ICI therapy was preserved. Results of the live biopsy culture studies will be presented.ConclusionsThese preliminary studies demonstrate that the candidate therapeutic has potential to become a novel next-generation oral therapy for ICI-colitis because it effectively limits leukocyte function in-vitro and in-vivo with minimal systemic absorption and minimal expected side effects. Given the favorable drug profile and the rapid growth of ICI therapies, our colon-restricted colitis therapeutic has the potential to improve outcomes in a large number of cancer patients. We anticipate commencing first-in-human studies in Q4 of 2021.AcknowledgementsNoneEthics ApprovalThe study was approved by City of Hope Cancer Center Institutional Review Board with the approval number of 19304.

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