scholarly journals Metabolic modulation of tumors with engineered bacteria for immunotherapy

2021 ◽  
Author(s):  
Roger Geiger ◽  
Fernando Canale ◽  
Camilla Basso ◽  
Gaia Antonini ◽  
Michela Perotti ◽  
...  
Keyword(s):  
T Cells ◽  
Checkpoint Inhibitors ◽  
Synergistic Effects ◽  
Waste Product ◽  
T Cell Response ◽  
Metabolic Modulation ◽  
Escherichia Coli Nissle 1917 ◽  
Blocking Antibodies ◽  
Engineered Bacteria ◽  
Escherichia Coli Nissle

Abstract The availability of L-arginine in tumors is a key determinant of an efficient anti-tumor T cell response. Consequently, elevation of typically low L-arginine levels within the tumor may greatly potentiate the anti-tumor responses of immune checkpoint inhibitors, such as PD-L1 blocking antibodies. However, currently no means are available to locally increase intra-tumoral L-arginine levels. Here, we used a synthetic biology approach to develop an engineered probiotic Escherichia coli Nissle 1917 strain that colonizes tumors and continuously converts ammonia, a metabolic waste product that accumulates in tumors4, into L-arginine. Colonization of tumors with these bacteria elevated intra-tumoral L-arginine concentrations, increased the amount of tumor-infiltrating T cells, and had striking synergistic effects with PD-L1 blocking antibodies in the clearance of tumors. The anti-tumor effect of the living therapeutic was mediated by L-arginine and was dependent on T cells. These results show that engineered microbial therapies enable metabolic modulation of the tumor microenvironment leading to enhanced efficacy of immunotherapies.

577 Engineered non-pathogenic synthetic biotic producing L-arginine synergize with PD-1-based cancer immunotherapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A611-A611
Author(s):  
Fernando Canale ◽  
Camilla Basso ◽  
Ning Li ◽  
Anna Sokolovska ◽  
Michela Perotti ◽  
...  
Keyword(s):  
T Cells ◽  
Synergistic Effects ◽  
Waste Product ◽  
T Cell Response ◽  
Escherichia Coli Nissle 1917 ◽  
Check Point Inhibitors ◽  
Blocking Antibodies ◽  
Metabolic Waste Product ◽  
Synthetic Biology Approach ◽  
Escherichia Coli Nissle

BackgroundThe availability of L-arginine in tumors is a key determinant of an efficient anti-tumor T cell response. Consequently, the elevation of typically low L-arginine levels within the tumor may greatly potentiate the anti-tumor responses of immune check point inhibitors, such as PD-L1 blocking antibodies. However, currently no means are available to locally increase intra-tumoral L-arginine levels.MethodsWe used a synthetic biology approach to develop an engineered probiotic Escherichia coli Nissle 1917 strain that colonizes tumors and continuously converts ammonia, a metabolic waste product that accumulates in tumors, into L-arginine.ResultsColonization of tumors with these bacteria elevated intra-tumoral L-arginine concentrations, increased the amount of tumor-infiltrating T cells, and had striking synergistic effects with PD-L1 blocking antibodies in the clearance of tumors. The anti-tumor effect of the living therapeutic was mediated by L-arginine and was dependent on T cells.ConclusionsThese results show that engineered microbial therapies enable metabolic modulation of the tumor microenvironment leading to enhanced efficacy of immunotherapies.

NEUROBLASTOMA IMMUNOTHERAPY

2019 ◽  
Vol 65 (2) ◽  
pp. 181-187
Author(s):  
Aleksandr Druy ◽  
Svetlana Kuleva
Keyword(s):  
T Cells ◽  
Monoclonal Antibodies ◽  
High Risk ◽  
Checkpoint Inhibitors ◽  
Innate And Adaptive Immunity ◽  
Car T Cells ◽  
Car T ◽  
Membrane Antigens ◽  
Theoretical Evidence ◽  
Blocking Antibodies

The recent data about innate and adaptive immunity against neuroblastoma are described in the article. The era of neuroblastoma immunotherapy started since the evidence of anti-GD2 monoclonal antibodies efficiency. Nowadays monoclonal antibodies against GD2 are introduced into schemes of maintenance therapy for high-risk neuroblastoma patients. Developing of T-cells expressing chimeric antigen receptor (CAR-T cells) directed to membrane antigens is the perspective of neuroblastoma immunotherapy. PD1/PD-L1 blocking antibodies as immune checkpoint inhibitors have the theoretical evidence of potential effectiveness. Application of immunotherapeutic approaches in high-risk neuroblastoma patients together with conventional multimodal therapies requires further investigation.

scholarly journals Early Investigations and Recent Advances in Intraperitoneal Immunotherapy for Peritoneal Metastasis

Vaccines ◽  
2018 ◽  
Vol 6 (3) ◽  
pp. 54 ◽  
Author(s):  
Anusha Thadi ◽  
Marian Khalili ◽  
William Morano ◽  
Scott Richard ◽  
Steven Katz ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Peritoneal Metastasis ◽  
Checkpoint Inhibitors ◽  
Folate Receptor ◽  
Malignant Ascites ◽  
T Cell Response ◽  
Adoptive Cell Transfer ◽  
Car T Cells ◽  
Car T

Peritoneal metastasis (PM) is an advanced stage malignancy largely refractory to modern therapy. Intraperitoneal (IP) immunotherapy offers a novel approach for the control of regional disease of the peritoneal cavity by breaking immune tolerance. These strategies include heightening T-cell response and vaccine induction of anti-cancer memory against tumor-associated antigens. Early investigations with chimeric antigen receptor T cells (CAR-T cells), vaccine-based therapies, dendritic cells (DCs) in combination with pro-inflammatory cytokines and natural killer cells (NKs), adoptive cell transfer, and immune checkpoint inhibitors represent significant advances in the treatment of PM. IP delivery of CAR-T cells has shown demonstrable suppression of tumors expressing carcinoembryonic antigen. This response was enhanced when IP injected CAR-T cells were combined with anti-PD-L1 or anti-Gr1. Similarly, CAR-T cells against folate receptor α expressing tumors improved T-cell tumor localization and survival when combined with CD137 co-stimulatory signaling. Moreover, IP immunotherapy with catumaxomab, a trifunctional antibody approved in Europe, targets epithelial cell adhesion molecule (EpCAM) and has shown considerable promise with control of malignant ascites. Herein, we discuss immunologic approaches under investigation for treatment of PM.

scholarly journals Influence of antigen density and immunosuppressive factors on tumor-targeted costimulation with antibody-fusion proteins and bispecific antibody-mediated T cell response

2020 ◽  
Vol 69 (11) ◽  
pp. 2291-2303
Author(s):  
Sabrina Sapski ◽  
Nadine Beha ◽  
Roland E. Kontermann ◽  
Dafne Müller
Keyword(s):  
T Cells ◽  
Fusion Proteins ◽  
Bispecific Antibody ◽  
Synergistic Effects ◽  
T Cell Response ◽  
Expression Levels ◽  
Egfr Expression ◽  
Immunosuppressive Microenvironment ◽  
The Impact ◽  
Immunosuppressive Factors

Abstract Target expression heterogeneity and the presence of an immunosuppressive microenvironment can hamper severely the efficiency of immunotherapeutic approaches. We have analyzed the potential to encounter and overcome such conditions by a combinatory two-target approach involving a bispecific antibody retargeting T cells to tumor cells and tumor-directed antibody-fusion proteins with costimulatory members of the B7 and TNF superfamily. Targeting the tumor-associated antigens EpCAM and EGFR with the bispecific antibody and costimulatory fusion proteins, respectively, we analyzed the impact of target expression and the influence of the immunosuppressive factors IDO, IL-10, TGF-β, PD-1 and CTLA-4 on the targeting-mediated stimulation of T cells. Here, suboptimal activity of the bispecific antibody at diverse EpCAM expression levels could be effectively enhanced by targeting-mediated costimulation by B7.1, 4-1BBL and OX40L in a broad range of EGFR expression levels. Furthermore, the benefit of combined costimulation by B7.1/4-1BBL and 4-1BBL/OX40L was demonstrated. In addition, the expression of immunosuppressive factors was shown in all co-culture settings, where blocking of prominent factors led to synergistic effects with combined costimulation. Thus, targeting-mediated costimulation showed general promise for a broad application covering diverse target expression levels, with the option for further selective enhancement by the identification and blockade of main immunosuppressive factors of the particular tumor environment.

scholarly journals Circulating mucosal associated invariant T cells identify patients responding to anti-PD1 therapy

2020 ◽  
Author(s):  
Sara De Biasi ◽  
Lara Gibellini ◽  
Domenico Lo Tartaro ◽  
Emilia Mazza ◽  
Simone Puccio ◽  
...  
Keyword(s):  
T Cells ◽  
Metastatic Melanoma ◽  
Cd8 T Cells ◽  
Checkpoint Inhibitors ◽  
In Silico Analysis ◽  
T Cell Response ◽  
Response To Treatment ◽  
Multiparameter Flow Cytometry ◽  
Mait Cells ◽  
Silico Analysis

Abstract Immune checkpoint inhibitors that maintain anti-tumor T cell response are used for treating patients with metastatic melanoma. Since the response to treatment is extremely variable, biomarkers are urgently needed to identify patients who could benefit from such therapy. We combined single-cell RNA-sequencing and multiparameter flow cytometry to determine changes in circulating CD8+ T cells in patients with metastatic melanoma. A total of 28 patients starting anti-PD1 therapy were enrolled and followed for 6 months: 17 responded to therapy, whilst 11 did not. The proportion of activated and proliferating CD8+ T cells and of mucosal associated invariant T (MAIT) cells was significantly higher in responders before starting therapy and was maintained over time. MAIT cells expressed higher level of CXCR4 and produced more granzyme B; in silico analysis revealed that they are present in the tumor microenvironment. Finally, patients with higher levels of MAIT showed a better response to treatment.

scholarly journals Severity of Experimental Autoimmune Uveitis Is Reduced by Pretreatment with Live Probiotic Escherichia coli Nissle 1917

Cells ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 23
Author(s):  
Otakar Dusek ◽  
Alena Fajstova ◽  
Aneta Klimova ◽  
Petra Svozilkova ◽  
Tomas Hrncir ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Lymph Nodes ◽  
Developed Countries ◽  
T Cell Response ◽  
Experimental Autoimmune Uveitis ◽  
Cervical Lymph Nodes ◽  
Autoimmune Uveitis ◽  
Escherichia Coli Nissle 1917 ◽  
Escherichia Coli Nissle ◽  
Experimental Autoimmune

Non-infectious uveitis is considered an autoimmune disease responsible for a significant burden of blindness in developed countries and recent studies have linked its pathogenesis to dysregulation of the gut microbiota. We tested the immunomodulatory properties of two probiotics, Escherichia coli Nissle 1917 (EcN) and E. coli O83:K24:H31 (EcO), in a model of experimental autoimmune uveitis (EAU). To determine the importance of bacterial viability and treatment timing, mice were orally treated with live or autoclaved bacteria in both preventive and therapeutic schedules. Disease severity was assessed by ophthalmoscopy and histology, immune phenotypes in mesenteric and cervical lymph nodes were analyzed by flow cytometry and the gut immune environment was analyzed by RT-PCR and/or gut tissue culture. EcN, but not EcO, protected against EAU but only as a live organism and only when administered before or at the time of disease induction. Successful prevention of EAU was accompanied by a decrease in IRBP-specific T cell response in the lymph nodes draining the site of immunization as early as 7 days after the immunization and eye-draining cervical lymph nodes when the eye inflammation became apparent. Furthermore, EcN promoted an anti-inflammatory response in Peyer’s patches, increased gut antimicrobial peptide expression and decreased production of inducible nitric oxide synthase in macrophages. In summary, we show here that EcN controls inflammation in EAU and suggest that probiotics may have a role in regulating the gut–eye axis.

Clinical and pharmacodynamic (PD) results of a phase I trial with AMP-224 (B7-DC Fc) that binds to the PD-1 receptor.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3044-3044 ◽  
Author(s):  
Jeffrey R. Infante ◽  
John D. Powderly ◽  
Howard A. Burris ◽  
Muaiad Kittaneh ◽  
Jessica Houston Grice ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Response ◽  
Tumor Immune Evasion ◽  
Effector Cells ◽  
Multiple Tumor ◽  
Infusion Reactions ◽  
Pre Treatment ◽  
Tumor Types ◽  
Blocking Antibodies

3044 Background: PD-1/B7-H1 (PD-L1) axis blockade can reinvigorate T cells, and overcome tumor immune evasion of multiple tumor types. AMP-224 is the first recombinant B7-DC-Fc fusion protein tested in patients that binds to and modulates the PD-1 axis through a unique MOA. The MoA hypothesis for AMP-224 is depletion of PD-1high expressing T-cells representing exhausted effector cells. Subsequent replenishment of the T-cell pool with functional T-cells may restore immune function. Methods: Patients with advanced solid tumors received low dose CTX on Day 0, followed by AMP-224 (IV infusion) on Days 1 and 15 of each 28-day cycle in doses ranging from 0.3 to 30 mg/kg. Blood samples were assessed serially for changes in lymphocyte subsets, PD-1HIT cells and T cell effector function. IHC staining of paired biopsies for B7-H1, CD8, PD-1, CD4 and FoxP3 was performed to assess immunological status of the tumor at baseline and following treatment and then relative to peripheral readouts. Results: 42 patients (83% melanoma) were treated with varying doses of AMP-224 [0.3 mg/kg (n = 6); 1 mg/kg (n=4); 3 mg/kg (n = 4); 10 mg/kg (n = 22); 30 mg/kg (n = 6)]. Infusion reactions were common (69% across dose cohorts) and occurred mostly at higher doses (86% at the 10 mg/kg dose). No drug-related inflammatory adverse events were identified contrary to PD-1 blocking antibodies. Fresh pre-treatment biopsies were collected from 33/42 (78.5%) patients and paired biopsies have been collected thus far from 19/36 (52.7%) patients on study. 31% of baseline tumors were B7-H1+. Several PD readouts in the periphery showed reductions in PD-1HIcells and emergence of a functional T cell response (increases in IFNg+, TNFa+, IL-2+ CD4 and CD8 T cells) in individual patients where partial response, stable disease, and mixed responses were seen. Conclusions: Data from peripheral readouts is consistent with hypothesized AMP-224 MoA. B7-H1+ was not always predictive of functional response to AMP-224 immunotherapy. Comprehensive PD readouts and evaluation of PK/PD relationships will be presented and may ultimately predict restoration of immune competence even in the presence of initial disease progression. Clinical trial information: NCT01352884.

scholarly journals Understanding the Role of T-Cells in the Antimyeloma Effect of Immunomodulatory Drugs

2021 ◽  
Vol 12 ◽  
Author(s):  
Criselle D'Souza ◽  
H. Miles Prince ◽  
Paul J. Neeson
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Nk Cell ◽  
Checkpoint Inhibitors ◽  
Synergistic Effects ◽  
T Cell Proliferation ◽  
Immunomodulatory Drugs ◽  
Cell Secretion ◽  
Myeloma Cells

Immunomodulatory drugs (IMiDs) are effective treatments for patients with multiple myeloma. IMiDs have pleotropic effects including targeting the myeloma cells directly, and improving the anti-myeloma immune response. In the absence of myeloma cells, lenalidomide and pomalidomide induce CD4+ T cell secretion of IL-2 and indirect activation of Natural Killer (NK) cells. In the context of T cell receptor ligation, IMiDs enhance T cell proliferation, cytokine release and Th1 responses, both in vivo and in vitro. Furthermore, combination treatment of IMiDs and myeloma-targeting monoclonal antibodies eg. daratumumab (anti-CD38) and elotuzumab (anti-SLAMF7), checkpoint inhibitors, or bispecific T cell engagers showed synergistic effects, mainly via enhanced T and NK cell dependent cellular toxicity and T cell proliferation. Conversely, the corticosteroid dexamethasone can impair the immune modulatory effects of IMiDs, indicating that careful choice of myeloma drugs in combination with IMiDs is key for the best anti-myeloma therapeutic efficacy. This review presents an overview of the role for T cells in the overall anti-myeloma effects of immunomodulatory drugs.

scholarly journals Combined Anti-Cancer Strategies Based on Anti-Checkpoint Inhibitor Antibodies

Antibodies ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 17 ◽  
Author(s):  
Josée Golay ◽  
Alain E. Andrea
Keyword(s):  
Tumor Antigens ◽  
Checkpoint Inhibitors ◽  
Synergistic Effects ◽  
Phase Iii ◽  
Significant Activity ◽  
Anti Cancer ◽  
Anti Cd20 ◽  
Blocking Antibodies ◽  
Therapeutic Monoclonal Antibodies ◽  
Phase Iii Studies

Therapeutic monoclonal antibodies for the treatment of cancer came of age in 1997, with the approval of anti-CD20 Rituximab. Since then, a wide variety of antibodies have been developed with many different formats and mechanisms of action. Among these, antibodies blocking immune checkpoint inhibitors (ICI) have revolutionized the field, based on the novelty of their concept and their demonstrated efficacy in several types of cancer otherwise lacking effective immunotherapy approaches. ICI are expressed by tumor, stromal or immune cells infiltrating the tumor microenvironment, and negatively regulate anti-tumor immunity. Antibodies against the first discovered ICI, CTLA-4, PD-1 and PD-L1, have shown significant activity in phase III studies against melanoma and other solid cancers, alone or in combination with chemotherapy or radiotherapy. However, not all cancers and not all patients respond to these drugs. Therefore, novel antibodies targeting additional ICI are currently being developed. In addition, CTLA-4, PD-1 and PD-L1 blocking antibodies are being combined with each other or with other antibodies targeting novel ICI, immunostimulatory molecules, tumor antigens, angiogenic factors, complement receptors, or with T cell engaging bispecific antibodies (BsAb), with the aim of obtaining synergistic effects with minimal toxicity. In this review, we summarize the biological aspects behind such combinations and review some of the most important clinical data on ICI-specific antibodies.

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