scholarly journals 4,5-Disubstituted 1,2,3-triazoles: Effective Inhibition of Indoleamine 2,3-Dioxygenase 1 Enzyme Regulates T cell Activity and Mitigates Tumor Growth

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Subhankar Panda ◽  
Nirmalya Pradhan ◽  
Soumya Chatterjee ◽  
Sudhir Morla ◽  
Abhishek Saha ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Cell Activity ◽  
Tumor Growth Inhibition ◽  
Structural Class ◽  
Cell Functions ◽  
Indoleamine 2,3 Dioxygenase ◽  
Potential Applications

AbstractThe improvement of body’s own immune system is considered one of the safest approaches to fight against cancer and several other diseases. Excessive catabolism of the essential amino acid, L-tryptophan (L-Trp) assists the cancer cells to escape normal immune obliteration. The formation of disproportionate kynurenine and other downstream metabolites suppress the T cell functions. Blocking of this immunosuppressive mechanism is considered as a promising approach against cancer, neurological disorders, autoimmunity, and other immune-mediated diseases. Overexpression of indoleamine 2,3-dioxygenase 1 (IDO1) enzyme is directly related to the induction of immunosuppressive mechanisms and represents an important therapeutic target. Several classes of small molecule-based IDO1 inhibitors have been already reported, but only few compounds are currently being evaluated in various stages of clinical trials as adjuvants or in combination with chemo- and radiotherapies. In the quest for novel structural class(s) of IDO1 inhibitors, we developed a series of 4,5-disubstituted 1,2,3-triazole derivatives. The optimization of 4,5-disubstituted 1,2,3-triazole scaffold and comprehensive biochemical and biophysical studies led to the identification of compounds, 3i, 4i, and 4k as potent and selective inhibitors of IDO1 enzyme with IC50 values at a low nanomolar level. These potent compounds also showed strong IDO1 inhibitory activities in MDA-MB-231 cells with no/negligible level of cytotoxicity. The T cell activity studies revealed that controlled regulation of IDO1 enzyme activity in the presence of these potent compounds could induce immune response against breast cancer cells. The compounds also showed excellent in vivo antitumor efficacy (of tumor growth inhibition = 79–96%) in the female Swiss albino mice. As a consequence, this study describes the first example of 4,5-disubstituted 1,2,3-triazole based IDO1 inhibitors with potential applications for immunotherapeutic studies.

scholarly journals Ethaselen synergizes with oxaliplatin in tumor growth inhibition by inducing ROS production and inhibiting TrxR1 activity in gastric cancer

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Haiyong Zhang ◽  
Jing Wu ◽  
Jinqiu Yuan ◽  
Huafu Li ◽  
Yawei Zhang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Cancer Cells ◽  
Nude Mice ◽  
Combined Treatment ◽  
Thioredoxin Reductase ◽  
Tumor Growth Inhibition ◽  
Gastric Cancer Cells

Abstract Background Oxaliplatin is one of the most commonly used chemotherapeutic agent for the treatment of various cancers, including gastric cancer. It has, however, a narrow therapeutic index due to its toxicity and the occurrence of drug resistance. Hence, it is of great significance to develop novel therapies to potentiate the anti-tumor effect and reduce the toxicity of oxaliplatin. In our previous study, we demonstrated that ethaselen (BBSKE), an inhibitor of thioredoxin reductase, effectively inhibited the growth of gastric cancer cells and promoted apoptosis in vitro. In the present study, we investigated whether BBSKE can potentiate the anti-tumor effect of oxaliplatin in gastric cancer in vivo and vitro. Methods Cellular apoptosis and ROS levels were analyzed by flow cytometry. Thioredoxin reductase 1 (TrxR1) activity in gastric cancer cells, organoid and tumor tissues was determined by using the endpoint insulin reduction assay. Western blot was used to analyze the expressions of the indicated proteins. Nude mice xenograft models were used to test the effects of BBSKE and oxaliplatin combinations on gastric cancer cell growth in vivo. In addition, we also used the combined treatment of BBSKE and oxaliplatin in three cases of gastric cancer Patient-Derived organoid (GC-PDO) to detect the anti-tumor effect. Results We found that BBSKE significantly enhanced oxaliplatin-induced growth inhibition in gastric cancer cells by inhibiting TrxR1 activity. Because of the inhibition of TrxR1 activity, BBSKE synergized with oxaliplatin to enhance the production of ROS and activate p38 and JNK signaling pathways which eventually induced apoptosis of gastric cancer cells. In vivo, we also found that BBSKE synergized with oxaliplatin to suppress the gastric cancer tumor growth in xenograft nude mice model, accompanied by the reduced TrxR1 activity. Remarkably, we found that BBSKE attenuated body weight loss evoked by oxaliplatin treatment. We also used three cases of GC-PDO and found that the combined treatment of BBSKE and oxaliplatin dramatically inhibited the growth and viability of GC-PDO with increased ROS level, decreased TrxR1 activity and enhanced apoptosis. Conclusions This study elucidates the underlying mechanisms of synergistic effect of BBSKE and oxaliplatin, and suggests that the combined treatment has potential value in gastric cancer therapy.

scholarly journals Pluripotent stem cell-derived CAR-macrophage cells with antigen-dependent anti-cancer cell functions

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Li Zhang ◽  
Lin Tian ◽  
Xiaoyang Dai ◽  
Hua Yu ◽  
Jiajia Wang ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Activity ◽  
Great Success ◽  
Antigen Receptors ◽  
T Cell Therapy ◽  
Cell Functions ◽  
Macrophage Cells ◽  
Car T Cell Therapy ◽  
Induced Pluripotent

Abstract The Chimera antigen receptor (CAR)-T cell therapy has gained great success in the clinic. However, there are still major challenges for its wider applications in a variety of cancer types including lack of effectiveness due to the highly complex tumor microenvironment, and the forbiddingly high cost due to the personalized manufacturing procedures. In order to overcome these hurdles, numerous efforts have been spent focusing on optimizing Chimera antigen receptors, engineering and improving T cell capacity, exploiting features of subsets of T cell or NK cells, or making off-the-shelf universal cells. Here, we developed induced pluripotent stem cells (iPSCs)-derived, CAR-expressing macrophage cells (CAR-iMac). CAR expression confers antigen-dependent macrophage functions such as expression and secretion of cytokines, polarization toward the pro-inflammatory/anti-tumor state, enhanced phagocytosis of tumor cells, and in vivo anticancer cell activity. This technology platform for the first time provides an unlimited source of iPSC-derived engineered CAR-macrophage cells which could be utilized to eliminate cancer cells.

Polymalic Acid–Based Nanobiopolymer Provides Efficient Systemic Breast Cancer Treatment by Inhibiting both HER2/neu Receptor Synthesis and Activity

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Breast Cancer ◽  
Cancer Therapy ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Tumor Growth Inhibition ◽  
Human Breast ◽  
Akt Phosphorylation

Biodegradable nanopolymers are believed to offer great potential in cancer therapy. Here, we report thecharacterization of a novel, targeted, nanobiopolymeric conjugate based on biodegradable, nontoxic, andnonimmunogenic PMLA [poly(b-L-malic acid)]. The PMLA nanoplatform was synthesized for repetitive systemictreatments of HER2/neu-positive human breast tumors in a xenogeneic mouse model. Various moieties werecovalently attached to PMLA, including a combination of morpholino antisense oligonucleotides (AON) directedagainst HER2/neu mRNA, to block new HER2/neu receptor synthesis; anti-HER2/neu antibody trastuzumab(Herceptin), to target breast cancer cells and inhibit receptor activity simultaneously; and transferrin receptorantibody, to target the tumor vasculature and mediate delivery of the nanobiopolymer through the hostendothelial system. The results of the study showed that the lead drug tested significantly inhibited the growth ofHER2/neu-positive breast cancer cells in vitro and in vivo by enhanced apoptosis and inhibition of HER2/neureceptor signaling with suppression of Akt phosphorylation. In vivo imaging analysis and confocal microscopydemonstrated selective accumulation of the nanodrug in tumor cells via an active delivery mechanism. Systemictreatment of human breast tumor-bearing nude mice resulted in more than 90% inhibition of tumor growth andtumor regression, as compared with partial (50%) tumor growth inhibition in mice treated with trastuzumab orAON, either free or attached to PMLA. Our findings offer a preclinical proof of concept for use of the PMLAnanoplatform for combination cancer therapy.

scholarly journals Pharmacologic studies of CDH17/CD3 bispecific antibodies to treat colorectal and pancreatic cancers.

2019 ◽  
Vol 5 (suppl) ◽  
pp. 116-116
Author(s):  
Kwong-Fai Wong ◽  
William Chi-shing Tai ◽  
Kronos Chow ◽  
John M. Luk ◽  
Don Staunton
Keyword(s):  
T Cell ◽  
Cancer Cells ◽  
Dose Range ◽  
Specific Antigen ◽  
Bispecific Antibodies ◽  
Tumor Growth Inhibition ◽  
Cynomolgus Monkeys ◽  
Pancreatic Cancer Cells

116 Background: Immunotherapy has emerged as a new hope for cancer patients who do not respond to conventional therapies. In addition to the widely investigated immune checkpoint inhibitors such as PD-L1 antibody, bispecific T cell redirecting antibodies have also drawn much attention from pharmaceutical companies. The popularity of bispecific T cell engager has been increasing since the US FDA’s accelerated approval of blinatumomab for treatment of haematological malignancies. The clinical efficacy of such engagers in solid tumors have however remained to be demonstrated. Cadherin-17 (CDH17) is a promising immunotherapeutic target for gastrointestinal (GI) cancers. It is a highly tumor-specific antigen with restricted expression limited to the tight junction of intestine that is normally inaccessible to biologics. CDH17 overexpression correlates with tumor burden and poor prognosis. Methods: Fully humanized CDH17/CD3 bispecific antibodies were generated. T cell-mediated cytotoxicity was tested in vitro and in vivo. Safety was addressed in cynomolgus monkeys with intestinal CDH17 level equivalent to that of human. Results: One lead antibody, ARB202 exhibited high-affinity binding to CDH17 and CD3. In the presence of CDH17-positive pancreatic cancer cells, ARB202 stimulated in vitro IL-2 release in CD3/CD28-expanded PBMC. In the absence of tumor cells ARB202 stimulated cytokine production in PBMCs required over 600-fold greater concentrations. ARB202 specifically directed in vitro T cell killing of GI cancer cells expressing CDH17, but not of cells lacking CDH17 expression. In mouse xenograft models reconstituted with human immune cells, ARB202 demonstrated significant tumor growth inhibition with concomitant IL-2 response. No dose-dependent toxicities on cynomolgus monkeys were observed over a 3-log dose range. ARB202 displayed favourable in vivo pharmacokinetic profiles in mice and monkeys. ARB202 is a stable bispecific antibody retaining functional activity after incubation for a month at 37°C at pH6.0. Conclusions: ARB202 is a promising candidate for clinical trials. A proprietary cell line is generated for the pilot manufacturing of ARB202 for IND enabling studies.

scholarly journals 838 The role of microbiota in metastatic brain tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A879-A879
Author(s):  
Sarah Johnson ◽  
Golnaz Morad ◽  
Nadim Ajami ◽  
Jennifer Wargo ◽  
Matthew Wong ◽  
...  
Keyword(s):  
T Cell ◽  
Brain Metastasis ◽  
Gut Microbiota ◽  
Tumor Growth ◽  
Microbial Communities ◽  
Clinical Studies ◽  
Cell Activity ◽  
The Brain

BackgroundDespite the substantial advances in the treatment of systemic cancer, brain metastases are still responsible for significant morbidity and mortality, necessitating a better understanding of the mechanisms underlying this disease. Microbiota has emerged as a significant hallmark of cancer. Our group and others have demonstrated a prominent role for gut and intratumoral microbiota in tumorigenesis, tumor immunity, and response to treatment. However, the role of microbiota in brain metastasis is poorly understood. We hypothesize that distinct microbial communities can alter the immune microenvironment in the brain and modulate the different steps of brain metastasis formation.MethodsTo explore the role of microbiota in brain metastasis, we evaluated the gut and oral microbial signatures in brain metastasis patients through shotgun metagenomics sequencing. Furthermore, we conducted mechanistic in vivo studies in which the gut microbiota was depleted in conventionally raised mice using a broad-spectrum non-absorbable antibiotic regimen. Subsequently, melanoma tumor cells were injected intracranially to evaluate the effect of gut microbiota depletion and associated immune changes on tumor growth. Tumor growth was measured through in vivo bioluminescent imaging and histology. Peripheral and tumor immune profiling was conducted through flow cytometry and immunohistochemistry.ResultsOur clinical studies demonstrated the enrichment of distinct bacterial and viral taxa within the gut and oral microbiota in brain metastasis patients. Depletion of the gut microbiota in mice decreased tumor growth in the brain. Evaluation of the peripheral and tumor immune profiles suggested the underlying mechanisms to involve alterations in the circulating cytokine profiles and an increase in anti-tumor T cell activity.ConclusionsOur clinical studies suggest the association of distinct microbial communities with brain metastasis. Our pre-clinical findings demonstrate that the absence of gut microbiota can modulate the regulation of T cell activity to induce an anti-tumor response in the brain. Further studies, currently in progress, will determine the mechanistic role of dysbiotic microbiota and distinct microbial communities in this process.AcknowledgementsThis work was supported by the National Institute of Health (1F32CA260769-01).

scholarly journals Targeting tumor-derived NLRP3 reduces melanoma progression by limiting MDSCs expansion

2021 ◽  
Vol 118 (10) ◽  
pp. e2000915118
Author(s):  
Isak W. Tengesdal ◽  
Dinoop R. Menon ◽  
Douglas G. Osborne ◽  
Charles P. Neff ◽  
Nicholas E. Powers ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Growth ◽  
Nlrp3 Inflammasome ◽  
Antitumor Immunity ◽  
Normal Skin ◽  
Cell Activity ◽  
Suppressor Cells ◽  
Inflammasome Activation ◽  
Primary Tumors

Interleukin-1β (IL-1β)–mediated inflammation suppresses antitumor immunity, leading to the generation of a tumor-permissive environment, tumor growth, and progression. Here, we demonstrate that nucleotide-binding domain, leucine-rich containing family, pyrin domain-containing-3 (NLRP3) inflammasome activation in melanoma is linked to IL-1β production, inflammation, and immunosuppression. Analysis of cancer genome datasets (TCGA and GTEx) revealed greater NLRP3 and IL-1β expression in cutaneous melanoma samples (n = 469) compared to normal skin (n = 324), with a highly significant correlation between NLRP3 and IL-1β (P < 0.0001). We show the formation of the NLRP3 inflammasome in biopsies of metastatic melanoma using fluorescent resonance energy transfer analysis for NLRP3 and apoptosis-associated speck-like protein containing a CARD. In vivo, tumor-associated NLRP3/IL-1 signaling induced expansion of myeloid-derived suppressor cells (MDSCs), leading to reduced natural killer and CD8+ T cell activity concomitant with an increased presence of regulatory T (Treg) cells in the primary tumors. Either genetic or pharmacological inhibition of tumor-derived NLRP3 by dapansutrile (OLT1177) was sufficient to reduce MDSCs expansion and to enhance antitumor immunity, resulting in reduced tumor growth. Additionally, we observed that the combination of NLRP3 inhibition and anti–PD-1 treatment significantly increased the antitumor efficacy of the monotherapy by limiting MDSC-mediated T cell suppression and tumor progression. These data show that NLRP3 activation in melanoma cells is a protumor mechanism, which induces MDSCs expansion and immune evasion. We conclude that inhibition of NLRP3 can augment the efficacy of anti–PD-1 therapy.

scholarly journals 446 Immunopeptidome changes mediated by a novel ERAP1 inhibitor leads to tumor growth inhibition

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A472-A472
Author(s):  
Peter Joyce ◽  
Lesley Young ◽  
Martin Quibell ◽  
Jason Shiers ◽  
Carmen Tong ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Hla Class I ◽  
Class I ◽  
Tumor Growth Inhibition ◽  
Mouse Tumor ◽  
Cell Repertoire

BackgroundClinical data demonstrates increased antigen presentation diversity is a key factor in determining response rates to checkpoint inhibitors.1 In addition to tumour mutational burden/microsatellite instability, increased HLA heterozygosity and HLA evolutionary diversity are non-overlapping factors recently identified to further diversify the immunopeptidome and improve clinical response to checkpoint therapies.2 3 Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an enzyme that trims peptides loaded into classical and nonclassical class I MHC molecules.4 5 Ablation of mouse ERAAP modifies the immunopeptidome, resulting in improved immunogenicity, generation of CD8 T cell responses and tumor growth inhibition.6 7 Recently identified selective small molecules potently inhibit ERAP1 across key species and haplotypes.8 We report the further profiling of lead candidate ERAP1 inhibitors in human primary T cell in vitro assays and in vivo tumor models in mice.MethodsHuman cancer cell lines treated with ERAP1 inhibitors in vitro or in vivo in xenograft mouse models were assessed by immunopeptidomics9 to profile peptide repertoire changes. Novel or upregulated peptides were also tested in human immunogenicity assays. FACS analysis of T cells stimulated with Tyrosinase mRNA transfected human dendritic cells ± ERAP1 inhibition was to assess T cell repertoire changes. ERAP1 inhibitor and anti PD-1 mAb combination was assessed in syngeneic mouse tumor models to investigate tumour growth inhibition and PD end-points (e.g. IHC).ResultsAnalysis of human cervical, lung, colorectal and melanoma cell lines carrying distinct HLA haplotypes demonstrates a consistent and profound effect of ERAP1 inhibition on the immunopeptidome. Novel and upregulated cancer associated antigens identified in association with multiple different HLA-A and B alleles stimulate IFNγ production in primary naïve human T cell immunogenicity assays. The impact of ERAP1 inhibition on the T cell repertoire to the melanoma antigen tyrosinase is ongoing. The combination of ERAP1 inhibitor and anti PD-1 mAb led to significant tumor growth inhibition in the CT26 syngeneic mouse tumor model that correlated with increased infiltration of T cells to the tumor. Further PD end-points to be analysed include immune gene array and TCR Vbeta repertoire.ConclusionsGrey Wolf ERAP1 inhibitors significantly modify the immunopeptidome both in vitro and in vivo across a broad range of HLA and tumor types. Combination of these inhibitors with anti PD-1 leads to significant T cell infiltration and tumor growth inhibition. Thus, ERAP1 mediated modulation of the immunopeptidome has the potential to drive anti tumor T cell responses and be a transformative immunotherapy.ReferencesRizvi N, Hellmann MD, Snyder A, et al. Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer. Science. 2015;348(6230):124–128.Chowell D, Morris LGT, Grigg CM, et al. Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy. Science 2018;359 (6375):582–587.Chowell D, Krishna C, Pierini F, et al. Evolutionary divergence of HLA class I genotype impacts efficacy of cancer immunotherapy. Nature Medicine 2019;25(11):1715–1720.Shastri N, Nagarajan N, Lind KC, et al. Monitoring peptide processing for MHC class I molecules in the endoplasmic reticulum. Curr Opin Immunol 2014; 26:123–127.Mpakali A, Maben Z, Stern LJ, et al. Molecular pathways for antigenic peptide generation by ER aminopeptidase 1. Mol Immunol 2018; 13:50–57.James E, Bailey I, Sugiyarto G, et al. Induction of protective antitumor immunity through attenuation of ERAAP function. J Immunol 2013;190(11):5839–5846.Manguso RT, Pope HW, Zimmer MD, et al. In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Nature 2017;547(7664):413–418.Leonard, H Remtulla A, Poynton F, et al. AACR Annual Meeting 2020.Purcell AW, Ramarathinam SH, Ternette N. Mass spectrometry–based identification of MHC-bound peptides for immunopeptidomics. Nat Protoc 2019;14(6):1687–1707.

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.

Enhancement of the therapeutic effects of oncolytic vaccinia virus by using autologous and allogeneic cell-based delivery platforms.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15271-e15271
Author(s):  
Boris Minev ◽  
Antonio F. Santidrian ◽  
Ivelina Minev ◽  
Duong Nguyen ◽  
Dmitriy Zamarin ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Vaccinia Virus ◽  
Tumor Growth Inhibition ◽  
Therapeutic Effects ◽  
Adaptive Immune ◽  
Allogeneic Cell

e15271 Background: Clinical trials with oncolytic viruses for cancer treatment have shown limited efficacy due to viruses’ rapid clearance by patients’ innate and adaptive immune systems. In a recent first-in-human clinical trial, we confirmed the safety and feasibility of our approach to enhance oncolytic vaccinia virus (OVV) delivery and improve tumor targeting by utilizing an autologous cell-based cell delivery system (auto-OVV). We also developed an allogeneic cell-based platform (SuperNova1c - SNV1c) aiming to protect and potentiate OVV’s antitumor effects in large patient populations. Methods: We evaluated the immunomodulatory potential of auto-OVV by an extensive time-course analysis of cytokines in patients’ plasma (Luminex profiling) and peripheral blood immune cells (flow cytometry). We also analyzed the ability of SNV1c to protect the OVV from antibody/complement inactivation in vitro and in vivo following intratumoral injection in various mouse tumors. The immune cell infiltrations of the injected tumors were also analyzed. Results: Therapy with auto-OVV induced a coordinated activation of cytokine, T cell and NK responses in patients as early as 1 day, peaking around 1-week and lasting for up to 1-month post treatment. Effective OVV amplification in cancer patients correlated with significant changes of multiple innate and adaptive immune parameters. Patient stratification into groups with transient versus persistent viral DNA was linked to opposing and mutually exclusive patterns of robust activation of NK versus T cell responses, respectively. SNV1c showed significantly enhanced protection of OVV in vitro and led to statistically significant tumor growth inhibition as compared to control non-treated tumors or to naked OVV-treated tumors. Importantly, local administration of SNV1c induced systemic therapeutic effects. Five days after SNV1c administration, tumor infiltrating lymphocytes from both treated and untreated tumors showed increased CD4 and CD8 T-cell infiltrations, decreased Tregs, and improved effector to Treg ratios, associated with tumor growth inhibition at both treated and untreated tumor sites. Conclusions: This study establishes the timeline of treatment-related immunological changes and identifies potential immunological correlates associated with the OVV persistence in vivo. We also demonstrate the ability of our cell-based platforms to protect and potentiate OVV by circumventing innate and adaptive immune barriers, resulting in enhanced oncolytic virotherapy.

scholarly journals Notch1/TAZ axis promotes aerobic glycolysis and immune escape in lung cancer

2021 ◽  
Vol 12 (9) ◽  
Author(s):  
Mian Xie ◽  
Xin-ge Fu ◽  
Ke Jiang
Keyword(s):  
Lung Cancer ◽  
T Cell ◽  
Cancer Cells ◽  
Immune Escape ◽  
Aerobic Glycolysis ◽  
Cell Activity ◽  
Metabolic Reprogramming ◽  
Cytotoxic T Cell ◽  
Cell Functions ◽  
Notch1 Signaling

AbstractOncogenic signaling pathway reprograms cancer cell metabolism to promote aerobic glycolysis in favor of tumor growth. The ability of cancer cells to evade immunosurveillance and the role of metabolic regulators in T-cell functions suggest that oncogene-induced metabolic reprogramming may be linked to immune escape. Notch1 signaling, dysregulated in lung cancer, is correlated with increased glycolysis. Herein, we demonstrate in lung cancer that Notch1 promotes glycolytic gene expression through functional interaction with histone acetyltransferases p300 and pCAF. Notch1 signaling forms a positive feedback loop with TAZ. Notch1 transcriptional activity was increased in the presence of TAZ and the activation was TEAD1 independent. Notably, aerobic glycolysis was critical for Notch1/TAZ axis modulation of lung cancer growth in vitro and in vivo. Increased level of extracellular lactate via Notch1/TAZ axis inhibited cytotoxic T-cell activity, leading to the invasive characteristic of lung cancer cells. Interaction between Notch1 and TAZ promoted aerobic glycolysis and immune escape in lung cancer. Our findings provide potential therapeutic targets against Notch1 and TAZ and would be important for clinical translation in lung cancer.

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