scholarly journals Molecular Response to Combined Molecular- and External Radiotherapy in Head and Neck Squamous Cell Carcinoma (HNSCC)

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5595
Author(s):  
Treewut Rassamegevanon ◽  
Louis Feindt ◽  
Lydia Koi ◽  
Johannes Müller ◽  
Robert Freudenberg ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Combination Therapy ◽  
Combination Treatment ◽  
Xenograft Model ◽  
Local Tumor Control ◽  
Tumor Control ◽  
External Irradiation ◽  
Molecular Response ◽  
External Radiotherapy

Combination treatment of molecular targeted and external radiotherapy is a promising strategy and was shown to improve local tumor control in a HNSCC xenograft model. To enhance the therapeutic value of this approach, this study investigated the underlying molecular response. Subcutaneous HNSCC FaDuDD xenografts were treated with single or combination therapy (X-ray: 0, 2, 4 Gy; anti-EGFR antibody (Cetuximab) (un-)labeled with Yttrium-90 (90Y)). Tumors were excised 24 h post respective treatment. Residual DNA double strand breaks (DSB), mRNA expression of DNA damage response related genes, immunoblotting, tumor histology, and immunohistological staining were analyzed. An increase in number and complexity of residual DNA DSB was observed in FaDuDD tumors exposed to the combination treatment of external irradiation and 90Y-Cetuximab relative to controls. The increase was observed in a low oxygenated area, suggesting the expansion of DNA DSB damages. Upregulation of genes encoding p21cip1/waf1 (CDKN1A) and GADD45α (GADD45A) was determined in the combination treatment group, and immunoblotting as well as immunohistochemistry confirmed the upregulation of p21cip1/waf1. The increase in residual γH2AX foci leads to the blockage of cell cycle transition and subsequently to cell death, which could be observed in the upregulation of p21cip1/waf1 expression and an elevated number of cleaved caspase-3 positive cells. Overall, a complex interplay between DNA damage repair and programmed cell death accounts for the potential benefit of the combination therapy using 90Y-Cetuximab and external radiotherapy.

Combination Bortezomib (PS341, Velcade) and Rituximab Treatment Affects Multiple Survival and Death Pathways To Promote Apoptosis in Mantle Cell Lymphoma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2407-2407 ◽  
Author(s):  
Navin Wadehra ◽  
Teresa Lin ◽  
Timothy Ryan ◽  
Ashley Schneider ◽  
Allison Pepple ◽  
...  
Keyword(s):  
Animal Model ◽  
Cell Death ◽  
Combination Therapy ◽  
Mantle Cell Lymphoma ◽  
Combination Treatment ◽  
Cell Lymphoma ◽  
Proteasome Inhibition ◽  
Mantle Cell ◽  
Induction Of Apoptosis ◽  
Induced Apoptosis

Abstract Mantle cell lymphoma (MCL) is a distinct histologic subtype of B cell non-Hodgkin’s lymphoma that is associated with an aggressive clinical course and a particularly poor prognosis. The mechanisms that contribute to resistance of MCL to chemotherapy are not clear, however, recent work examining the consequences of ubiquitin-proteasome pathway inhibition on cell cycle (p21, p27) and key survival/death networks (NFkB, p53, Bcl2) has provided rationale for exploring combination regimens that include tumor-specific reagents (rituximab) and the 26S proteasome inhibitor bortezomib. In this study, we examined the effects of combination treatment with bortezomib and rituximab on MCL patient samples and three patient-derived cell lines (Jeko, Mino, SP53). Cells treated with bortezomib (10 – 100nM) for 4 hours demonstrated proteasome inhibition that persisted for 24 hours but returned to baseline activity at 48 hours after treatment. Despite transient proteasome inhibition, combination therapy with bortezomib (10–100nM for 4hrs) and rituximab (1 mg/ml immobilized with 20 mg/ml goat anti-human IgG) resulted in synergistic induction of apoptosis that persisted for as long as 72 hours after treatment. While bortezomib (100 nM) induced apoptosis in 18.3 ± 6.5% and rituximab induced apoptosis in 24.5 ± 4.5% of MCL cells, combination treatment resulted in 57.4 ± 5.1% apoptosis at 48 hours (p ≤ 0.02). Pretreatment of MCL cells with the broad spectrum caspase inhibitor zVAD-FMK (10 mM) showed that bortezomib-induced cell death occurred by caspase-dependent mechanisms, however, when immobilized rituximab was added, cell death occurred via caspase dependent and independent pathways. Single agent bortezomib (10 nM) or rituximab treatment of Mino and Jeko lines resulted in decreased levels of nuclear NFkB complex(s) capable of binding p65 consensus oligonucleotides (28% and 21% reduction, respectively), while combination treatment resulted in enhanced reduction of detectable nuclear NFkB (36% reduction, p ≤ 0.0007). Similar trends were observed with primary MCL cells. Experiments with an IKK inhibitor (PS1145, Millenium Pharmaceuticals) resulted in nuclear NFkB reduction without equivalent induction of apoptosis which led us to hypothesize that other pro-death pathways might be operable with combination treatment. Western blot analysis of BCL2-family members revealed that combination treatment of MCL lines resulted in near complete elimination of Bcl-xL protein while Bcl-2 protein levels remained unchanged. The pro-death gene product Bax was induced in a synergistic fashion with combined bortezomib and rituximab treatment. Finally, we have developed a reliable preclinical animal model utilizing the severe combined immune deficient (SCID) mouse engrafted with three patient-derived MCL cell lines. Each cell line results in a characteristic pattern of tumor burden and highly reproducible time to develop advanced disease. We are currently evaluating combination therapy with bortezomib and rituximab in this preclinical animal model. Our preclinical evaluation provides clear rationale for pursuing combination strategies that inhibit the proteasome in combination with tumor-specific immunotherapy in patients with MCL.

Azacitidine/Decitabine Synergism with the NEDD8-Activating Enzyme Inhibitor MLN4924 in Pre-Clinical AML Models

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 578-578 ◽  
Author(s):  
Peter G Smith ◽  
Tary Traore ◽  
Steve Grossman ◽  
Usha Narayanan ◽  
Jennifer S Carew ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Synthetic Lethality ◽  
Single Agent ◽  
Xenograft Model ◽  
S Phase ◽  
Myelogenous Leukemia ◽  
Phase Accumulation

Abstract Abstract 578 MLN4924 is an investigational small molecule inhibitor of NEDD8-activating enzyme that has shown clinical activity in a Phase I clinical trial in Acute Myelogenous Leukemia (AML). To identify potential combination partners of MLN4924 we performed a high-throughput viability screen in AML cells with 40 approved and investigational agents. In vitro characterization of AML cell lines revealed two distinct cell cycle phenotypes suggesting alternate mechanism of action following MLN4924 inhibition of NAE. One group demonstrated moderate S-phase accumulation with greater than 4N DNA content consistent with DNA-rereplication as a result of CDT1 dysregulation. The second group demonstrated distinct and rapid accumulation of subG1 cells without S-phase accumulation or DNA re-replication suggesting induction of apoptosis and cell death. These observations led us to choose two cells lines representative of each mechanism to understand potential for synergy in AML cells. Two hypomethylating agents were included in the screen (decitabine and azacitidine) and were found to be synergistic with MLN4924 by Combination Index and Blending Synergy Analysis. These data were confirmed with a second NAE inhibitor that is structurally dissimilar to MLN4924. The combination of azacitidine and MLN4924 were shown to result in significantly increased DNA-damage and cell death compared to single agent alone as measured by Western Blotting and FACS analysis of cell cycle distributions. In vivo studies were performed in HL-60 and THP-1 xenografts using MLN4924 on a clinically relevant dosing schedule twice weekly. Single agent azacitidine at its Maximum Tolerated Dose (MTD) had minimal activity in the HL-60 model and was combined with a sub-optimal dose of MLN4924 that when combined induced complete and sustained tumor regressions. The mechanism for the apparent synthetic lethality in this in vivo model is currently under evaluation; however it is supported by a dramatic elevation in DNA damage and cleaved caspase-3 in vivo in the combination arm. A second xenograft model (THP-1) that was also insensitive to single agent azacitidine treatment underwent complete and sustained tumor regressions when combined with MLN4924. Thus MLN4924 and azacitidine can combine to produce synergistic antitumor activity in pre-clinical models of AML. Coupled with their non-overlapping clinical toxicities these data suggest the potential for future combination studies in clinical trials. Disclosures: Smith: Millennium Pharmaceuticals: Employment. Traore:Millennium Pharmaceuticals: Employment. Grossman:Millennium Pharmaceuticals: Employment. Narayanan:Millennium Pharmaceuticals: Employment. Carew:Millennium Pharmaceuticals: Research Funding. Lublinksky:Millennium Pharmaceuticals: Employment. Kuranda:Millennium Pharmaceuticals: Employment. Milhollen:Millennium Pharmaceuticals: Employment.

scholarly journals Combination Therapy of Bifidobacterium longum RAPO With Anti-PD-1 Treatment Enhances Anti-tumor Immune Response in Association With Gut Microbiota Modulation

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 1131-1131
Author(s):  
Hyeyoon Kim ◽  
Rira Oh ◽  
Sangjun Park ◽  
Geun Eog Ji ◽  
Myeong Soo Park ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
Cell Death ◽  
Combination Therapy ◽  
Gut Microbiota ◽  
Bifidobacterium Longum ◽  
Relative Proportion ◽  
Tumor Control ◽  
Rrna Gene ◽  
Potential Candidate

Abstract Objectives Triple negative breast cancer (TNBC) has a poor prognosis with a high risk of metastasis and relapse, and accounts for approximately 35% of breast cancer death. Immune checkpoint inhibitors (ICI) have been in the spotlight recently as a novel treatment of TNBC due to the higher expressions of programmed cell death ligand 1 (PD-L1) and tumor-infiltrating lymphocytes in TNBC. Considering that gut microbiome is associated with immune response and ICI efficacy, we investigated whether Bifidobacterium longum RAPO supplementation would affect the efficacy of anti-PD-1 therapy against TNBC in vivo. Methods Female BALB/c mice bearing 4T1 breast cancer cells were randomly divided into four groups; tumor control (TC), Anti-PD-1, B. longum RAPO (RAPO), or Anti-PD-1 + RAPO (Combi). Anti-PD-1 antibody was injected i.p. 5 times at 3-day intervals and B. longum RAPO was orally administered daily from 2 days before the first injection of anti-PD-1. Spleen and tumor tissues were analyzed by flow cytometry, IHC, and qRT-PCR. Fecal samples were analyzed by 16S rRNA gene sequencing. Results Tumor volume was reduced in the Combi group than TC and Anti-PD-1 groups on day 12. PD-L1 IHC score and PD-L1 mRNA expression were significantly increased in tumors of the Combi group. The levels of the spleen CD8/CD4 ratio and tumor NK cells were also increased in the Combi group. Compared with the Anti-PD-1 group, the pro-tumor M2 macrophages and related cytokines (IL10, Arg1) were significantly decreased, while anti-tumor M1 cytokines (IFNγ, TNFα) were elevated in tumors of the Combi group. Consistently, immunogenic cell death-associated markers were significantly higher in the Combi group. We found that the relative proportion of the genus Bifidobacterium, Lachnoclostridium, Lachnospiraceae NK4A136 group, and Clostridium sensu stricto 1, which are known to be associated with the better response to ICI therapy, were significantly increased, while the genus Mucispirillum and Dubosiella were decreased in the Combi group than the Anti-PD-1 group. Conclusions Our data indicates that combination therapy of B. longum RAPO with anti-PD-1 enhances anti-tumor immune response in association with modulation of gut microbiota, suggesting that B. longum RAPO might be a potential candidate for pharmabiotics in ICI treatment. Funding Sources BIFIDO CO, the National Research Foundation of Korea grant.

scholarly journals Enhanced Antitumor Effect in Liver Cancer by Amino Acid Depletion-Induced Oxidative Stress

2021 ◽  
Vol 11 ◽  
Author(s):  
Keiichiro Okuda ◽  
Atsushi Umemura ◽  
Seita Kataoka ◽  
Kota Yano ◽  
Aya Takahashi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Liver Cancer ◽  
Combination Therapy ◽  
Cell Lines ◽  
Antitumor Effect ◽  
Xenograft Model ◽  
Expression Levels ◽  
Huh7 Cells ◽  
Hcc Cells

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. HCC cells consume large amounts of glutamine to survive, but can adapt to glutamine depletion in the presence of an exogenous asparagine. L-asparaginase (ASNase) converts glutamine and asparagine to glutamate and aspartate, respectively, and has been used to treat leukemia. Here we examined the effects of ASNase treatment on HCC cells and explored the potential impact of combining ASNase with the tyrosine kinase inhibitor lenvatinib (Len) for HCC treatment. Cell viability and death of HCC cell lines treated with either Len or ASNase alone or with Len and ASNase combined were determined. We assessed mRNA and protein expression levels of glutamine synthetase (GS) and asparagine synthetase (ASNS) by real-time quantitative PCR and immunoblotting. The antitumor effect of the combination therapy relative to Len or ASNase monotherapy was also evaluated in a xenograft tumor mouse model. ASNase treatment inhibited growth of SNU387 and SNU398 HCC cells, which have low GS and high ASNS expression levels, respectively, but did not clearly inhibit growth of the other cell lines. Len plus ASNase combination therapy synergistically inhibited proliferation and induced oxidative stress leading to cell death of some HCC cells lines. However, cell death of Huh7 cells, which express ASCT2, an important glutamine transporter for cancer cells, was not affected by the combination treatment. In a xenograft model, Len combined with ASNase significantly attenuated tumor development relative to mice treated with Len or ASNase alone. ASNase-mediated targeting of two amino acids, glutamine and asparagine, which are indispensable for HCC survival, induces oxidative stress and can be a novel cancer treatment option that exerts a synergistic effect when used in combination with Len.

Abstract 1680: Modulation of MDM2 in context of DNA damage enhances cell death in a metastatic breast-to-lung xenograft model

2014 ◽  
Author(s):  
Eva Tonsing-Carter ◽  
Harlan E. Shannon ◽  
Barbara J. Bailey ◽  
Anthony L. Sinn ◽  
Kacie M. Peterman ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Xenograft Model ◽  
Metastatic Breast

scholarly journals Injectable diblock copolypeptide hydrogel provides platform to maintain high local concentrations of taxol and local tumor control

2019 ◽  
Author(s):  
Matthew C. Garrett ◽  
Timothy M. O’Shea ◽  
Alexander L. Wollenberg ◽  
Alexander M. Bernstein ◽  
Derek Hung ◽  
...  
Keyword(s):  
Surgical Resection ◽  
Xenograft Model ◽  
Tumor Location ◽  
Local Tumor Control ◽  
Tumor Control ◽  
Local Concentration ◽  
Local Tumor ◽  
Immunodeficient Mice ◽  
Wide Range ◽  
Systemic Side Effects

AbstractIntroductionSurgical resection and systemic chemotherapy with temozolomide remain the mainstay for treatment of glioblastoma. However, many patients are not candidates for surgical resection given inaccessible tumor location or poor health status. Furthermore, despite being first line treatment, temozolomide has only limited efficacy.MethodsThe development of injectable hydrogel-based carrier systems allows for the delivery of a wide range of chemotherapeutics that can achieve high local concentrations, thus potentially avoiding systemic side effects and wide-spread neurotoxicity. To test this modality in a realistic environment, we developed a diblock copolypeptide hydrogel (DCH) capable of carrying and releasing paclitaxel, a compound that we found to be highly potent against primary gliomasphere cells.ResultsThe DCH produced minimal tissue reactivity and was well tolerated in the immune-competent mouse brain. Paclitaxel-loaded hydrogel induced less tissue damage, cellular inflammation and reactive astrocytes than cremaphor-taxol (typical taxol-carrier) or hydrogel alone. In a deep subcortical xenograft model, of glioblastoma in immunodeficient mice, injection of paclitaxel-loaded hydrogel led to a high local concentration of paclitaxel and led to local tumor control and improved survival. However, the tumor cells were highly migratory and were able to eventually escape the area of treatment.ConclusionsThese findings suggest this technology may be ultimately applicable to patients with deep-seated inoperable tumors, but as currently formulated, complete tumor eradication would be highly unlikely. Future studies should focus on targeting the migratory potential of surviving cells.

scholarly journals EXTH-58. INHIBITION OF DNA TOPOISOMERASE 1 AND POLY(ADP-RIBOSE) POLYMERASE SYNERGISTICALLY INDUCES CELL DEATH IN GLIOBLASTOMA WITH PTEN LOSS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi94-vi95
Author(s):  
Madison Butler ◽  
Yu-Ting Su ◽  
Lee Hwang ◽  
Laetitia Marzi ◽  
Mark Gilbert ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Dna Damage ◽  
Cell Death ◽  
Cell Viability ◽  
Combination Treatment ◽  
Dna Supercoiling ◽  
Glioblastoma Cell ◽  
Pten Loss ◽  
Topoisomerase 1

Abstract BACKGROUND Glioblastoma is known for its aggressive behavior and resistance to most available treatments. Topoisomerase 1 (Top1) functions by relaxing DNA supercoiling to facilitate replication. The novel Top1 inhibitor, LMP400, traps the enzyme and prevents its normal function, particularly in highly proliferative cells, resulting in DNA damage. Poly(ADP-ribose) polymerase (PARP) is involved in DNA repair responses triggered by Top1 inhibition. Phosphatase and tensin homolog (PTEN) loss, a frequent occurrence in glioblastoma, promotes DNA damage repair deficiency. We hypothesize that PTEN loss presents a vulnerability to combined induction of DNA damage and inhibition of repair mechanisms. METHODS Human glioblastoma cells were treated with LMP400 and/or Olaparib, a PARP inhibitor. Effects on cell proliferation and cell death were determined using a Beckman Coulter cell viability analyzer and colony formation assays. Synergism was calculated using COMPUSYN software. Cell cycle analysis was performed by FACS with EdU/DAPI staining, and Western blotting of lysate from drug-treated cells was performed to explore mechanisms of cytotoxicity. RESULTS LMP400 inhibited cell proliferation with an EC50 of 8.0 nM in U251 cells, and combination of LMP400 and Olaparib had a synergistic cytotoxic effect. Combination treatment enhanced activation of ATM-Chk2 and ATR-Chk1 pathways involved in DNA damage response signaling and increased S phase arrest. Increased protein expression of gamma-H2AX, cleaved caspase 3, and cleaved PARP was observed in combination-treated cells compared to single agents. Cell viability assays using isogenic glioblastoma cell lines with and without PTEN indicate that PTEN loss increases sensitivity to combination treatment. CONCLUSION Our results suggest that LMP400 and Olaparib combined treatment synergistically induces glioblastoma cell death, partially through inducing DNA damage, cell cycle arrest, and apoptosis. Mechanistic studies to investigate this vulnerability in glioblastoma with PTEN loss are ongoing. These results may lead to an effective personalized therapy for a molecularly defined subset of glioblastoma patients.

scholarly journals Injectable diblock copolypeptide hydrogel provides platform to maintain high local concentrations of taxol and local tumor control

2019 ◽  
Author(s):  
Matthew C. Garrett ◽  
Timothy M. O’Shea ◽  
Alexander L. Wollenberg ◽  
Alexander M. Bernstein ◽  
Derek Hung ◽  
...  
Keyword(s):  
Surgical Resection ◽  
Xenograft Model ◽  
Tumor Location ◽  
Local Tumor Control ◽  
Tumor Control ◽  
Local Concentration ◽  
Local Tumor ◽  
Immunodeficient Mice ◽  
Wide Range ◽  
Systemic Side Effects

AbstractIntroductionSurgical resection and systemic chemotherapy with temozolomide remain the mainstay for treatment of glioblastoma. However, many patients are not candidates for surgical resection given inaccessible tumor location or poor health status. Furthermore, despite being first line treatment, temozolomide has only limited efficacy.MethodsThe development of injectable hydrogel-based carrier systems allows for the delivery of a wide range of chemotherapeutics that can achieve high local concentrations, thus potentially avoiding systemic side effects and wide-spread neurotoxicity. To test this modality in a realistic environment, we developed a diblock copolypeptide hydrogel (DCH) capable of carrying and releasing paclitaxel, a compound that we found to be highly potent against primary gliomasphere cells.ResultsThe DCH produced minimal tissue reactivity and was well tolerated in the immune-competent mouse brain. Paclitaxel-loaded hydrogel induced less tissue damage, cellular inflammation and reactive astrocytes than cremaphor-taxol (typical taxol-carrier) or hydrogel alone. In a deep subcortical xenograft model, of glioblastoma in immunodeficient mice, injection of paclitaxel-loaded hydrogel led to a high local concentration of paclitaxel and led to local tumor control and improved survival. However, the tumor cells were highly migratory and were able to eventually escape the area of treatment.ConclusionsThese findings suggest this technology may be ultimately applicable to patients with deep-seated inoperable tumors, but as currently formulated, complete tumor eradication would be highly unlikely. Future studies should focus on targeting the migratory potential of surviving cells.

scholarly journals The targeted SMAC mimetic SW IV-134 augments platinum-based chemotherapy in pre-clinical models of ovarian cancer

2022 ◽  
Author(s):  
Pratibha S. Binder ◽  
Yassar M. Hashim ◽  
James Cripe ◽  
Tommy Buchanan ◽  
Abigail Zamorano ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Death ◽  
Combination Therapy ◽  
Cell Lines ◽  
Xenograft Model ◽  
Advanced Ovarian Cancer ◽  
Tumor Growth Rate ◽  
Tumor Cell Death ◽  
Patient Derived Xenograft ◽  
Platinum Based Chemotherapy

Abstract Background: Ovarian cancer is initially responsive to frontline chemotherapy. Unfortunately, it often recurs and becomes resistant to available therapies and the survival rate for advanced and recurrent ovarian cancer is unacceptably low. We thus hypothesized that it would be possible to achieve more durable treatment responses by combining cisplatin chemotherapy with SW IV-134, a cancer-targeted peptide mimetic and inducer of cell death. SW IV-134 is a recently developed small molecule conjugate linking a sigma-2 ligand with a peptide analog (mimetic) of the intrinsic death pathway activator SMAC (second-mitochondria activator of caspases). The sigma-2 receptor is overexpressed in ovarian cancer and the sigma-2 ligand portion of the conjugate facilitates cancer selectivity. The effector portion of the conjugate is expected to synergize with cisplatin chemotherapy and the cancer selectivity is expected to reduce putative off-target toxicities. Methods: Ovarian cancer cell lines were treated with cisplatin alone, SW IV-134 alone and a combination of the two drugs. Treatment efficacy was determined using luminescent cell viability assays. Caspase-3/7,-8 and-9 activities were measured as complementary indicators of death pathway activation. Syngeneic mouse models and patient-derived xenograft (PDX) models of human ovarian cancer were studied for response to SW IV-134 and cisplatin monotherapy as well as combination therapy. Efficacy of the therapy was measured by tumor growth rate and survival as the primary readouts. Potential drug related toxicities were assessed at necropsy. Results: The combination treatment was consistently superior in multiple cell lines when compared to the single agents in vitro. The expected mechanism of tumor cell death, such as caspase activation, was confirmed using luminescent and flow cytometry-based assay systems. Combination therapy proved to be superior in both syngeneic and PDX-based murine models of ovarian cancer. Most notably, combination therapy resulted in a complete resolution of established tumors in all study animals in a patient-derived xenograft model of ovarian cancer. Conclusions: The addition of SW IV-134 in combination with cisplatin chemotherapy represents a promising treatment option that warrants further pre-clinical development and evaluation as a therapy for women with advanced ovarian cancer.

scholarly journals Ginseng polysaccharides alter the gut microbiota and kynurenine/tryptophan ratio, potentiating the antitumour effect of antiprogrammed cell death 1/programmed cell death ligand 1 (anti-PD-1/PD-L1) immunotherapy

Gut ◽  
2021 ◽  
pp. gutjnl-2020-321031
Author(s):  
Jumin Huang ◽  
Di Liu ◽  
Yuwei Wang ◽  
Liang Liu ◽  
Jian Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Combination Therapy ◽  
Gut Microbiota ◽  
Single Molecule ◽  
Combination Treatment ◽  
Lung Cancer Patients ◽  
New Strategy ◽  
Microbial Analysis ◽  
Programmed Death 1

ObjectiveProgrammed death 1 and its ligand 1 (PD-1/PD-L1) immunotherapy is promising for late-stage lung cancer treatment, however, the response rate needs to be improved. Gut microbiota plays a crucial role in immunotherapy sensitisation and Panax ginseng has been shown to possess immunomodulatory potential. In this study, we aimed to investigate whether the combination treatment of ginseng polysaccharides (GPs) and αPD-1 monoclonal antibody (mAb) could sensitise the response by modulating gut microbiota.DesignSyngeneic mouse models were administered GPs and αPD-1 mAb, the sensitising antitumour effects of the combination therapy on gut microbiota were assessed by faecal microbiota transplantation (FMT) and 16S PacBio single-molecule real-time (SMRT) sequencing. To assess the immune-related metabolites, metabolomics analysis of the plasma samples was performed.ResultsWe found GPs increased the antitumour response to αPD-1 mAb by increasing the microbial metabolites valeric acid and decreasing L-kynurenine, as well as the ratio of Kyn/Trp, which contributed to the suppression of regulatory T cells and induction of Teff cells after combination treatment. Besides, the microbial analysis indicated that the abundance of Parabacteroides distasonis and Bacteroides vulgatus was higher in responders to anti-PD-1 blockade than non-responders in the clinic. Furthermore, the combination therapy sensitised the response to PD-1 inhibitor in the mice receiving microbes by FMT from six non-responders by reshaping the gut microbiota from non-responders towards that of responders.ConclusionOur results demonstrate that GPs combined with αPD-1 mAb may be a new strategy to sensitise non-small cell lung cancer patients to anti-PD-1 immunotherapy. The gut microbiota can be used as a novel biomarker to predict the response to anti-PD-1 immunotherapy.

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