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Frontiers in Immunology 2022Radiation therapy (XRT) has a well-established role in cancer treatment. Given the encouraging results on immunostimulatory effects, radiation has been increasingly used...
Radiation therapy (XRT) has a well-established role in cancer treatment. Given the encouraging results on immunostimulatory effects, radiation has been increasingly used with immune-check-point inhibitors in metastatic disease, especially when immunotherapy fails due to tumor immune evasion. We hypothesized that using high-dose stereotactic radiation in cycles (pulses) would increase T-cell priming and repertoire with each pulse and build immune memory in an incremental manner. To prove this hypothesis, we studied the combination of anti-CTLA-4 and Pulsed radiation therapy in our 344SQ non-small cell lung adenocarcinoma murine model. Primary and secondary tumors were bilaterally implanted in 129Sv/Ev mice. In the Pulsed XRT group, both primary and secondary tumors received 12Gyx2 radiation one week apart, and blood was collected seven days afterwards for TCR repertoire analysis. As for the delayed-Pulse group, primary tumors received 12Gyx2, and after a window of two weeks, the secondary tumors received 12Gyx2. Blood was collected seven days after the second cycle of radiation. The immunotherapy backbone for both groups was anti-CTLA-4 antibody to help with priming. Treatment with Pulsed XRT + anti-CTLA-4 led to significantly improved survival and resulted in a delayed tumor growth, where we observed enhanced antitumor efficacy at primary tumor sites beyond XRT + anti-CTLA-4 treatment group. More importantly, Pulsed XRT treatment led to increased CD4 effector memory compared to single-cycle XRT. Pulsed XRT demonstrated superior efficacy to XRT in driving antitumor effects that were largely dependent on CD4 T cells and partially dependent on CD8 T cells. These results suggest that combinatorial strategies targeting multiple points of tumor immune evasion may lead to a robust and sustained antitumor response.
Topics: Mice; Animals; Tumor Burden; CD8-Positive T-Lymphocytes; Immunologic Memory; Immunotherapy; Adenocarcinoma; Receptors, Antigen, T-Cell
PubMed: 36275767
DOI: 10.3389/fimmu.2022.984318 -
Oncotarget Feb 2015c-Kit/α-PDGFR targeted therapies are effective for gastrointestinal stromal tumors (GIST), but, >50% develop drug resistance.
BACKGROUND
c-Kit/α-PDGFR targeted therapies are effective for gastrointestinal stromal tumors (GIST), but, >50% develop drug resistance.
METHODS
RTK expression (c-Kit, c-Met, AXL, HER-1, HER-2, IGF-1R) in pre-/post-imatinib (IM) GIST patient samples (n=16) and 4 GIST cell lines were examined for RTK inhibitor activity. GIST-882 cells were cultured in IM every other day, cells collected (1 week to 6 months) and analyzed by qRT-PCR and Western blotting.
RESULTS
Immunohistochemistry pre-/post-IM demonstrated continued expression of c-Kit and HER1, while a subset expressed IGF-1R, c-Met and AXL. In GIST cells (GIST-882, GIST430/654, GIST48) c-Kit, HER1 and c-Met are co-expressed. Acute IM over-express c-Kit while chronic IM, lose c-Kit and HER-1 in GIST882 cells. GIST882 and GIST430/654 cells have an IC50 0.077 and 0.59 µM to IM respectively. GIST48 have an IC50 0.66 µM to IM, 0.91 µM to amuvatinib [AMU] and 0.67 µM to erlotinib (Erl). Synergistic combinations: GIST882, AMU + Erl (CI 0.20); IM + AMU (CI 0.50), GIST430/654, IM + afatinib (CI 0.39); IM + AMU (CI 0.42), GIST48, IM + afatinib (CI 0.03); IM + AMU (CI 0.04); AMU + afatinib (CI 0.36); IM + Erl (CI 0.63).
CONCLUSION
Targeting c-Kit plus HER1 or AXL/c-Met abrogates IM resistance in GIST.
Topics: Afatinib; Aged; Aged, 80 and over; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; ErbB Receptors; Erlotinib Hydrochloride; Female; Gastrointestinal Stromal Tumors; Gene Expression Regulation, Neoplastic; Humans; Imatinib Mesylate; Immunoblotting; Immunohistochemistry; Male; Middle Aged; Molecular Targeted Therapy; Piperazines; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-kit; Proto-Oncogene Proteins c-met; Pyrimidines; Quinazolines; Receptor Protein-Tyrosine Kinases; Reverse Transcriptase Polymerase Chain Reaction; Thiourea; Axl Receptor Tyrosine Kinase
PubMed: 25557174
DOI: 10.18632/oncotarget.3021 -
Oncotarget Oct 2017Amuvatinib (MP-470) is a multi-targeted kinase inhibitor with potent activity against c-Kit, synergistic with DNA-damaging agents. We evaluated amuvatinib in combination...
BACKGROUND
Amuvatinib (MP-470) is a multi-targeted kinase inhibitor with potent activity against c-Kit, synergistic with DNA-damaging agents. We evaluated amuvatinib in combination with platinum-etoposide (EP) chemotherapy by objective response rate, survival, and tolerability in platinum-refractory small cell lung cancer (SCLC) patients.
METHODS
This study used a Simon 2-stage design requiring ≥3 centrally confirmed responses in the first 21 subjects. Subjects received EP with 300 mg amuvatinib orally three times daily in cycles of 21 days. A three-day amuvatinib run-in period before EP occurred in Cycle 1. Subjects received the same EP chemotherapy regimen given prior to progression/relapse.
RESULTS
Among 23 subjects treated, we observed four PRs (17.4%) per RECIST 1.1, only two of which were centrally confirmed (8.7%, response duration 119, 151 days). Three subjects (13%) had confirmed stable disease. c-Kit H-score was ≥100 in two subjects whose respective durations of disease control were 151 and 256 days.
CONCLUSIONS
The addition of amuvatinib to EP chemotherapy in unselected, platinum-refractory SCLC did not meet the primary endpoint of ≥3 confirmed responses in stage 1. However, high c-Kit expression in two subjects with durable disease control suggests the potential for further study of amuvatinib in SCLC patients with high c-Kit expression.
PubMed: 29113403
DOI: 10.18632/oncotarget.19888 -
Nature Communications Sep 2020Immunotherapies revolutionized cancer treatment by harnessing the immune system to target cancer cells. However, most patients are resistant to immunotherapies and the...
Immunotherapies revolutionized cancer treatment by harnessing the immune system to target cancer cells. However, most patients are resistant to immunotherapies and the mechanisms underlying this resistant is still poorly understood. Here, we report that overexpression of BMP7, a member of the TGFB superfamily, represents a mechanism for resistance to anti-PD1 therapy in preclinical models and in patients with disease progression while on immunotherapies. BMP7 secreted by tumor cells acts on macrophages and CD4 T cells in the tumor microenvironment, inhibiting MAPK14 expression and impairing pro-inflammatory responses. Knockdown of BMP7 or its neutralization via follistatin in combination with anti-PD1 re-sensitizes resistant tumors to immunotherapies. Thus, we identify the BMP7 signaling pathway as a potential immunotherapeutic target in cancer.
Topics: Animals; Antibodies, Monoclonal, Humanized; Bone Morphogenetic Protein 7; CD4-Positive T-Lymphocytes; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Follistatin; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Immunotherapy; Mice; Mitogen-Activated Protein Kinase 14; Neoplasms; Programmed Cell Death 1 Receptor; RAW 264.7 Cells; Smad1 Protein; Transcriptome; Tumor Microenvironment
PubMed: 32973129
DOI: 10.1038/s41467-020-18617-z -
Frontiers in Immunology 2022The efficacy of immunoradiotherapy consisting of radiation therapy and immune checkpoint blockade relies on effectively promoting the systemic antitumor immune...
The efficacy of immunoradiotherapy consisting of radiation therapy and immune checkpoint blockade relies on effectively promoting the systemic antitumor immune response's activation while simultaneously reducing local factors favoring immune suppression. We previously demonstrated that NBTXR3, a nanoparticle radioenhancer, significantly improved immune responses in a murine anti-PD1-resistant metastatic lung cancer model. We hypothesize that radioactivated-NBTXR3 addition to anti-PD1 and a second-generation anti-CTLA4 could improve treatment effectiveness. To test this hypothesis, we inoculated mice with 344SQR cells in the right and left legs to establish primary and secondary tumors. The primary tumors were intratumorally injected with NBTXR3 nanoparticles on day 7, followed by three fractions of 12 Gy radiation on days 8, 9, and 10. The secondary tumors received two fractions of 1Gy radiation on days 13 and 14. Multiple rounds of anti-PD1, anti-CTLA4 or nonfucosylated anti-CTLA4 were given to the mice. Immune profiling of the tumors revealed that the combination of NBTXR3 with immunoradiotherapy significantly upregulated the activities of a wide range of antitumor immune pathways and reduced the abundance of regulatory suppressor T cells. This combination effectively eradicated the primary and secondary tumors and increased animal survival to 75%. Remarkably, previously treated with NBTXR3-containing treatment, the survivor mice exhibited a long-lasting antitumor memory immune response. This data provides compelling evidence of the efficacy of NBTXR3 to synergize with the immunoradiotherapy approach when combined with an anti-PD1 and multiple checkpoints such as a second generation anti-CTLA4 and show the potential for clinical uses of antitumor immunomodulatory effects of NBTXR3.
Topics: Animals; Mice; Radioimmunotherapy; Programmed Cell Death 1 Receptor; Lung Neoplasms; Immunotherapy; Antineoplastic Agents
PubMed: 36405757
DOI: 10.3389/fimmu.2022.1022011 -
Vaccines Aug 2022The pandemic of SARS-CoV-2 infections is a severe threat to human life and the world economic condition. Although vaccination has reduced the outspread, but still the...
The pandemic of SARS-CoV-2 infections is a severe threat to human life and the world economic condition. Although vaccination has reduced the outspread, but still the situation is not under control because of the instability of RNA sequence patterns of SARS-CoV-2, which requires effective drugs. Several studies have suggested that the SARS-CoV-2 infection causing hub differentially expressed genes (Hub-DEGs). However, we observed that there was not any common hub gene (Hub-DEGs) in our analyses. Therefore, it may be difficult to take a common treatment plan against SARS-CoV-2 infections globally. The goal of this study was to examine if more representative Hub-DEGs from published studies by means of hub of Hub-DEGs (hHub-DEGs) and associated potential candidate drugs. In this study, we reviewed 41 articles on transcriptomic data analysis of SARS-CoV-2 and found 370 unique hub genes or studied genes in total. Then, we selected 14 more representative Hub-DEGs (, , , , , , , , , , , , , ) as hHub-DEGs by their protein-protein interaction analysis. Their associated biological functional processes, transcriptional, and post-transcriptional regulatory factors. Then we detected hHub-DEGs guided top-ranked nine candidate drug agents (Digoxin, Avermectin, Simeprevir, Nelfinavir Mesylate, Proscillaridin, Linifanib, Withaferin, Amuvatinib, Atazanavir) by molecular docking and cross-validation for treatment of SARS-CoV-2 infections. Therefore, the findings of this study could be useful in formulating a common treatment plan against SARS-CoV-2 infections globally.
PubMed: 36016137
DOI: 10.3390/vaccines10081248 -
JAMA Oncology Nov 2019Effective treatment options for locally advanced esophageal cancer are limited, and rates of local recurrence after standard chemoradiotherapy remain high.
IMPORTANCE
Effective treatment options for locally advanced esophageal cancer are limited, and rates of local recurrence after standard chemoradiotherapy remain high.
OBJECTIVE
To evaluate toxic effects, local control, and overall survival rates after chemoradiotherapy with a simultaneous integrated boost of radiotherapy dose to the gross tumor and nodal disease for patients with unresectable locally advanced esophageal cancer.
DESIGN, SETTING, AND PARTICIPANTS
A phase 1/2, single-arm trial was conducted in 46 patients from April 28, 2010, to April 9, 2015 (median follow-up, 52 months [range, 2-86 months]), at a tertiary academic cancer center. Outcomes of the study patients were compared with those of 97 similar patients treated at the same institution from January 10, 2010, to December 5, 2014, as part of the interim analysis. Statistical analysis was performed from December 15, 2018, to February 12, 2019.
INTERVENTIONS
Chemoradiotherapy with a simultaneous integrated boost of radiotherapy dose (50.4 Gy to subclinical areas at risk and 63.0 Gy to the gross tumor and involved nodes, all given in 28 fractions) with concurrent docetaxel and capecitabine or fluorouracil.
MAIN OUTCOMES AND MEASURES
Toxic effects, local (in-field) control, and overall survival rates.
RESULTS
All 46 patients (11 women and 35 men; median age, 65.5 years [range, 37.3-84.4 years]) received per-protocol therapy, as intensity-modulated photon therapy (39 [85%]) or intensity-modulated proton therapy (7 [15%]); 11 patients (24%) ultimately underwent resection. No patients experienced grade 4 or 5 toxic effects; the 10 acute grade 3 toxic events were esophagitis (4), dysphagia (3), and anorexia (3) and the 3 late grade 3 toxic events were all esophageal strictures. The actuarial local recurrence rates were 22% (95% CI, 11%-35%) at 6 months, 30% (95% CI, 18%-44%) at 1 year, and 33% (95% CI, 20%-46%) at 2 years. Overall, 15 patients (33%) experienced local failure, at a median interval of 5 months (range, 1-24 months). The median overall survival time was 21.5 months (range, 2.3-86.4 months). Exploratory comparison with a 97-patient contemporaneous institutional cohort receiving standard-dose (non-simultaneous integrated boost) chemoradiotherapy showed superior local control (hazard ratio, 0.49; 95% CI, 0.26-0.92; P = .03) and overall survival (hazard ratio, 0.66; 95% CI, 0.47-0.94; P = .02) in the group that received chemoradiotherapy with a simultaneous integrated boost.
CONCLUSIONS AND RELEVANCE
These findings suggest that chemoradiotherapy with a simultaneous integrated boost of radiotherapy dose for locally advanced esophageal cancer is well tolerated, with encouraging local control, and thus warrants further study.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT01102088.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemoradiotherapy; Docetaxel; Esophageal Neoplasms; Female; Fluorouracil; Humans; Male; Middle Aged; Proton Therapy; Radiotherapy Dosage; Radiotherapy, Intensity-Modulated; Survival Analysis; Treatment Outcome
PubMed: 31529018
DOI: 10.1001/jamaoncol.2019.2809 -
Oncotarget Jun 2017Resistance to docetaxel is a major clinical problem in advanced prostate cancer. The overexpression of AXL receptor tyrosine kinase (AXL) has been correlated with...
Resistance to docetaxel is a major clinical problem in advanced prostate cancer. The overexpression of AXL receptor tyrosine kinase (AXL) has been correlated with chemotherapeutic drug resistance. However, the role of AXL expression in docetaxel resistance in prostate cancer is yet unclear. In this study, we demonstrate that AXL is overexpressed and activated independent of Gas6 in docetaxel-resistant prostate cancer cells (PC3-DR and DU145-DR). Moreover, we show that forced overexpression of AXL in PC3 and DU145 cells is sufficient to induce resistance to docetaxel in these cell lines. Notably, genetic or pharmacologic inhibition of AXL in the resistant models suppressed cell proliferation, migration, invasion, and tumor growth, and these effects were significantly augmented when AXL inhibition was combined with docetaxel treatment. Mechanistically, we found that AXL inhibition led to reversion of the epithelial-mesenchymal transition (EMT) phenotype and decreased the expression of ATP-binding cassette B1 (ABCB1). Overall, our results identify AXL as an important mediator of docetaxel resistance in prostate cancer. We propose that AXL-targeted therapy, in combination with docetaxel, has the potential to improve the response to docetaxel therapy and reduce resistance induced by prolonged docetaxel therapy in prostate cancer.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzocycloheptenes; Cell Line, Tumor; Docetaxel; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Humans; Male; Mice, Nude; Piperazines; Prostatic Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Pyrimidines; RNA Interference; Receptor Protein-Tyrosine Kinases; Taxoids; Thiourea; Triazoles; Xenograft Model Antitumor Assays; Axl Receptor Tyrosine Kinase
PubMed: 28455956
DOI: 10.18632/oncotarget.17026 -
Journal For Immunotherapy of Cancer Jun 2020Despite outstanding responses to anti-PD-1 agents in a subset of non-small cell lung cancer (NSCLC) patients, approximately 80% of patients fail to have prolonged...
BACKGROUND
Despite outstanding responses to anti-PD-1 agents in a subset of non-small cell lung cancer (NSCLC) patients, approximately 80% of patients fail to have prolonged favorable response. Recent studies show that tumor cell oxidative metabolism is a barrier to PD-1 immunotherapy and radiotherapy could overcome PD-1 resistance, so it is urgent to determine if combination treatment with radiotherapy and a novel oxidative phosphorylation (OXPHOS) inhibitor (IACS-010759) is an effective strategy against PD-1 resistance in NSCLC.
METHODS
The antitumor effect of this combinational treatment was evaluated in vitro and in vivo. For in vivo experiments, we treated 129Sv/Ev mice with anti-PD1-sensitive and anti-PD1-resistant 344SQ NSCLC adenocarcinoma xenografts with oral IACS-010759 combined with radiotherapy (XRT). In vitro experiments included PCR, seahorse bioenergetic profiling, flow cytometry phenotyping, and clonogenic survival assay.
RESULTS
In the current study, we found that our PD-1-resistant model utilized OXPHOS to a significantly greater extent than the PD-1-sensitive model and XRT increased OXPHOS in vitro and in vivo. Thus, we explored the effect of the novel OXPHOS inhibitor IACS-010759 on PD-1-resistant NSCLC in an effort to overcome XRT-induced immunosuppression and maximize response to PD-1. Additionally, combined XRT and IACS-010759 promoted antitumor effects in the PD-1-resistant model, but not in the sensitive model. After elucidation of the most optimal dose/fractionation scheme of XRT with IACS-010759, the combinatorial therapy with this regimen did not increase the abscopal antitumor effect, although IACS-010549 did not decrease CD45+, CD4+, and CD8+ immune cells. Finally, triple therapy with IACS-010759, XRT, and anti-PD-1 promoted abscopal responses and prolonged survival time.
CONCLUSION
OXPHOS inhibition as part of a combinatorial regimen with XRT is a promising strategy to address PD-1-resistant NSCLC, and this combination is being tested clinically.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; CD8-Positive T-Lymphocytes; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Chemoradiotherapy; Disease Models, Animal; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Female; Humans; Immune Checkpoint Inhibitors; Lung Neoplasms; Mice; Oxadiazoles; Oxidative Phosphorylation; Piperidines; Programmed Cell Death 1 Receptor
PubMed: 32581056
DOI: 10.1136/jitc-2019-000289 -
Journal of Hematology & Oncology Oct 2016
PubMed: 27737688
DOI: 10.1186/s13045-016-0335-5