scholarly journals Single Radiotherapy Fraction with Local Anti-CD40 Therapy Generates Effective Abscopal Responses in Mouse Models of Cervical Cancer

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1026
Author(s):  
Jana Wood ◽  
Sayeda Yasmin-Karim ◽  
Romy Mueller ◽  
Akila N. Viswanathan ◽  
Wilfred Ngwa
Keyword(s):  
Cervical Cancer ◽  
Tumor Regression ◽  
Treatment Options ◽  
Metastatic Tumor ◽  
Current Treatment ◽  
Immune Memory ◽  
Advanced Cervical Cancer ◽  
Term Survival ◽  
Fraction Dose ◽  
Radiotherapy Dose

Current treatment options for advanced cervical cancer are limited, especially for patients in poor-resource settings, with a 17% 5-year overall survival rate. Here, we report results in animal models of advanced cervical cancer, showing that anti-CD40 therapy can effectively boost the abscopal effect, whereby radiotherapy of a tumor at one site can engender therapeutically significant responses in tumors at distant untreated sites. In this study, two subcutaneous cervical cancer tumors representing one primary and one metastatic tumor were generated in each animal. Only the primary tumor was treated and the responses of both tumors were monitored. The study was repeated as a function of different treatment parameters, including radiotherapy dose and dosing schedule of immunoadjuvant anti-CD40. The results consistently suggest that one fraction dose of radiotherapy with a single dose of agonistic anti-CD40 can generate highly effective abscopal responses, with a significant increase in animal survival (p = 0.0004). Overall, 60% of the mice treated with this combination showed long term survival with complete tumor regression, where tumors of mice in other cohorts continued to grow. Moreover, re-challenged responders to the treatment developed vitiligo, suggesting developed immune memory for this cancer. The findings offer a potential new therapy approach, which could be further investigated and developed for the treatment of advanced cervical cancer, with major potential impact, especially in resource-poor settings.

EXTH-81. STING ACTIVATION PROMOTES ROBUST IMMUNE RESPONSE AND TUMOR REGRESSION IN GLIOBLASTOMA MODELS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi182-vi182
Author(s):  
Gilles Berger ◽  
Erik Knelson ◽  
Michal Nowicki ◽  
David Mooney ◽  
E Antonio Chiocca ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Tumor Regression ◽  
Immune Checkpoint Blockade ◽  
Immune Memory ◽  
Term Survival ◽  
Major Barrier ◽  
Robust Immune Response ◽  
Immunosuppressive Tumor Microenvironment ◽  
Human Gbm ◽  
Sting Pathway

Abstract The immunosuppressive tumor microenvironment in glioblastoma presents a major barrier to effective application of immunotherapeutic approaches in this disease. Although immunotherapy has had a tremendous impact on cancer treatment in the past decade, with hitherto unseen responses at advanced and metastatic stages of the disease glioblastoma remains largely refractory to current immunotherapeutic approaches. The cGAS-STING cytoplasmic double stranded DNA sensing pathway has emerged as a next-generation immunotherapy target with potent local immune stimulatory properties, but has not been well investigated in glioblastoma to date. Here we investigated the presence of STING pathway components in glioblastoma patient specimens and cell lines by Western blotting and immunostaining. The functionality of the pathway was determined by ELISA, and immune infiltrates, and animal survival were investigated in mouse glioblastoma models after treatment with the STING agonist ADU-S100. Our data reveal the presence of STING in human GBM specimens, where it stains strongly in the tumor vasculature, and appears to be activated as evidenced by elevated phosphoTBK1 staining. We show that human GBM cells do not respond agonists, but that GBM explants can respond to STING agonist treatment by secretion of inflammatory cytokines. In murine GBM models, we show a profound shift in the tumor immune landscape after STING agonist treatment, with massive infiltration of the tumor-bearing hemisphere with innate immune cells including inflammatory macrophages, neutrophils and NK populations. Treatment of established murine intracranial GL261 and CT-2A tumors by biodegradable ADU-S100-loaded intracranial implants demonstrated a significant increase in survival in both models and long-term survival with immune memory in GL261. This study reveals therapeutic potential and deep remodeling of the TME by STING activation in GBM and warrants the further examination of STING agonists alone or in combination with other immunotherapies such as cancer vaccines, CAR T cells, or immune checkpoint blockade.

Molecular profiles and immune checkpoint inhibitor-related biomarkers analysis in advanced cervical cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e18003-e18003
Author(s):  
Qin Xu ◽  
Chuanben Chen ◽  
Yang Sun ◽  
Yibin Lin ◽  
Jing Liu ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Figo Stage ◽  
Advanced Cervical Cancer ◽  
Single Nucleotide Variants ◽  
Paired Samples ◽  
Target Capture ◽  
Pathological Subtype ◽  
Molecular Profiles

e18003 Background: Treatment options for advanced cervical cancer (ACC) are limited and patients experiencing recurrence after first-line chemotherapy and bevacizumab have a poor prognosis. Checkpoint inhibitors targeting the PD-1/PD-L1 are promising treatment option. However, related genomic biomarker study is rare reported in ACC. Methods: We prospectively enrolled 102 pts with ACC. Tumor and plasma samples were obtained to analysis genomic profiles. DNA was sequenced by target-capture deep sequencing with the pan-cancer panel. TMB of tissue (tTMB) and blood (bTMB) analysis interrogated single nucleotide variants, small insertion and deletion. PD-L1 expression was evaluated in tumor specimens by immunohistochemistry (IHC) using a combined-positive-score (CPS) cutoff of ≥1. Results: The median age of enrolled pts was 63 yrs, and most (84.3 %, 86/102 pts) weresquamous carcinoma. A total of 93 tissues and 96 plasma were collected from 102 pts. The most frequently mutated genes were PIK3CA (40.9%, 38/93 pts), KMT2D (35.5%, 33/93 pts), and KMT2C (28.0%, 26/93 pts) in tissues. 80% (77/96 pts) of plasma was detected positive, with PIK3CA (23.4%, 18/77 pts), KMT2D (20.8%, 16/77 pts), KMT2C (20.8%, 17/77 pts) mutant frequently. Among 87 pts with paired samples, at least a tumor-derived mutation was detected in 35 (40.2%)plasma. Median of tTMB was 11.9 mut/Mb, and 45% pts were TMB-H. Significant correlation was found between tTMB and bTMB (Pearson r = 0.39, P = 0.001). Higher tTMB was identified in KMT2D- or KMT2C-mut pts (P = 0.002 or P = 0.01, respectively). tTMB showed no relation with clinic characteristics, including pathological subtype, FIGO stage, and status of distant metastasis. PD-L1 expression (CPS≥1) was identified in 53 pts (93 %, 53/57) and mutually independent with TMB status. Conclusions: Molecular profiles and TMB in plama showed high consistence with that in tissue. Prospective clinical trial is ongoing to determine the genomic biomarkers and the PD-L1 expression as predictive factors for the ICI efficacy in ACC (ChiCTR1900023015).

scholarly journals The Efficacy of Current Treatment Options for Metastatic Cervical Cancer

2014 ◽  
Vol 17 (7) ◽  
pp. A616
Author(s):  
H.J. Palin ◽  
A.L. McCormick ◽  
E. Sabaté
Keyword(s):  
Cervical Cancer ◽  
Treatment Options ◽  
Current Treatment

scholarly journals Phase II study of atezolizumab in combination with bevacizumab in patients with advanced cervical cancer

2020 ◽  
Vol 8 (2) ◽  
pp. e001126
Author(s):  
Claire F Friedman ◽  
Alexandra Snyder Charen ◽  
Qin Zhou ◽  
Michael A Carducci ◽  
Alexandre Buckley De Meritens ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Phase Ii ◽  
Response Rate ◽  
Treatment Options ◽  
Objective Response ◽  
Primary Objective ◽  
Advanced Cervical Cancer ◽  
Open Label ◽  
Recurrent Cervical Cancer ◽  
Platinum Based Chemotherapy

BackgroundThere are limited treatment options for patients with metastatic or recurrent cervical cancer. Platinum-based chemotherapy plus the anti-vascular endothelial growth factor antibody bevacizumab remains the mainstay of advanced treatment. Pembrolizumab is Food and Drug Agency approved for programmed death ligand 1 (PD-L1) positive cervical cancer with a modest response rate. This is the first study to report the efficacy and safety of the PD-L1 antibody atezolizumab in combination with bevacizumab in advanced cervical cancer.MethodsWe report the results from a phase II, open-label, multicenter study (NCT02921269). Patients with advanced cervical cancer were treated with bevacizumab 15 mg/kg intravenous every 3 weeks and atezolizumab 1200 mg intravenous every 3 weeks. The primary objective was to measure the objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.ResultsIn the total evaluable population (n=10), zero patients achieved an objective response as assessed by Response Evaluation Criteria In Solid Tumors (RECIST) V.1.1, resulting in a confirmed ORR of 0%. Of note, there were two patients who achieved an unconfirmed PR. The DCR by RECIST V.1.1 was 60% (0% complete response, 0% partial response, 60% stable disease). Median PFS was 2.9 months (95% CI, 1.8 to 6) and median OS was 8.9 months (95% CI, 3.4 to 21.9). Safety results were generally consistent with the known safety profile of both drugs, notably with two high-grade neurologic events.ConclusionsThe combination of bevacizumab and atezolizumab did not meet the predefined efficacy endpoint, as addition of bevacizumab to PD-L1 blockade did not appear to enhance the ORR in cervical cancer.

scholarly journals Intratumoral Injection of H101 in Combination With Concurrent Chemoradiotherapy for Locally Advanced Cervical Cancer

2021 ◽  
Author(s):  
Xiang Zhang ◽  
Yingchang Wang ◽  
xiaojuan Lv ◽  
Fangfang Wang ◽  
Qiong Zhou ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Concurrent Chemoradiotherapy ◽  
Tumor Regression ◽  
Locally Advanced ◽  
Control Group ◽  
Advanced Cervical Cancer ◽  
Tumor Length ◽  
Locally Advanced Cervical Cancer ◽  
Gynecology And Obstetrics ◽  
And Control

Abstract BackgroundTo evaluate the clinical benefit of concurrent chemoradiotherapy in combination with H101 injection for the treatment of locally advanced cervical cancer (LACC) patients.MethodsThe patients, all diagnosed with stage IIB or III cervical cancer according to The International Federation of Gynecology and Obstetrics (FIGO) stage (2009) with tumor length ≥6cm were enrolled at Zhejiang Cancer Hospital from July 2015 to April 2017. All patients received concurrent chemoradiotherapy (CCRT) in combination with intratumoral H101 injection before and during external beam radiotherapy (EBRT). The parameters recorded and analyzed included progression-free survival (PFS), overall survival (OS), tumor regression after EBRT and side effects, which were compared to another group of patients with similar characteristics treated with CCRT alone.ResultsTwenty patients were treated with CCRT in combination with intratumoral H101 injection and another group of 20 patients treated with CCRT alone was selected as control. The median follow-up time was 38 months (range 10-58 months). The 3-year local, regional, and overall PFS rates were 95% vs 66.6%(p = 0.02), 95% vs 62.5%(p = 0.029), and 65% vs 43.8%(p = 0.19), for H101 group and control group respectively. The 3-year (OS) was 74.3% vs 54.5%(p = 0.098), respectively. The median reduction of tumor length and volume for H101 group and control group were 37.7% vs 28.7%(p = 0.016) and 75.1% vs 62.4%(p = 0.001), respectively. The major adverse event related to H101 was fever.ConclusionCCRT in combination with intratumoral H101 injection is effective in treating LACC, and has an acceptable safety profile.Trial registrationThe study was registered at Chinese Clinical Trail Registry (ChiCTR-OPC-15006142).

scholarly journals Locally advanced cervical cancer: Preliminary results of the prospective randomized study

2003 ◽  
Vol 11 (3) ◽  
pp. 196-196
Author(s):  
Vesna Stankovic ◽  
Ivanka Marjanov ◽  
Slobodan Cikaric ◽  
Ljubomir Grzetic ◽  
Slobodanka Colakovic ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Tumor Regression ◽  
Randomized Study ◽  
Locally Advanced ◽  
Pathological Examination ◽  
Advanced Cervical Cancer ◽  
Early Complications ◽  
External Beam Irradiation ◽  
Preliminary Results ◽  
Locally Advanced Cervical Cancer

Background: The aim of this study is to show preliminary results of the randomized study that has been conducted among patients with advanced cervical cancer managed by loco-regional radiotherapy alone or combined treatment (radiotherapy with chemotherapy as radiosensitiser). Methods: From the beginning of 2002 till today 182 patients with locally advanced cervical cancer have been enrolled in the study (FIGO IIb-IVa). They have been treated by combined external beam irradiation (46Gy/22fr) and HDR brachyterapy (5x7Gy/A). Eighty-nine of them underwent the same radiotherapy regime with concomitant chemotherapy cisplatin (CDDP) 40mg per week). Median age for both groups were 52 years. Pathological examination showed: Squamous cell carcinoma in most cases 175, adeno Ca 6 and others 1. Effect of the therapy and early irradiation complications have been estimated by the tumor regression and toxicity grade. Results: Tumor regression have been occurred as complete response in 10.1% for RT group and for RT-HT group in 16.86%. Partial regression was for RT group 86% and for RT-HT group 87%. Early complications (haematological, urological and intestinal) in RT group were noted in 34% and in RT-HT group in 43% of patients. Conclusion: There was no benefit of RT-HT comparing to RT alone in the tumor regression of locally advanced cervical cancer. Early complications of combined therapy are more experienced than in RT group.

scholarly journals Analysis of local control rate and toxicity of radiotherapy dose of cervical cancer.

2019 ◽  
Vol 5 (suppl) ◽  
pp. 136-136
Author(s):  
Hanyi Zhang ◽  
Shun Lu ◽  
Chang Sun ◽  
Jin Yi Lang
Keyword(s):  
Cervical Cancer ◽  
Local Control ◽  
Univariate Analysis ◽  
Local Control Rate ◽  
External Beam Radiation ◽  
Youden Index ◽  
High Dose ◽  
Advanced Cervical Cancer ◽  
Beam Radiation ◽  
Radiotherapy Dose

136 Background: The standard of care for treatment of advanced cervical cancer is the combination of external beam radiation therapy (EBRT) and intracavitary brachytherapy with cisplatin based concurrent chemotherapy. Radiotherapy plays a crucial role in treatment of cervical cancer. Recent GEC-ESTRO guidelines recommend that the dose to 90% (D90) of the high-risk clinical target volume (HRCTV) in cervical cancer be at least 85Gy with higher doses for poor response to radiotherapy. This study was aim to analyze our institution’s patients with locally advanced cervical cancer in regards to whether higher brachytherapy dose delivery lead to a better outcome, and to investigate the proper dose to balance the local control rate and toxicity. Methods: A total of 262 patients with local advanced cervical cancer treated at a single institution were retrospectively analyzed for the association between dosimetry and outcomes. Youden index was used to identify the optimal cut-off point of continuous tumor parameters and divide patients into subgroups. Significance of radiotherapy dose parameters on OS, PFS, LRFS and DMFS and toxicity was evaluated. Results: In the univariate analysis, for both HR-CTV and LR-CTV, the high dose group (EQD2 D90 >75Gy, LR-CTV>68Gy, respectively) have a better LRFS than low-dose groups (P<0.05). LR-CTV remains significance after adjusted for age and FIGO stage. Moreover, in the high-dose LR-CTV group, there is no association between dose of LR-CTV and LRFS was found, however, higher dose of HR-CTV significant associated with higher ratio of side effect was found. In addition, no association of dose of HR-CTV or LR-CTV and OS were found for all patients. Conclusions: Our results showed that dose of LR-CTV may be a useful prognostic factor of LRFS of patients with cervical cancer. Moreover, after D90 of LR-CTV reaches 68Gy, increasing dose did not show a better LRFS but lead to higher ratio of toxicity, supporting that LR-CTV at 68Gy might be a safety and efficacy dose of radiotherapy to the patients with cervical cancer. However, further improved in dose had no significant benefit on local control rate, and it might increase the risks of toxicity.

scholarly journals Will the carboplatin-paclitaxel-bevacizumab combination become the preferred option as the first line in advanced cervical cancer? A small experience from a single oncologic Center

2017 ◽  
Vol 5 (1) ◽  
pp. 21-24
Author(s):  
Raquel Bratos Lorenzo ◽  
Luisa Sánchez Lorenzo ◽  
Antonio González-Martín
Keyword(s):  
Cervical Cancer ◽  
Metastatic Cancer ◽  
Treatment Options ◽  
Advanced Cervical Cancer ◽  
Recurrent Cervical Cancer ◽  
Curative Therapy ◽  
Screening Programs ◽  
Medical Need ◽  
Important Health ◽  
Future Therapy

Background: Despite the widespread introduction of screening programs, cervical cancer remains an important health problem, particularly in developing countries. Treatment options for patients with metastatic cancer and persistent or recurrent disease after curative therapy are limited and represent an unmet medical need. Patients and Methods: We report three clinical cases of metastatic cervical cancer in women treated with the combination of carboplatin, paclitaxel and bevacizumab. We also discuss current and future therapy for metastatic or recurrent cervical cancer, including ongoing investigations into the addition of bevacizumab to carboplatin/paclitaxel chemotherapy and the role of bevacizumab as maintenance therapy. Results and Conclusion: All three women received clinical benefit from the combination, including one complete and two partial responses. The tolerability of bevacizumab was excellent. Carboplatin/paclitaxel appears to be an acceptable and better tolerated alternative to cisplatin/paclitaxel in advanced or recurrent/persistent disease, and the carboplatin/paclitaxel/bevacizumab combination is under investigation for metastatic, recurrent or persistent cervical cancer in clinical trials such as the CECILIA trial (NCT02467907); the awaited results will add to the evidence for the use of this combination chemotherapy regimen in advanced cervical cancer.

scholarly journals Endostar, an Anti-angiogenesis Inhibitor, Combined with Chemoradiotherapy for Locally Advanced Cervical Cancer

2021 ◽  
Author(s):  
Heming Lu ◽  
Yuying Wu ◽  
Xu Liu ◽  
Huixian Huang ◽  
Hailan Jiang ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Locally Advanced ◽  
Angiogenesis Inhibitor ◽  
Progression Free Survival ◽  
Late Toxicity ◽  
Advanced Cervical Cancer ◽  
Term Survival ◽  
Free Survival ◽  
Locally Advanced Cervical Cancer ◽  
The Impact

This phase II randomized clinical trial aimed to assess the efficacy and toxicity of Endostar, an anti-angiogenesis inhibitor, combined with concurrent chemoradiotherapy (CCRT) for locally advanced cervical cancer (LACC). Patients with LACC were randomly assigned to either CCRT plus Endostar(CCRT+E arm) or CCRT alone (CCRT arm). All patients received pelvic intensity-modulated radiation therapy (IMRT)and brachytherapy. Weekly cisplatin was administered concurrently with IMRT. Patients in the CCRT+E arm also received concurrent Endostar every 3 weeks for 2 cycles. The primary endpoint was progression-free survival (PFS) and acute toxicities. The exploratory endpoint was the impact of vascular endothelial growth factor receptor-2 (VEGFR2) expression on long-term survival. A total of 116patientswere enrolled. Patients in the CCRT+E arm and in the CCRT arm had similar acute and late toxicity profile. The 1-and 2-year PFS were 91.4% vs. 82.1% and 80.8% vs. 63.5%（p=0.091）, respectively. The1-and 2-year distance metastasis-free survival （DMFS）were92.7% vs. 81.1% and 86.0% vs. 65.1%（p=0.031）, respectively. Patients with positive VEGFR2 expression had significant longer PFS and overall survival (OS), compared with those with negative VEGFR2 expression. Patients in the CCRT+E arm had significantly longer PFS, OS, and DMFS than those in the CCRT arm whenVEGFR2 expression was positive. In conclusion, CCRT plus Endostar significantly improved DMFS but not PFS over CCRT alone. The addition of Endostar could significantly improve survival for patients with positive VEGFR2 expression.

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