Abstract LB-086: Combination therapy of immune checkpoint and nuclear exporter inhibitors in a renal cell carcinoma mouse model

2016 ◽  
Author(s):  
Josephine Trott ◽  
Katie Anderson ◽  
Jeffrey Kim ◽  
Ashley Graef ◽  
Sharon Shacham ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Combination Therapy ◽  
Mouse Model ◽  
Cell Carcinoma ◽  
Immune Checkpoint ◽  
Renal Cell

541 Investigating myeloid derived suppressor cells (MDSCs) and oligonucleotide based targeting of STAT3 in renal cell carcinoma

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A577-A577
Author(s):  
Marice Alcantara ◽  
Dayson Moreira ◽  
Chia-Yang Hung ◽  
Dongfang Wang ◽  
JoAnn Hsu ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Flow Cytometry ◽  
T Cell ◽  
Combination Therapy ◽  
Cell Carcinoma ◽  
Immune Checkpoint ◽  
Peripheral Blood ◽  
Renal Cell ◽  
Myeloid Cells ◽  
Cd8 T Cell

BackgroundRecent advancements in the treatment of renal cell carcinoma (RCC) using immune checkpoint inhibitors (ICI) against PD1 or CTLA-4 receptors have improved survival rates in patients. However, more than half of RCC patients does not respond to anti-PD-1/-CTLA-4 combination immunotherapy. Thus, we decided to investigate mechanisms underpinning the resistance to ICI at the cellular and molecular levels.MethodsWe utilized multicolour flow cytometry and Luminex assays to investigate patient peripheral blood and used syngeneic mouse models to determine the efficacy of oligonucleotide based targeting of STAT3ResultsFirst, we characterized immunosuppressive myeloid cell populations, T cell subsets and immune biomarkers in blood samples from RCC patients with advanced stage IV disease, undergoing anti-PD-1/-CTLA-4 (nivolumab/ipilimumab) combination therapy. Results of our multicolor flow cytometry and plasma analysis suggested that ICI therapy is associated with a significant almost 15-fold increase of polymorphonuclear MDSCs (PMN-MDSCs) in the peripheral blood of RCC patients over the course of 3 therapeutic cycles. Notably, we found that PMN-MDSCs showed high levels of activated Signal Transducer and Activator of Transcription 3 (pSTAT3) and a significant increase its downstream target Arginase-I between cycle 1 and cycle 8 of treatment (P=0.0008). The pSTAT3/ARG-1 signaling is known for promoting tumor immune evasion, thus strongly suggesting that immature PMN-MDSCs are potentially involved in limiting outcome of ICI therapy in RCC patients similar as shown before in other genitourinary cancers such as prostate and bladder cancers. We recently developed a strategy to target STAT3 selectively in tumor-associated myeloid cells using using STAT3 antisense oligonucleotide (STAT3ASO) conjugated to immunostimulatory CpG oligodeoxynucleotides acting as targeting moiety. In our initial efficacy studies, we assessed activity of three versions of CpG-STAT3ASO conjugates with various chemical modifications, such as 2’-O’methyl- or locked nucleic acid, in a syngeneic bladder tumor model (MB49). MB49 cancer cells were subcutaneously injected into two flanks of male C57BL/6 mice and treated every second day with 5 mg/kg of various CpG-STAT3ASO injected intratumorally into one of the tumor sites. All CpG-STAT3ASOs inhibited tumor cell growth in both treated and distant tumors in comparison to controls. The immunohistochemical analysis indicated an increase in the percentage of CD8+ T cell with reduction of regulatory T cells within CpG-STAT3ASO treated tumors in comparison to controls, suggesting activation of CD8 T cell-mediated antitumor immunity.ConclusionsOverall, our preliminary results suggest that immune suppressive pSTAT3+/ARG-1+ PMN-MDSCs accumulate in patients with RCC undergoing ICI combination therapy, which may potentially contribute to resistance to ICIs. Targeting STAT3 signaling in the RCC-associated myeloid cells using CpG-STAT3ASO may provide a potential novel strategy for augmenting immune checkpoint therapies.

Synergy of optimized administration sequence and timing of active DC immunotherapy with a PD1 checkpoint inhibitor in a mouse model of renal cell carcinoma.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 31-31
Author(s):  
Olga A. Zubkova ◽  
Larissa S. Agapova ◽  
Armen A. Ovsepyan ◽  
Vilena Ivanova ◽  
Elmira Zeynalova ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Combination Therapy ◽  
Mouse Model ◽  
Cell Carcinoma ◽  
Mechanism Of Action ◽  
Renal Cell ◽  
Checkpoint Inhibitor ◽  
Model System ◽  
Active Immunotherapy ◽  
Combination Therapies

31 Background: AGS-003 is an immunotherapy consisting of autologous dendritic cells electroporated with amplified total tumor RNA plus synthetic CD40L RNA and is currently being tested in combination with standard of care to extend survival of newly diagnosed metastatic renal cell carcinoma (RCC) patients in the Phase 3 ADAPT clinical trial. We set out to establish a model system based on the Renca mouse model to more thoroughly study the AGS-003 mechanism of action and identify optimal combination therapies, including with a PD1 checkpoint inhibitor (aPD1 CPI). Methods: Mouse DC precursors were processed in a similar manner to how human monocytes are processed to manufacture AGS-003. Mature DCs were injected s.c. to treat BALB/c mice in an orthotopic syngeneic RCC model. This model system was utilized to test the efficacy and mechanism of action of the AGS-003-like homologous mouse DCs in combination with a murine monoclonal antibody PD1 CPI (anti-mPD1). Results: Murine DCs with similar properties to AGS-003 in combination with anti-mPD1 and sunitinib, resulted in recruitment and migration of lymphocytes into the tumor microenvironment and an increase in peripheral blood CD8+CD28+CD45RA- memory T cells in vivo. Multiple combination dosing strategies were tested and only one dosing regimen (DCs administered prophylactically followed by aPD1 mAb administered therapeutically) showed a substantial synergistic effect (67 days median OS) while all other DC/aPD1 dosing combinations did not exceed the efficacy of DC monotherapy treatment (44.5-48 days median OS). Control animals treated with PBS had a median OS of 29 days. Conclusions: These data demonstrate the importance of the administration sequence for active immunotherapy and aPD1 CPI combination therapy. Our data suggest that the cellular immune response must be initiated and established prior to administration of the aPD1 CPI/sunitinib combination therapy in order to observe synergy in this RCC mouse model. This model may be useful to explore additional combination therapies and effective treatment regimens with other therapeutic agents to guide future clinical development.

scholarly journals Myocarditis as an immune-related adverse event following treatment with ipilimumab and nivolumab combination therapy for metastatic renal cell carcinoma: a case report

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Yasuyuki Miyauchi ◽  
Hirohito Naito ◽  
Hiroyuki Tsunemori ◽  
Ryosuke Tani ◽  
Yusuke Hasui ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Adverse Event ◽  
Combination Therapy ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Immune Checkpoint ◽  
Renal Cell ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Related Adverse Event

Abstract Background Immune checkpoint inhibitors are new immunotherapy drugs globally used for many malignancies, including renal cell carcinoma. Myocarditis as an immune-related adverse event is rare but highly fatal, suggesting that its frequency may be higher than reported. This paper describes a case of myocarditis that developed asymptomatically following ipilimumab and nivolumab combination therapy for renal cell carcinoma. Case presentation A 71-year-old Asian man who presented to hospital with fever, fatigue, and weight loss of approximately 10 kg within 2 months was diagnosed with Xp.11.2 translocation renal cell carcinoma. Computed tomography revealed multiple lung masses, mediastinal lymph node enlargement, and a level II tumor thrombus reaching the inferior vena cava (cT3bN0M1; International Metastatic Renal Cell Carcinoma Database Consortium, poor risk). Ipilimumab/nivolumab combination therapy was started as induction therapy. The patient experienced acute interstitial nephritis as an immune-related adverse event after treatment initiation; however, a good response to steroid therapy was observed. The antitumor effect of the immunotherapy was notable. Although he experienced pulmonary embolism, it seemed asymptomatic and harmless; thus, a second infusion was introduced. From the eighth day, he demonstrated rapidly worsening cardiogenic shock with asymptomatic electrocardiographic changes and drastic drop in cardiac biomarkers, and a diagnosis of myocarditis as an immune-related adverse event was made. Although immediate methylprednisolone mini-pulse therapy followed by tapered prednisolone prevented mortality, extensive myocardial fibrosis with marked ejection fraction decline persisted as a sequela. Consequently, follow-up without treatment was instituted; however, much of the tumor response initially observed was maintained over several months. Conclusion Physicians treating patients with immune checkpoint inhibitors should be aware of their potentially life-threatening cardiotoxic effects. This study emphasized the importance of a high index of suspicion, prompt diagnosis, and early intervention in patients who present with cardiac abnormalities and possible myocarditis after receiving immunotherapy.

First-Line Immunotherapy Combinations in Advanced Renal Cell Carcinoma – A Rapid Review and Meta-Analysis

Kidney Cancer ◽  
2021 ◽  
pp. 1-11
Author(s):  
Jason Shpilsky ◽  
Paul J. Catalano ◽  
David F. McDermott
Keyword(s):  
Renal Cell Carcinoma ◽  
Combination Therapy ◽  
Cell Carcinoma ◽  
Immune Checkpoint ◽  
Renal Cell ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Advanced Renal Cell Carcinoma

Background: Combination or multi-agent therapy including immune checkpoint inhibitors has shifted the landscape of the treatment of advanced/metastatic renal cell carcinoma. There are several approved immune checkpoint inhibitor (ICI) combinations featuring antibodies against programmed cell death protein 1 (PD-1) receptor or its ligand 1 (PD-L1) combined with other immune checkpoint inhibitors, multi-targeted tyrosine kinase inhibitors (TKIs), or other agents active in renal cell carcinoma. Objective: This study aims to compile the evidence of available first-line combination therapies compared to sunitinib monotherapy in advanced renal cell carcinoma. Methods: A systematic literature search was conducted according to the PRISMA statement to identify all randomized Phase III clinical trial data in previously untreated metastatic renal cell carcinoma featuring an immune checkpoint inhibitor combination compared against sunitinib. A two-stage selection process was utilized to determine eligible studies. Of a total of 124 studies and 94 additional abstracts, 6 studies were considered for final analysis. These studies were evaluated for progression free survival (PFS), overall survival (OS), Grade III or higher adverse events (AEs), objective response rate (ORR), and complete response rate (CRR). Results: 6 studies with 5,121 patients met our search criteria. For OS, ICI combination therapy was favored over sunitinib with an estimated combined hazard ratio of 0.74 (0.67–0.81 95% CI). For PFS, ICI combination therapy was favored over sunitinib with an estimated combined hazard ratio of 0.65 (0.52–0.82, 95% CI). The combination of nivolumab and ipilimumab had the longest duration of response and less incidence of grade III or higher adverse events compared to the combination of anti-PD-1/PD-L1 with TKI. The combination of anti-PD-1/PD-L1 with TKI had higher rates of overall response and longer PFS than the combination of nivolumab/ipilimumab. Conclusions: This meta-analysis supports the recommendation of immune checkpoint inhibitor combination therapy over sunitinib monotherapy for previously untreated advanced renal cell carcinoma by virtue of improved PFS and OS. The choice of which ICI combination therapy to use may be guided by patient-specific characteristics including IMDC risk status, adverse effect profile, and need for early response.

scholarly journals Balancing the Risk-Benefit Ratio of Immune Checkpoint Inhibitor and Anti-VEGF Combination Therapy in Renal Cell Carcinoma: A Systematic Review and Meta-Analysis

2021 ◽  
Vol 11 ◽  
Author(s):  
Li Tao ◽  
Huiyun Zhang ◽  
Guangyu An ◽  
Haoning Lan ◽  
Yaoqi Xu ◽  
...  
Keyword(s):  
Systematic Review ◽  
Renal Cell Carcinoma ◽  
Combination Therapy ◽  
Cell Carcinoma ◽  
Immune Checkpoint ◽  
Renal Cell ◽  
Statistical Difference ◽  
Meta Analysis ◽  
High Grade ◽  
Anti Vegf

BackgroundAlthough immune checkpoint inhibitors (ICIs) combined with vascular endothelial growth factor receptor (VEGFR)-targeted therapy and sunitinib monotherapy have been widely applied to metastatic renal cell carcinoma (mRCC), effectiveness and safety data are still lacking. To optimize clinical decision-making, we conducted a systematic review and meta-analysis of published randomized clinical trials to characterize the efficacy and the risk of adverse events (AEs) in patients treated with ICIs plus anti-VEGF therapy.Materials and MethodsWe used PubMed, EMBASE, and the Cochrane Library to retrieve randomized controlled trials (RCTs) published before March 27, 2021. The efficacy outcomes were progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). The pooled risk ratio (RR) and 95% confidence intervals (CI) of AEs were calculated in the safety analysis.ResultsSix RCTs involving 4,227 patients were identified after a systematic search. For OS, ICI and anti-VEGF combination therapy decreased mortality approximately 30% in the intention-to-treat population (ITT) (hazard ratio (HR) = 0.70, 95% CI: 0.57–0.87), but there was no statistical difference in patients evaluated as “favorable” by the International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) criteria compared with monotherapy (HR = 0.90, 95% CI: 0.55–1.46, p = 0.66). In terms of PFS, the progression risk for all participants declined 35% (HR = 0.65, 95% CI: 0.50–0.83) and patients evaluated as “poor” by IMDC benefited further (HR = 0.46, 95% CI: 0.36–0.58). No evident divergence was found in age and sex subgroups. The RRs of all-grade hypertension, arthralgia, rash, proteinuria, high-grade (grades 3–5) arthralgia, and proteinuria developed after combination therapy were increased compared with sunitinib. The risk of high-grade hypertension and rash showed no statistical difference. However, the risk of hand-foot skin reaction (HFSR), stomatitis, and dysgeusia decreased in combination therapy groups.ConclusionsCompared with sunitinib, OS, PFS, and ORR were significantly improved in patients receiving ICI and anti-VEGF combination therapy at the expense of increased specific AEs. More attention should be paid to individualized application of these combination therapies to achieve the best benefit-risk ratio in the clinic.Systematic Review Registration[https://inplasy.com/] INPLASY: 202130104.

223 Racial differences in outcomes for metastatic renal cell carcinoma (mRCC) patients managed on immune-checkpoint inhibitor (ICI) therapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A242-A242
Author(s):  
T Anders Olsen ◽  
Dylan Martini ◽  
Subir Goyal ◽  
Yuan Liu ◽  
Sean Evans ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
African American ◽  
Retrospective Study ◽  
Cell Carcinoma ◽  
Clinical Outcomes ◽  
Immune Checkpoint ◽  
Renal Cell ◽  
Clear Cell ◽  
Emory University ◽  
Caucasian Patients

BackgroundImmune checkpoint inhibitors (ICIs) have increased in prevalence for the treatment of metastatic clear-cell renal cell carcinoma (mccRCC) in recent years given their efficacy and favorable toxicity profile. However, there has been insufficient investigation in the literature of how clinical outcomes differ on the basis of race. In this paper, we investigated differences in clinical outcomes between African American (AA) and Caucasian mRCC patients treated with ICI therapy.MethodsWe performed a retrospective study of 198 patients with mRCC who received ICI at the Emory Winship Cancer Institute from 2015–2020. Clinical outcomes were measured by overall survival (OS), progression-free survival (PFS), and clinical benefit (CB). OS and PFS were calculated from ICI-initiation to date of death and radiographic or clinical progression, respectively. CB was defined as a best radiographic response of complete response, partial response, or stable disease maintained for at least 6 months per response evaluation criteria in solid tumors version 1.1. The association of self-identified race with OS and PFS was generally modeled by Cox proportional hazards model. Univariable and multivariable logistic regression models were used for binary outcomes of CB. The univariate association of immune-related adverse events (irAEs) and non-clear-cell RCC (nccRCC) with race was assessed using Chi-square test.ResultsOur cohort was made up of 38 AA (19%) and 160 Caucasian (81%) patients. Most of the patients were diagnosed with ccRCC (78%) and more than half received PD-1 monotherapy (57%). Most patients were international mRCC database consortium (IMDC) intermediate (57%) or poor-risk (25%) groups. AA patients displayed significantly shorter PFS (HR=1.52, 95% CI: 1.01–2.3, p=0.045) and trended towards decreased CB (OR=0.51, 95% CI: 0.22–1.17, p=0.111) in MVA (table 1). There was no difference in OS (HR=1.09, 95% CI: 0.61–1.95, p=0.778) between the two racial groups in MVA (table 1). On Kaplan-Meier method, AA patients had shorter median OS (17 vs 25 months, p=0.3676) and median PFS (3.1 vs 4.4 months, p=0.0676) relative to Caucasian patients (figure 1). Additionally, AA patients more commonly had nccRCC compared to Caucasian patients (41.7% vs 17.5% nccRCC, p-0.002). AA patients also trended towards a lower incidence of irAEs compared to Caucasian patients in UVA (23.7% vs 35.8%, p=0.153).Abstract 223 Table 1*MVA controlled for age, race, gender, IMDC risk group, number of prior lines of therapy, PD-1 monotherapy, and ccRCC**statistical significance at alpha < 0.05Abstract 223 Figure 1African-American (black) and Caucasian (white) for OS (left panel) and PFS (right panel)ConclusionsIn this group of mRCC patients treated with ICI, African American patients had significantly shorter PFS compared to Caucasian patients. These findings suggest race could play a role in the management of late-stage mRCC. Larger, prospective studies are needed to validate these findings.AcknowledgementsResearch reported in this publication was supported in part by the Breen Foundation and the Biostatistics Shared Resource of Winship Cancer Institute of Emory University and NIH/NCI under award number P30CA138292. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.Trial RegistrationNot applicable.Ethics ApprovalThis retrospective study was approved by the Emory University Institutional Review Board.ConsentNot applicable.ReferencesNot applicable

scholarly journals Modified Glasgow Prognostic Score associated with survival in metastatic renal cell carcinoma treated with immune checkpoint inhibitors

2021 ◽  
Vol 9 (7) ◽  
pp. e002851
Author(s):  
Jacqueline T Brown ◽  
Yuan Liu ◽  
Julie M Shabto ◽  
Dylan Martini ◽  
Deepak Ravindranathan ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Immune Checkpoint ◽  
Renal Cell ◽  
Checkpoint Inhibitors ◽  
Prognostic Score ◽  
Univariate Analysis ◽  
Glasgow Prognostic Score ◽  
Modified Glasgow Prognostic Score

BackgroundThe modified Glasgow Prognostic Score (mGPS) is a composite biomarker that uses albumin and C reactive protein (CRP). There are multiple immune checkpoint inhibitor (ICI)-based combinations approved for metastatic renal cell carcinoma (mRCC). We investigated the ability of mGPS to predict outcomes in patients with mRCC receiving ICI.MethodsWe retrospectively reviewed patients with mRCC treated with ICI as monotherapy or in combination at Winship Cancer Institute between 2015 and 2020. Overall survival (OS) and progression-free survival (PFS) were measured from the start date of ICI until death or clinical/radiographical progression, respectively. The baseline mGPS was defined as a summary score based on pre-ICI values with one point given for CRP>10 mg/L and/or albumin<3.5 g/dL, resulting in possible scores of 0, 1 and 2. If only albumin was low with a normal CRP, no points were awarded. Univariate analysis (UVA) and multivariate analysis (MVA) were carried out using Cox proportional hazard model. Outcomes were also assessed by Kaplan-Meier analysis.Results156 patients were included with a median follow-up 24.2 months. The median age was 64 years and 78% had clear cell histology. Baseline mGPS was 0 in 36%, 1 in 40% and 2 in 24% of patients. In UVA, a baseline mGPS of 2 was associated with shorter OS (HR 4.29, 95% CI 2.24 to 8.24, p<0.001) and PFS (HR 1.90, 95% CI 1.20 to 3.01, p=0.006) relative to a score of 0; this disparity in outcome based on baseline mGPS persisted in MVA. The respective median OS of patients with baseline mGPS of 0, 1 and 2 was 44.5 (95% CI 27.3 to not evaluable), 15.3 (95% CI 11.0 to 24.2) and 10 (95% CI 4.6 to 17.5) months (p<0.0001). The median PFS of these three cohorts was 6.7 (95% CI 3.6 to 13.1), 4.2 (95% CI 2.9 to 6.2) and 2.6 (95% CI 2.0 to 5.6), respectively (p=0.0216). The discrimination power of baseline mGPS to predict survival outcomes was comparable to the IMDC risk score based on Uno’s c-statistic (OS: 0.6312 vs 0.6102, PFS: 0.5752 vs 0.5533).ConclusionThe mGPS is prognostic in this cohort of patients with mRCC treated with ICI as monotherapy or in combination. These results warrant external and prospective validation.

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