Browsing by Subject "Immune checkpoint inhibitor"

Now showing 1 - 6 of 6
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    Augmenting antibody response to EGF-depleting immunotherapy: Findings from a phase I trial of CIMAvax-EGF in combination with nivolumab in advanced stage NSCLC
    (Frontiers Media, 2022-08-03) Evans, Rachel; Lee, Kelvin; Wallace, Paul K.; Reid, Mary; Muhitch, Jason; Dozier, Askia; Mesa, Circe; Luaces, Patricia L.; Santos-Morales, Orestes; Groman, Adrienne; Cedeno, Carlos; Cinquino, Aileen; Fisher, Daniel T.; Puzanov, Igor; Opyrchal, Mateusz; Fountzilas, Christos; Dai, Tong; Ernstoff, Marc; Attwood, Kristopher; Hutson, Alan; Johnson, Candace; Mazorra, Zaima; Saavedra, Danay; Leon, Kalet; Lage, Agustin; Crombet, Tania; Dy, Grace K.; Medicine, School of Medicine
    Background: CIMAvax-EGF is an epidermal growth factor (EGF)-depleting immunotherapy which has shown survival benefit as a switch maintenance treatment after platinum-based chemotherapy in advanced non-small cell lung cancer (NSCLC). The primary objective of this trial is to establish the safety and recommended phase II dose (RP2D) of CIMAvax-EGF in combination with nivolumab as second-line therapy for NSCLC. Methods: Patients with immune checkpoint inhibitor-naive metastatic NSCLC were enrolled using a "3+3" dose-escalation design. Toxicities were graded according to CTCAE V4.03. Thirteen patients (one unevaluable), the majority with PD-L1 0%, were enrolled into two dose levels of CIMAvax-EGF. Findings: The combination was determined to be safe and tolerable. The recommended phase 2 dose of CIMAvax-EGF was 2.4 mg. Humoral response to CIMAvax-EGF was achieved earlier and in a greater number of patients with the combination compared to historical control. Four out of 12 evaluable patients had an objective response.
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    Benefits of combination therapy with immune checkpoint inhibitors and predictive role of tumour mutation burden in hepatocellular carcinoma: A systematic review and meta-analysis
    (Elsevier, 2022-11) Zheng, Jiaxi; Shao, Minghai; Yang , Weifang; Ren , Justin; Chen, Xiaofeng; Yang, Haihua; Radiation Oncology, School of Medicine
    Objectives To investigate the clinical benefits of combination therapy with immune checkpoint inhibitors (ICIs) and best combination regimen for people with advanced hepatocellular carcinoma (HCC) and to explore the predictive performance of tumour mutation burden (TMB). Methods We conducted a systematic literature search to identify clinical trials. Meta-analysis and subgroup analyses were performed to estimate the benefits of combination regimens with PD-1/PD-L1 inhibitors for patients with advanced HCC and compare the effectiveness of PD-1/PD-L1 inhibitors and sorafenib as first-line therapy. Individualized analysis and Kaplan-Meier were used to assess the prognostic value of TMB. Results A total of 29 studies with 5396 patients were included. ICIs’ combination therapy had higher ORR (26 % vs 15 %) and DCR (73 % vs 55 %), longer PFS (5.5 vs 3.1 months) and OS (15.9 vs 12.6 months) compared to monotherapy. Anti-PD-1/PD-L1 agents provided improved ORR, DCR, PFS and OS compared to sorafenib. The overall ORs of ORR and DCR in subgroup analysis were 3.49 (95 % CI 2.36–5.17, p < 0.01) and 1.60 (95 % CI 1.15–2.21, p < 0.01). The overall HRs of PFS and OS were 0.68 (95 % CI 0.48–0.96, p = 0.03) and 0.73 (95 % CI 0.62–0.85, p < 0.01). PD-1/PD-L1 inhibitors plus anti-VEGF agents had an advantage in DCR (0.80 vs 0.48, meta-regression = − 0.32, P < 0.001), but an equal ORR (0.29 vs 0.26) compared to dual immune checkpoint inhibitors. The total OS in Dua-ICIs were 16.5 months (95 % CI 14.2–18.7), yet not reached in the major studies of ICI plus anti-VEGF regimen. In individualized analysis, the 1-year OS was superior for patients who had high-TMB (>10, mutations/Mb) than moderate-TMB (1–10, mutations/Mb; 28 % vs 15 %, P = 0.025). Conclusion Immune checkpoint inhibitors’ combination therapy improved clinical outcomes in the management of advanced hepatocellular carcinoma. However, the overall objective response rate still did not exceed 30%. PD-1/PD-L1 inhibitors plus anti-angiogenic agents and dual immunotherapy provided significantly increased survival over sorafenib, which also pose new challenges for future research, and more appropriate and guided control regimens are required. Also, TMB may be a promising prognostic biomarker for immunotherapy in HCC. However, the validation of prospective and large sample studies is needed.
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    Cetuximab for Immunotherapy-Refractory/Ineligible Cutaneous Squamous Cell Carcinoma
    (MDPI, 2023-06-14) Marin-Acevedo, Julian A.; Withycombe, Bethany M.; Kim, Youngchul; Brohl, Andrew S.; Eroglu, Zeynep; Markowitz, Joseph; Tarhini, Ahmad A.; Tsai, Kenneth Y.; Khushalani, Nikhil I.; Medicine, School of Medicine
    Anti-PD1 therapy demonstrated impressive, prolonged responses in advanced cutaneous squamous cell carcinoma (CSCC). Therapy for ICI-refractory/ineligible disease remains unclear. We performed a retrospective analysis in locally-advanced/metastatic CSCC using cetuximab across three cohorts: immediately after ICI failure (A), not immediately following ICI failure (B), or without prior ICI (C). The primary endpoint was the overall response rate (ORR). Secondary endpoints included disease-control rate (DCR), progression-free survival (PFS), overall survival (OS), time-to-response (TTR) and toxicity. Twenty-three patients were included. In cohort A (n = 11), the ORR was 64% and DCR was 91%, with six ongoing responses at data cutoff. In cohort B (n = 2), all patients had progression as the best response. At a median follow-up of 21 months for A and B, TTR and PFS were 2.0 and 17.3 months, respectively. The median OS was not reached. In cohort C (n = 10), the ORR and DCR were 80%, including five ongoing responses at the data cutoff. At a median follow-up of 22.4 months, the TTR, PFS and OS were 2.5, 7.3 and 23.1 months, respectively. Cetuximab was well tolerated in all cohorts. In summary, cetuximab is effective in patients with failure/contraindications to ICI. Cetuximab immediately after ICI failure yielded particularly fast, durable responses. If confirmed, this could be the preferred therapy following ICI failure.
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    Deep Learning-Based Classification of Epithelial-Mesenchymal Transition for Predicting Response to Therapy in Clear Cell Renal Cell Carcinoma
    (Frontiers Media, 2022) Chen, Qiwei; Kuai, Yue; Wang, Shujing; Zhu, Xinqing; Wang, Hongyu; Liu, Wenlong; Cheng, Liang; Yang, Deyong; Pathology and Laboratory Medicine, School of Medicine
    Epithelial–mesenchymal transition (EMT) profoundly impacts prognosis and immunotherapy of clear cell renal cell carcinoma (ccRCC). However, not every patient is tested for EMT status because this requires additional genetic studies. In this study, we developed an EMT gene signature to classify the H&E-stained slides from The Cancer Genome Atlas (TCGA) into epithelial and mesenchymal subtypes, then we trained a deep convolutional neural network to classify ccRCC which according to our EMT subtypes accurately and automatically and to further predict genomic data and prognosis. The clinical significance and multiomics analysis of the EMT signature was investigated. Patient cohorts from TCGA (n = 252) and whole slide images were used for training, testing, and validation using an algorithm to predict the EMT subtype. Our approach can robustly distinguish features predictive of the EMT subtype in H&E slides. Visualization techniques also detected EMT-associated histopathological features. Moreover, EMT subtypes were characterized by distinctive genomes, metabolic states, and immune components. Deep learning convolutional neural networks could be an extremely useful tool for predicting the EMT molecular classification of ccRCC tissue. The underlying multiomics information can be crucial in applying the appropriate and tailored targeted therapy to the patient.
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    Immune Checkpoint Inhibitors for the Treatment of Bladder Cancer
    (MDPI, 2021-01-03) Lopez-Beltran, Antonio; Cimadamore, Alessia; Blanca, Ana; Massari, Francesco; Vau, Nuno; Scarpelli, Marina; Cheng, Liang; Montironi, Rodolfo; Pathology and Laboratory Medicine, School of Medicine
    A number of immune checkpoint inhibitors (ICIs) have been approved as first-line therapy in case of cisplatin-ineligible patients or as second-line therapy for patients with metastatic urothelial carcinoma (mUC) of the bladder. About 30% of patients with mUC will respond to ICIs immunotherapy. Programmed death-ligand 1 (PD-L1) expression detected by immunohistochemistry seems to predict response to immune checkpoint inhibitors in patients with mUC as supported by the objective response rate (ORR) and overall survival (OS) associated with the response observed in most clinical trials. Pembrolizumab, an anti-PD-1 antibody, demonstrated better OS respective to chemotherapy in a randomized phase 3 study for second-line treatment of mUC. Nivolumab, a PD-1 antibody, also demonstrated an OS benefit when compared to controls. Atezolizumab, Durvalumab, and Avelumab antibodies targeting PD-L1 have also received approval as second-line treatments for mUC with durable response for more than 1 year in selected patients. Atezolizumab and Pembrolizumab also received approval for first-line treatment of patients that are ineligible for cisplatin. A focus on the utility of ICIs in the adjuvant or neoadjuvant setting, or as combination with chemotherapy, is the basis of some ongoing trials. The identification of a clinically useful biomarker, single or in association, to determine the optimal ICIs treatment for patients with mUC is very much needed as emphasized by the current literature. In this review, we examined relevant clinical trial results with ICIs in patients with mUC alone or as part of drug combinations; emphasis is also placed on the adjuvant and neoadjuvant setting. The current landscape of selected biomarkers of response to ICIs including anti-PD-L1 immunohistochemistry is also briefly reviewed.
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    VISTA Emerges as a Promising Target against Immune Evasion Mechanisms in Medulloblastoma
    (MDPI, 2024-07-24) Muñoz Perez, Natalia; Pensabene, Juliana M.; Galbo, Phillip M., Jr.; Sadeghipour, Negar; Xiu, Joanne; Moziak, Kirsten; Yazejian, Rita M.; Welch, Rachel L.; Bell, W. Robert; Sengupta, Soma; Aulakh, Sonikpreet; Eberhart, Charles G.; Loeb, David M.; Eskandar, Emad; Zheng, Deyou; Zang, Xingxing; Martin, Allison M.; Pathology and Laboratory Medicine, School of Medicine
    Background: Relapsed medulloblastoma (MB) poses a significant therapeutic challenge due to its highly immunosuppressive tumor microenvironment. Immune checkpoint inhibitors (ICIs) have struggled to mitigate this challenge, largely due to low T-cell infiltration and minimal PD-L1 expression. Identifying the mechanisms driving low T-cell infiltration is crucial for developing more effective immunotherapies. Methods: We utilize a syngeneic mouse model to investigate the tumor immune microenvironment of MB and compare our findings to transcriptomic and proteomic data from human MB. Results: Flow cytometry reveals a notable presence of CD45hi/CD11bhi macrophage-like and CD45int/CD11bint microglia-like tumor-associated macrophages (TAMs), alongside regulatory T-cells (Tregs), expressing high levels of the inhibitory checkpoint molecule VISTA. Compared to sham control mice, the CD45hi/CD11bhi compartment significantly expands in tumor-bearing mice and exhibits a myeloid-specific signature composed of VISTA, CD80, PD-L1, CTLA-4, MHCII, CD40, and CD68. These findings are corroborated by proteomic and transcriptomic analyses of human MB samples. Immunohistochemistry highlights an abundance of VISTA-expressing myeloid cells clustering at the tumor-cerebellar border, while T-cells are scarce and express FOXP3. Additionally, tumor cells exhibit immunosuppressive properties, inhibiting CD4 T-cell proliferation in vitro. Identification of VISTA's binding partner, VSIG8, on tumor cells, and its correlation with increased VISTA expression in human transcriptomic analyses suggests a potential therapeutic target. Conclusions: This study underscores the multifaceted mechanisms of immune evasion in MB and highlights the therapeutic potential of targeting the VISTA-VSIG axis to enhance anti-tumor responses.