Evaluation of monocytic myeloid-derived suppressor cell (M-MDSC) frequency in patients with metastatic urothelial carcinoma (mUC).

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 356-356 ◽  
Author(s):  
Samuel Funt ◽  
Zhenyu Mu ◽  
Catharine Kline Cipolla ◽  
Brooke Elizabeth Kania ◽  
Junting Zheng ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Targeted Therapy ◽  
Immune Checkpoint ◽  
Whole Blood ◽  
Flow Cytometric Analysis ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Hla Dr ◽  
Time Of Collection

356 Background: M-MDSCs promote tumor progression through complex mechanisms, including immunosuppression and the production of mediators of angiogenesis and invasion. M-MDSCs are associated with poor outcomes in a number of malignancies. We conducted an exploratory analysis enumerating M-MDSCs (Lin-CD14+/HLA-DRlow/-) in the blood of pts with mUC and assessed for assay variability and correlation with clinical outcomes. Methods: Whole blood was collected at a single time point for each pt and stabilized in Cyto-Chex tubes. M-MDSC% was calculated by flow cytometric analysis of HLA-DR expression on CD14+ monocytes using an MSKCC developed computational algorithm-based approach (Kitano et al. 2014). Individual samples were run in quadruplicate at MSKCC. The mean MDSC% was used in subsequent analyses and the replicate standard deviation (SD) was considered a reflection of intra-assay variability. Clinical variables were collected and pts followed for OS, which was calculated from time of sample collection. Results: 21 pts with mUC who progressed after prior chemotherapy were included. At the time of collection, pts were on clinical trials with immune checkpoint blockade (n=13) or targeted therapy (n=1), receiving salvage chemotherapy (n=2), or awaiting treatment on clinical trials with immune checkpoint blockade (n=4) or targeted therapy (n=1). The median follow up from the time of collection in surviving patients (n=15) was 11.1 months (range: 10.5-11.5). Median OS was not reached. Mean (SD) M-MDSC% was 29.2 (4.92). The range of replicate SD was 0.13-1.05. M-MDSC% was not higher in pts with visceral mets (p=0.109). Pts with above median M-MDSC% had worse OS (p=0.01; 6 patients died during follow up, all with above median M-MDSC%). Conclusions: In a heterogeneous cohort of pts with mUC, the enumeration of M-MDSCs in stabilized whole blood was feasible and demonstrated marked inter-patient but not intra-assay variability. Pts with higher M-MDSC% values had worse OS. Additional characterization of M-MDSCs in larger cohorts and in pts receiving immunotherapy is ongoing and may have important prognostic and therapeutic implications in mUC.

scholarly journals Immunomodulatory Effects of BRAF, MEK, and CDK4/6 Inhibitors: Implications for Combining Targeted Therapy and Immune Checkpoint Blockade for the Treatment of Melanoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Emily J. Lelliott ◽  
Grant A. McArthur ◽  
Jane Oliaro ◽  
Karen E. Sheppard
Keyword(s):  
Clinical Trials ◽  
Targeted Therapy ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
New Combination ◽  
Immunomodulatory Activity ◽  
Immunomodulatory Effects ◽  
Current Standard

The recent advent of targeted and immune-based therapies has revolutionized the treatment of melanoma and transformed outcomes for patients with metastatic disease. The majority of patients develop resistance to the current standard-of-care targeted therapy, dual BRAF and MEK inhibition, prompting evaluation of a new combination incorporating a CDK4/6 inhibitor. Based on promising preclinical data, combined BRAF, MEK and CDK4/6 inhibition has recently entered clinical trials for the treatment of BRAFV600 melanoma. Interestingly, while BRAF- and MEK-targeted therapy was initially developed on the basis of potent tumor-intrinsic effects, it was later discovered to have significant immune-potentiating activity. Recent studies have also identified immune-related impacts of CDK4/6 inhibition, though these are less well defined and can be both immune-potentiating and immune-inhibitory. BRAFV600 melanoma patients are also eligible to receive immunotherapy, specifically checkpoint inhibitors against PD-1 and CTLA-4. The immunomodulatory activity of BRAF/MEK-targeted therapies has prompted interest in combination therapies incorporating these with immune checkpoint inhibitors, however recent clinical trials investigating this approach have produced variable results. Here, we summarize the immunomodulatory effects of BRAF, MEK and CDK4/6 inhibitors, shedding light on the prospective utility of this combination alone and in conjunction with immune checkpoint blockade. Understanding the mechanisms that underpin the clinical efficacy of these available therapies is a critical step forward in optimizing novel combination and scheduling approaches to combat melanoma and improve patient outcomes.

scholarly journals Aptamer targeted therapy potentiates immune checkpoint blockade in triple-negative breast cancer

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Simona Camorani ◽  
Margherita Passariello ◽  
Lisa Agnello ◽  
Silvia Esposito ◽  
Francesca Collina ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Targeted Therapy ◽  
Triple Negative Breast Cancer ◽  
Immune Checkpoint ◽  
Triple Negative ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

scholarly journals Combined irradiation and targeted therapy or immune checkpoint blockade in brain metastases: toxicities and efficacy

2017 ◽  
Vol 28 (12) ◽  
pp. 2962-2976 ◽  
Author(s):  
A.V. Tallet ◽  
F. Dhermain ◽  
E. Le Rhun ◽  
G. Noël ◽  
Y.M. Kirova
Keyword(s):  
Targeted Therapy ◽  
Brain Metastases ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

scholarly journals Distinct clinical patterns and immune infiltrates are observed at time of progression on targeted therapy versus immune checkpoint blockade for melanoma

2016 ◽  
Vol 5 (3) ◽  
pp. e1136044 ◽  
Author(s):  
Zachary A. Cooper ◽  
Alexandre Reuben ◽  
Christine N. Spencer ◽  
Peter A. Prieto ◽  
Jacob L. Austin-Breneman ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Clinical Patterns

scholarly journals Antitumor Peptide-Based Vaccine in the Limelight

Vaccines ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 70
Author(s):  
Takumi Kumai ◽  
Hidekiyo Yamaki ◽  
Michihisa Kono ◽  
Ryusuke Hayashi ◽  
Risa Wakisaka ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Tumor Antigens ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Recent Experimental Data ◽  
Proof Of Concept ◽  
Cell Responses ◽  
Tumor Reduction

The success of the immune checkpoint blockade has provided a proof of concept that immune cells are capable of attacking tumors in the clinic. However, clinical benefit is only observed in less than 20% of the patients due to the non-specific activation of immune cells by the immune checkpoint blockade. Developing tumor-specific immune responses is a challenging task that can be achieved by targeting tumor antigens to generate tumor-specific T-cell responses. The recent advancements in peptide-based immunotherapy have encouraged clinicians and patients who are struggling with cancer that is otherwise non-treatable with current therapeutics. By selecting appropriate epitopes from tumor antigens with suitable adjuvants, peptides can elicit robust antitumor responses in both mice and humans. Although recent experimental data and clinical trials suggest the potency of tumor reduction by peptide-based vaccines, earlier clinical trials based on the inadequate hypothesis have misled that peptide vaccines are not efficient in eliminating tumor cells. In this review, we highlighted the recent evidence that supports the rationale of peptide-based antitumor vaccines. We also discussed the strategies to select the optimal epitope for vaccines and the mechanism of how adjuvants increase the efficacy of this promising approach to treat cancer.

scholarly journals Acute neurologic toxicity of palliative radiotherapy for brain metastases in patients receiving immune checkpoint blockade

2018 ◽  
Vol 6 (4) ◽  
pp. 297-304 ◽  
Author(s):  
W Tristram Arscott ◽  
Simeng Zhu ◽  
John P Plastaras ◽  
Amit Maity ◽  
Michelle Alonso-Basanta ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Immune Checkpoint ◽  
Performance Status ◽  
Single Agent ◽  
Whole Brain Radiotherapy ◽  
Nonsmall Cell Lung Cancer ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Acute Neurotoxicity

Abstract Background The interaction between immune checkpoint blockade (ICB) and radiation (RT) for brain metastases has not been well understood. Given that acute neurotoxicity from this combination is not well characterized, we reviewed patients receiving ICB and RT for brain metastases. Methods Patients treated with ICB and cranial RT from 2010 through 2017 were reviewed. ICB and RT must have been administered within 30 days of each other. Treatment parameters, performance status, symptoms prior to treatment, and toxicity were extracted from the electronic medical record. Survival was calculated from the end of RT to last follow-up or death. Results Seventy-eight patients were included. Median follow-up was 177 days (range, 12-1603). Median age was 64 years old (range, 29-98) and 47 (63%) were male. The main tumor types were melanoma (n = 47) and nonsmall-cell lung cancer (n = 19). Fifty-seven patients were treated with stereotactic radiosurgery (SRS) and 21 with whole-brain radiotherapy (WBRT). Most patients received single-agent ICB, though 4 patients received nivolumab and ipilimumab. Forty-one (53%) patients reported no neurologic toxicity. Grade 2 or greater neurologic toxicities were reported in 12 (21%) and 8 (38%) patients in the SRS and WBRT groups, respectively. WBRT was associated with a greater risk of any neurotoxicity, though there was no correlation between ICB agent and toxicity. Sequencing of ICB and RT (ie, <30 days vs <7) did not influence rates of toxicity. Conclusions ICB during SRS or WBRT does not appear to worsen acute neurotoxicity compared to historical controls of RT alone.

scholarly journals Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution

2014 ◽  
Vol 21 (2) ◽  
pp. 371-381 ◽  
Author(s):  
Mabel Ryder ◽  
Margaret Callahan ◽  
Michael A Postow ◽  
Jedd Wolchok ◽  
James A Fagin
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Hormone Replacement ◽  
Symptomatic Relief ◽  
Hormone Secretion ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Increased Risk

Novel immune checkpoint blockade with ipilimumab, an antibody blocking the cytotoxic T-lymphocyte antigen 4 (CTLA4), is revolutionizing cancer therapy. However, ipilimumab induces symptomatic, sometimes severe, endocrine immune-related adverse events (irAEs) that are inconsistently recognized and reported. The objective of this review was to comprehensively characterize the incidence, presentation, and management of endocrinopathies following ipilimumab therapy in a single center that is highly specialized in immune checkpoint blockade. We carried out a retrospective analysis of endocrine irAEs in melanoma patients receiving ipilimumab therapy in clinical trials between 2007 and 2013. A total of 256 patients were included in this analysis. We reviewed pituitary-, thyroid-, and adrenal-related hormone test results, as well as radiographic studies and the clinical histories of patients, to identify and characterize cases of hypophysitis, hypothyroidism, thyroiditis, and adrenal dysfunction. Following ipilimumab therapy, the overall incidence of hypophysitis was 8% and that of hypothyroidism/thyroiditis 6%. Primary adrenal dysfunction was rare. Therapy with a combination of ipilimumab and nivolumab, an anti-programmed cell death 1 (PDCD1, also called PD1) receptor antibody, was associated with a 22% incidence of either thyroiditis or hypothyroidism and a 9% incidence of hypophysitis. Symptomatic relief, in particular, for hypophysitis, was achieved in all patients with hormone replacement, although endogenous hormone secretion rarely recovered. In summary, we observed that CTLA4 blockade alone, and in particular in combination with PD1 blockade, is associated with an increased risk of symptomatic, sometimes severe, hypophysitis as well as thyroid dysfunction. Prompt initiation with hormone replacement reverses symptoms. Evaluation and reporting of endocrine irAEs in clinical trials should be done using standardized diagnostic criteria and terminology.

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