Molecular and Immune Correlates of PDCD1 (PD-1), PD-L1 (CD274), and PD-L2 (PDCD1LG2) DNA Methylation in Triple Negative Breast Cancer
Immune checkpoints are important targets in oncological therapy. Recent studies have proven efficacy of immune checkpoint inhibition (ICI) in treatment of triple negative breast cancer (TNBC). However, only a proportion of TNBC-patients benefit from ICI. Thus, current scientific efforts in this context are focused on the identification of a robust biomarker that enables patient stratification. In the present study, we investigated the epigenetic regulation of PD-1 (PDCD1), PD-L1 (CD274), and PD-L2 (PDCD1LG2). Methylation data of PD-1, PD-L1, and PD-L2, and complex immunogenomic data were obtained from The Cancer Genome Atl...
Source: Journal of Immunotherapy - September 7, 2021 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research
Long-term Overall Survival and Predictors in Anti–PD-1-naive Melanoma Patients With Brain Metastases Treated With Immune Checkpoint Inhibitors in the Real-world Setting: A Multicohort Study
Long-term survival outcomes among melanoma patients with brain metastases treated with immune checkpoint inhibitors are limited. In this retrospective study at 2 centers, metastatic melanoma patients with radiographic evidence of brain metastases who received anti–programmed death-1 (PD-1) monotherapy or nivolumab in combination with ipilimumab between 2014 and 2017 were included. Overall survival (OS) was assessed in diagnosis-specific graded prognostic assessment (ds-GPA) and melanoma–molecular graded prognostic assessment (molGPA) prognostic risk groups. Baseline clinical covariates were used to identify predictors ...
Source: Journal of Immunotherapy - September 7, 2021 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research
Potent, Selective CARs as Potential T-Cell Therapeutics for HPV-positive Cancers
Next-generation T-cell therapies will likely continue to utilize T-cell receptors (TCRs) and chimeric antigen receptors (CARs) because each receptor type has advantages. TCRs often possess exceptional properties even when tested unmodified from patients’ T cells. CARs are generally less sensitive, possibly because their ligand-binding domains are grafted from antibodies selected for binding affinity or avidity and not broadly optimized for a functional response. Because of the disconnect between binding and function among these receptor types, the ultimate potential of CARs optimized for sensitivity and selectivity is no...
Source: Journal of Immunotherapy - September 7, 2021 Category: Allergy & Immunology Tags: Basic Studies Source Type: research
Inhibition of Polyamine Biosynthesis Using Difluoromethylornithine Acts as a Potent Immune Modulator and Displays Therapeutic Synergy With PD-1-blockade
Polyamines are known to play a significant role in cancer progression and treatment using difluoromethylornithine (DFMO), an inhibitor of polyamine biosynthesis, has shown some clinical promise. It is interesting to note that, while DFMO is directly cytostatic in vitro, recent work has suggested that it achieves its antitumor efficacy in vivo by enhancing adaptive antitumor immune responses. On the basis of these data, we hypothesized that DFMO might act as an immune sensitizer to increase tumor responsiveness to checkpoint blockade. To test this hypothesis, we treated tumors with DFMO, in either the presence or absence of...
Source: Journal of Immunotherapy - September 7, 2021 Category: Allergy & Immunology Tags: Basic Studies Source Type: research
Immune Checkpoint Inhibitor–related Guillain-Barré Syndrome: A Case Series and Review of the Literature
We present 3 cases of ICI-related GBS; review cases described in current literature, and discuss treatment strategies. Three patients developed GBS after ICI treatment. The first case with pembrolizumab had a fatal outcome despite treatment with multiple regimens, including steroids and intravenous immunoglobulin (IVIg). The other 2 cases with nivolumab-induced and pembrolizumab-induced GBS, respectively, responded well to treatment with IVIg and steroids. In the current literature, a total of 31 other cases were found. Treatment for ICI-related GBS mostly consisted of concurrent IVIg and steroids (44%), which led to clini...
Source: Journal of Immunotherapy - August 19, 2021 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research
A Phase I Study of an IDO-1 Inhibitor (LY3381916) as Monotherapy and in Combination With an Anti-PD-L1 Antibody (LY3300054) in Patients With Advanced Cancer
This study explored the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of LY3381916 monotherapy and in combination with a programmed death-ligand 1 (PD-L1) inhibitor (LY3300054) in patients with advanced solid tumors. During dose escalation, patients received escalating doses of LY3381916 at 60–600 mg once daily (qd) and 240 mg twice daily in monotherapy (n=21) and in combination with PD-L1 inhibitor at 700 mg every 2 weeks (n=21). A modified toxicity probability interval method was used to guide dose escalation. Dose-limiting toxicities occurred in 3 patients; 1 at LY3381916 240â€...
Source: Journal of Immunotherapy - August 19, 2021 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research
Myeloid Cell Infiltration Correlates With Prognosis in Cholangiocarcinoma and Varies Based on Tumor Location
In conclusion, the CC TIME is a heterogenous milieu highly infiltrated by innate and adaptive immune cells, which differs based on primary tumor location and between primary tumors and metastatic lesions. The correlation of intratumoral M2 macrophages and myeloid cells with a worse prognosis may suggest promising immunotherapeutic targets in CC. (Source: Journal of Immunotherapy)
Source: Journal of Immunotherapy - August 19, 2021 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research
Pretreatment Eosinophil Counts in Patients With Advanced or Metastatic Urothelial Carcinoma Treated With Anti-PD-1/PD-L1 Checkpoint Inhibitors
Eosinophils influence antitumor immunity and may predict response to treatment with immune checkpoint inhibitors (ICIs). To examine the association between blood eosinophil counts and outcomes in patients with advanced or metastatic urothelial carcinoma (mUC) treated with ICIs, we identified 2 ICI-treated cohorts: discovery (n=60) and validation (n=111). Chemotherapy cohorts were used as comparators (first-line platinum-based chemotherapy, n=75; second-line or more pemetrexed, n=77). The primary endpoint was overall survival (OS). Secondary endpoints were time on treatment (ToT) and progression-free survival. Univariate an...
Source: Journal of Immunotherapy - August 19, 2021 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research
Encephalitis Induced by Durvalumab During Treatment of Metastatic Small-Cell Lung Cancer: Illustrative Case and Review of the Literature
This report describes a 66-year-old female who received Durvalumab for metastatic small-cell lung cancer. Following 3 cycles of treatment, she developed encephalitis. (Source: Journal of Immunotherapy)
Source: Journal of Immunotherapy - August 19, 2021 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research
Risk Factors for Relapse after Intentional Discontinuation of Immune Checkpoint Inhibitors in Melanoma Patients
Immune checkpoint inhibitors (ICIs) have tremendously changed the therapeutic landscape of melanoma since they are associated with a durable response, allowing for intentional discontinuation of therapy after complete or partial remission. However, a subset of patients develops a relapse after cessation of ICI treatment and may not respond to reinduction of ICIs. The aim of the present study was to identify risk factors for relapse after intentional discontinuation of ICI therapy. Patients with intentional discontinuation of ICI therapy for metastatic or unresectable melanoma from 5 German university hospitals were analyze...
Source: Journal of Immunotherapy - June 10, 2021 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research
Immune Checkpoint Inhibition in Marjolin Ulcer: A Case Series
We describe the clinicopathologic features and clinical outcomes of our MU-SCC cohort. (Source: Journal of Immunotherapy)
Source: Journal of Immunotherapy - June 10, 2021 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research
Pembrolizumab Utilization and Clinical Outcomes Among Patients With Advanced Melanoma in the US Community Oncology Setting: An Updated Analysis
Favorable outcomes have been observed with pembrolizumab among patients with advanced melanoma in clinical trials; however, limited evidence exists on the long-term efficacy in the real-world setting. This was an updated, retrospective observational study of adult patients with advanced (unresectable or metastatic) melanoma who initiated pembrolizumab (in any line of therapy) between January 1, 2014, and December 31, 2016, in The US Oncology Network and were followed through December 31, 2019 [median follow-up: 18.2 mo (range: 0.1–63.1 mo)]. Study data were sourced from electronic health records. Patient demographic,...
Source: Journal of Immunotherapy - June 10, 2021 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research
PMEL as a Prognostic Biomarker and Negatively Associated With Immune Infiltration in Skin Cutaneous Melanoma (SKCM)
Premelanosome protein (PMEL) is crucial for the formation of melanosomal fibrils through the transition from stage I to stage II melanosomes. It was used as a target antigen in some adoptive T-cell therapy of melanoma. The correlation of PMEL to prognosis and immune cell infiltration level are unknown in melanoma. The PMEL expression was evaluated via Tumor Immune Estimation Resource, Oncomine and Gene Expression Profiling Interactive Analysis (GEPIA). We also evaluate the influence of PMEL on overall survival via GEPIA, PrognoScan, and immunohistochemistry in human tissue microarray. The correlation between PMEL expressio...
Source: Journal of Immunotherapy - June 10, 2021 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research
The Intracellular Domain of CD40 is a Potent Costimulatory Element in Chimeric Antigen Receptors
The costimulatory domains incorporated into second-generation and third-generation chimeric antigen receptors (CARs) strongly influence CAR-T-cell function. Here, we explored second-generation and third-generation CARs harboring the signaling domain of the CD40 receptor as a new costimulatory element in comparison with similar CARs carrying the 4-1BB domain. In CARs of both generations, CD40 was more potent than 4-1BB in triggering the NF-κB signaling pathway. In human T cells from 2 donors, CD40 was comparable to 4-1BB in upregulating costimulatory and activation markers, inducing proinflammatory cytokine secretion and m...
Source: Journal of Immunotherapy - June 10, 2021 Category: Allergy & Immunology Tags: Basic Study Source Type: research
Encephalitis Associated With Immune Checkpoint Inhibitor Treatment in Patients With Melanoma
Since the approval of immune checkpoint anti–programmed cell death protein 1 antibodies (pembrolizumab and nivolumab) and anti–cytotoxic T-lymphocyte–associated protein 4 (ipilimumab) in combination or monotherapy, significant advances have been made in the treatment of metastatic melanoma. The nonspecific immune stimulation resulting from these drugs can case a wide range of side effects in many organs including the nervous system, named immune-related adverse events. Few immune-related encephalitis associated with these antibodies have been described in the literature. It is a rare complication ( (Source: Journal of Immunotherapy)
Source: Journal of Immunotherapy - May 20, 2021 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research
