Development of a Tetravalent T-Cell Engaging Bispecific Antibody Against Glypican-3 for Hepatocellular Carcinoma
Cancer therapies benefit from accelerated development of biotechnology, and many immunotherapeutic strategies spring up including vaccines, the immune checkpoint blockade, chimeric antigen receptor T cells, and bispecific antibodies (BsAbs). Glypican-3 (GPC3) is a member of the heparan sulfate proteoglycan family of proteins and is highly expressed in hepatocellular carcinoma (HCC) cell membranes. Here, the authors describe a new tetravalent BsAb h8B-BsAb targeting GPC3 and CD3 antigens and studied its antitumor activities against HCC. h8B-BsAb was designed based on immunoglobulin G with a fragment variable fused to the li...
Source: Journal of Immunotherapy - March 18, 2021 Category: Allergy & Immunology Tags: Basic Studies Source Type: research
Re-examination of MAGE-A3 as a T-cell Therapeutic Target
In 2013, an innovative MAGE-A3-directed cancer therapeutic of great potential value was terminated in the clinic because of neurotoxicity. The safety problems were hypothesized to originate from off-target T-cell receptor activity against a closely related MAGE-A12 peptide. A combination of published and new data led us to test this hypothesis with current technology. Our results call into question MAGE-A12 as the source of the neurotoxicity. Rather, the data imply that an alternative related peptide from EPS8L2 may be responsible. Given the qualities of MAGE-A3 as an onco-testis antigen widely expressed in tumors and larg...
Source: Journal of Immunotherapy - March 18, 2021 Category: Allergy & Immunology Tags: Basic Studies Source Type: research
Case Report and Review of 7 Similar Cases in the Literature: Cutaneous Sarcoidosis as Side Effect of Pembrolizumab Plus Chemotherapy in Stage IV Squamous Cell Carcinoma of Lung
We present an unusual case of cutaneous sarcoidosis in a 63-year-old white female who was diagnosed with stage IV squamous cell lung cancer developed skin manifestations 3 months after started chemo/pembrolizumab. Sarcoidosis was confirmed by skin punch biopsy and resolved after a short course of systemic glucocorticoid while maintained on pembrolizumab with lower frequency. These sarcoid-like lesions associated with the blockage of programmed death receptor-1 have been increasingly described in many different malignancies especially in melanoma. There is a need for further investigation to the characterization of the popu...
Source: Journal of Immunotherapy - February 1, 2021 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research
Cardiovascular Toxicity and Mortality Associated With Adoptive Cell Therapy and Tumor-infiltrating Lymphocytes for Advanced Stage Melanoma
Adoptive cellular therapy (ACT) with tumor-infiltrating lymphocytes (TILs) has emerged as an effective treatment option for unresectable stage III/IV metastatic melanoma. Acute toxicities, particularly cardiovascular (CV), can have a significant effect on the completion of therapy. We abstracted information on 43 patients who received ACT-TIL treatment for melanoma at the Moffitt Cancer Center between 2010 and 2016. The Student t tests and χ2 tests were used to compare patient characteristics by presence versus absence of specific CV complications. In this cohort, 32.6% developed hypotension requiring treatment with intra...
Source: Journal of Immunotherapy - February 1, 2021 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research
Effects of Antibiotic Use on Outcomes in Cancer Patients Treated Using Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis
Antibiotic (ATB) use seems to negatively affect the outcomes of immune checkpoint inhibitors (ICIs). The aim of this review is to clarify whether ATB use influences the efficacy of ICI treatment in cancer patients. Databases of MEDLINE, Embase, and Cochrane Library were searched for reports published in English between January 2007 and December 2019. We included studies that compared the outcomes of ATB use and no-ATB use in cancer patients using ICIs. Two reviewers independently selected eligible studies and extracted the data. Meta-analysis was performed with pooling of unadjusted hazard ratios (HRs) for overall survival...
Source: Journal of Immunotherapy - February 1, 2021 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research
Primary Biliary Cirrhosis and Granulomatous Hepatitis After Immune Checkpoint Blockade in Patients With Metastatic Melanoma: Report of 2 Cases and Literature Discussion
We present here the case of a 69-year-old man with metastatic melanoma developing a severe primary biliary cirrhosis under pembrolizumab, and of a 52-year-old woman with metastatic melanoma with granulomatous hepatitis in the context of an immune-related multiorgan inflammatory reaction due to ipilimumab and nivolumab. Both cases were in part steroid refractory and required a complex diagnostic assessment and long-term therapeutic management. The liver biopsy was crucial for ensuring a correct diagnosis. Clinicians should be aware of rare liver diseases in the context of increased liver enzymes under immune checkpoint inhi...
Source: Journal of Immunotherapy - February 1, 2021 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research
Expanded Tumor-infiltrating Lymphocytes From Soft Tissue Sarcoma Have Tumor-specific Function
Adoptive cell transfer (ACT) with tumor-infiltrating lymphocytes (TILs) can generate durable clinical responses in patients with metastatic melanoma and ongoing trials are evaluating efficacy in other advanced solid tumors. The aim of this study was to develop methods for the expansion of tumor-reactive TIL from resected soft tissue sarcoma to a degree required for the ACT. From 2015 to 2018, 70 patients were consented to an institutional review board–approved protocol, and fresh surgical specimens were taken directly from the operating room to the laboratory. Fragments of the tumor (1 mm3) or fresh tumor digest were p...
Source: Journal of Immunotherapy - February 1, 2021 Category: Allergy & Immunology Tags: Basic Study Source Type: research
Gutting it Out: Developing Effective Immunotherapies for Patients With Colorectal Cancer
Risk factors for colorectal cancer (CRC) include proinflammatory diets, sedentary habits, and obesity, in addition to genetic syndromes that predispose individuals to this disease. Current treatment relies on surgical excision and cytotoxic chemotherapies. There has been a renewed interest in immunotherapy as a treatment option for CRC given the success in melanoma and microsatellite instable (MSI) CRC. Immunotherapy with checkpoint inhibitors only plays a role in the 4%–6% of patients with MSIhigh tumors and even within this subpopulation, response rates can vary from 30% to 50%. Most patients with CRC do not respond to...
Source: Journal of Immunotherapy - February 1, 2021 Category: Allergy & Immunology Tags: Review Article Source Type: research
Safety of Immunotherapy Rechallenge After Immune-related Adverse Events in Patients With Advanced Cancer
This retrospective study aimed to investigate the safety profile of continuing or rechallenging patients with advanced cancer who developed grade≥2 immune-related adverse events (irAEs) on immunotherapy-based regimens. Our study had 25, 20, and 40 patients (N=85) in the Treatment Continuation (TCG), Non-Rechallenge (NRG), and Rechallenge Groups (RG), respectively. Subsequent irAEs recurrence were more common in RG than TCG and NRG (78% vs. 56% vs. 25%, P (Source: Journal of Immunotherapy)
Source: Journal of Immunotherapy - December 13, 2020 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research
Prognostic Significance of Tumor-infiltrating Lymphocytes on Survival Outcomes of Patients With Resected Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-Analysis
Tumor-infiltrating lymphocytes (TILs) play an important role in mediating treatment response in pancreatic cancer. This meta-analysis investigated the prognostic significance of TIL subsets on overall survival (OS) and disease-free survival (DFS) of patients with pancreatic cancer. Studies were gathered via search of PubMed, Google Scholar, and Cochrane Library databases up to August 1, 2019. Using Review Manager version 5.3.5, pooled hazard ratios and 95% confidence intervals (CIs) were calculated using random or fixed-effects models, depending on the heterogeneity of studies. A total of 11 studies comprising 1760 patient...
Source: Journal of Immunotherapy - December 13, 2020 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research
High VISTA Expression Correlates With a Favorable Prognosis in Patients With Colorectal Cancer
In this study, immunohistochemical staining was used to investigate VISTA expression in tissue microarrays from 1434 patients with stage I–III CRC (816 in the exploratory cohort and 618 in the validation cohort). VISTA protein was evaluated separately in tumor cells and tumor-infiltrating immune cells (ICs). The associations between VISTA expression, mismatch repair (MMR) status, and clinicopathologic parameters were analyzed, as was the effect of VISTA on survival. High VISTA expression on ICs (ie, ≥5% staining) was more frequent in patients with N0 stage, T1–2 stage, low tumor grade, high CD8 density, and MMR-defic...
Source: Journal of Immunotherapy - December 13, 2020 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research
Analysis of Risk Factors for Hepatotoxicity Induced by Immune Checkpoint Inhibitors
In conclusion, close monitoring of liver function is recommended, especially in male patients, patients younger than 65 years old, and when there is concomitant use of hepatotoxic drugs including acetaminophen and HMG-CoA reductase inhibitors. (Source: Journal of Immunotherapy)
Source: Journal of Immunotherapy - December 13, 2020 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research
Checkpoint Blockade in Melanoma Patients With Underlying Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia (CLL) is associated with immune dysfunction and an increased risk of melanoma. For patients with metastatic melanoma, immunotherapy with checkpoint blocking antibodies is a standard of care. In patients with concomitant CLL and metastatic melanoma, it is not known whether CLL might influence the antimelanoma efficacy or immune-related toxicities of immune checkpoint blockade. Fifteen patients with locally advanced or metastatic melanoma and a concomitant diagnosis of CLL who received pembrolizumab or ipilimumab with or without nivolumab for the treatment of their melanoma at Memorial Sloan Kett...
Source: Journal of Immunotherapy - December 13, 2020 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research
Rapid Identification and Evaluation of Neoantigen-reactive T-Cell Receptors From Single Cells
We present a nonviral and non–next-generation sequencing platform for rapid, and efficient neoantigen-specific TCR identification and evaluation that does not require the use of recombinant cloning techniques. The platform includes an innovative method of TCRα detection using Sanger sequencing, TCR pairings and the use of TCRα/β gene fragments for putative TCR evaluation. Using patients’ samples, we validated and compared our new methods head-to-head with conventional approaches used for TCR discovery. Development of a unique demultiplexing method for identification of TCRα, adaptation of synthetic TCRs for gene tr...
Source: Journal of Immunotherapy - December 13, 2020 Category: Allergy & Immunology Tags: Basic Study Source Type: research
Efficacy of Pembrolizumab Monotherapy in Patients With or Without Brain Metastases From Advanced Non–Small Cell Lung Cancer With a PD-L1 Expression ≥50%
The authors conducted a multicenter retrospective study on the outcome of programmed death-ligand 1 tumor proportion score≥50% advanced non–small cell lung cancer patients treated with first-line pembrolizumab according to the presence/absence of brain metastases. A total of 282 patients were included, of whom 56 had brain metastases that were treated with upfront local radiation therapy in 80.3% of cases. The overall response rate was 39.2% and 44.4% in patients with and without brain metastases (P=0.48), respectively, while intracranial response rate and intracranial disease control rate were 67.5% and 85.0%, respect...
Source: Journal of Immunotherapy - October 7, 2020 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research
