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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Tremelimumab (formerly ticilimumab, CP-675206) is a fully human anti-CTLA-4 IgG2 monoclonal antibody being developed by Pfizer for its potential therapeutic application in melanoma, non-small-cell lung cancer (NSCLC) and colorectal cancer. Tremelimumab blocks the binding of the antigen-presenting cell ligands B7.1 and B7.2 to CTLA-4, resulting in inhibition of B7-CTLA-4-mediated down-regulation of T-cell activation. Subsequently, B7.1 or B7.2 may interact with another T-cell surface receptor protein, CD28, resulting in a B7-CD28-mediated T-cell activation unopposed by B7-CTLA-4-mediated inhibition. Thus, tremelimumab is thought to stimulate patients’ immune systems to attack their tumors.
Immunotherapy
Published in Prakash Srinivasan Timiri Shanmugam, Understanding Cancer Therapies, 2018
Sowmiya Renjith, Sathya Chandran
It is now evident that tumors co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumor antigens. Because many of the immune checkpoints are triggered by ligand-receptor interactions, they can be actively blocked by antibodies or manipulated by recombinant forms of ligands or receptors. Ipilimumab, a mAb against CTLA-4 that has acquired FDA approval for metastatic melanoma, is presently being evaluated in clinical trials along with cetuximab and intensity-modulated radiation therapy (IMRT) in individuals with advanced HNSCC (NCT01860430 and NCT01935921). A phase 1, open-label, dose escalation study of MGA271 (enoblituzumab, a humanized mAb against CD276 [B7-H3] in combination with ipilimumab in patients with B7-H3–expressing HNSCC and other solid tumors) is also proceeding (NCT02381314). Tremelimumab is another anti-CTLA4 antibody presently being assessed in clinical trials.
Diffuse malignant peritoneal mesothelioma: Current concepts in evaluation and management
Published in Wim P. Ceelen, Edward A. Levine, Intraperitoneal Cancer Therapy, 2015
Keli M. Turner, H. Richard Alexander
Immunotherapeutic approaches are now being tested as systemic treatment in patients with DMPM. Recently, the anti-CTLA-4 agent tremelimumab was administered to 29 patients with DMPM who had progressed after receiving a platinum-containing regimen. There were no complete responders, two partial responders, and seven patients with stable disease accounting for a disease control rate of 31%. The median overall survival (mos) was 10.7 months and the median progression-free survival was 6.2 months. The most common side effects were dermatologic and gastrointestinal, which resolved with steroids when administered [27]. This phase II study is the first to evaluate the role of an immunologic agent in patients with DMPM. While the disease control rate and median overall survival were noteworthy, further study is warranted to determine the value of this agent in the treatment of patients with peritoneal mesothelioma.
Upper gastrointestinal symptoms and associated endoscopic and histological features in patients receiving immune checkpoint inhibitors
Published in Scandinavian Journal of Gastroenterology, 2019
Tenglong Tang, Hamzah Abu-Sbeih, Wenyi Luo, Phillip Lum, Wei Qiao, Robert S. Bresalier, David M. Richards, Yinghong Wang
Immune checkpoint inhibitors (ICIs) are a new class of drug that represents one of the most exciting advances in cancer treatment [1]. ICIs upregulate the immune system to destroy cancer cells by targeting cytotoxic T-cell lymphocyte-associated protein 4 (CTLA-4), programed death receptor 1 (PD-1), or the PD-1 ligand (PD-L1). ICIs have been studied in many clinical trials for the past decade and have become the standard of care for multiple advanced tumor types [2]. Ipilimumab (anti-CTLA-4), nivolumab, pembrolizumab (anti-PD-1), and atezolizumab (anti-PD-L1) are approved by the US Food and Drug Administration (FDA) for the treatment of advanced malignancies including melanoma, solid tumors, and hematological cancers [3]. More recently approved by the FDA are durvalumab [4] (anti-PD-1) and avelumab [5] (anti-PD-L1). And, tremelimumab (anti-CTLA-4) is in late-stage development and is not yet approved by the FDA [6].
Recent developments with immunotherapy for hepatocellular carcinoma
Published in Expert Opinion on Biological Therapy, 2018
The proof of concept trial for the use of checkpoint inhibitors in HCC investigated tremelimumab in a phase 1 trial [25]. The trial enrolled 21 patients with HCC and chronic hepatitis C virus infection. The study included patients with Child-Pugh A (n = 12), as well as B cirrhosis (n = 9). All patients had advanced stage HCC and they were no candidates for locoregional treatments. Tremelimumab was administered every 90 days at a dose of 15 mg/kg intravenously until progression or untolerable toxicitiy. Tremelimumab was well tolerated without deterioration of liver function, although grade 3/4 liver enzyme elevations were noticed in 45% of patients. The objective response rate was 17% and 76% of patients achieved disease stabilization. The time to tumor progression was 6.5 months and the median overall survival was 8.2 months [25]. Currently, tremelimumab is investigated in an open label trial in advanced stage HCC alone or in combination with durvalumab (NCT02519348).
Emerging immune checkpoint inhibitors for the treatment of hepatocellular carcinoma
Published in Expert Opinion on Emerging Drugs, 2021
Landon L. Chan, Stephen L. Chan
A proof-of-concept study exploring the combination of immune checkpoint inhibitor and locoregional treatment such as TACE or ablative therapies was published in 2017 [57]. 32 patients were given tremelimumab at two dose levels (3.5 and 10 mg/kg) every 4 weeks for six doses, followed by three-monthly infusions until disease progression and intolerance. On day 36, patients underwent subtotal radiofrequency ablation or chemoablation. Subtotal ablation refers to complete treatment of a single lesion in the background of multifocal disease, leaving other lesions (both intrahepatic and extrahepatic) untreated. This group of studied patients were considered to have poor prognosis, with 21 (65.6%) patients received prior sorafenib and 21 patients (65.6%) were BCLC stage C. Of the 19 patients with lesions evaluable for response outside of the areas treated with locoregional therapy, five (26%) of them achieved partial response. Interestingly, all five patients had hepatic disease only. Median time-to-progression was 7.4 months and the median OS was 12.3 months. This combination of treatment was generally safe, with the most common severe adverse events as elevated AST (21.8%) and only 4 (13%) patients discontinued the study due to toxicity. This study demonstrated encouraging results that combining locoregional treatment and immune checkpoint inhibitors is a potentially feasible option for advanced HCC. However, as it was only a small, single-arm study, the relative contribution of locoregional treatment and immune checkpoint inhibitor to treatment response remains unclear. A randomized controlled trial would be needed to address this question.