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The Scientific Basis of Medicine
Published in John S. Axford, Chris A. O'Callaghan, Medicine for Finals and Beyond, 2023
Chris O'Callaghan, Rachel Allen
Although cancers are ‘self’ in origin, the molecular changes that result in tumorigenesis can result in the production of tumour-specific antigens and tumour-associated antigens which are recognized by the immune system as altered self. Cancer cells can employ a number of mechanisms to reduce their immunogenicity, including the upregulation of immune checkpoint proteins to inhibit the immune responses against the tumour and so prevent the killing of tumour cells. Checkpoint inhibitor therapies use monoclonal antibodies that specifically bind checkpoint proteins such as PD-L1 and CTLA4 and so block their ability to inhibit T cells. Checkpoint inhibitors are effective in a number of cancers, such as melanoma, but the immune activation that they cause increases the risk of autoimmune disease, such as colitis or diabetes (see Chapter 4, Rheumatic disease). Combination of checkpoint therapies is likely to increase the power of their effects, while further research is required to enhance our knowledge of immune checkpoint pathways and reduce the potential of the autoimmune related adverse events that can result from their use.
Immunotherapy in Head and Neck Cancers
Published in R James A England, Eamon Shamil, Rajeev Mathew, Manohar Bance, Pavol Surda, Jemy Jose, Omar Hilmi, Adam J Donne, Scott-Brown's Essential Otorhinolaryngology, 2022
There have been initial reports of single-agent activity in patients with relapsed/metastatic disease. For example, trials have used pembrolizumab (an anti-PD1 MAb). In the KEYN0TE-012 trial, patients with PD-L1-positive tumours were divided into HPV+ and HPV− cohorts and were treated with pembrolizumab. Overall, 26 of 51 patients had a reduction in tumour burden. There are several ongoing randomised phase II/III clinical trials with anti-PD1 agents (pembrolizumab, nivolumab, and durvalumab) in patients with relapsed/metastatic disease, and the results are likely to be reported in the next few years. The side effects of immune checkpoint inhibitors are autoimmune adverse reactions, such as skin rash, colitis, hepatitis, and endocrinopathy. In all instances, these treatments require specialist management because they can evolve into serious, even life-threatening, conditions. There is evolving work (both pre-clinical and clinical data) to demonstrate that immune checkpoint inhibition may enhance the effect of, and lead to systemic activity of, a local therapy, such as radiation. These observations, combined with the excitement over the efficacy of single-agent immune checkpoint inhibition, have led to a number of clinical studies that are combining immune checkpoint inhibitors with ionizing radiation.
BRCA Mutation and PARP Inhibitors
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Arjun Mittra, James H. Doroshow, Alice P. Chen
Immunotherapy using immune checkpoint inhibitors has revolutionized the landscape of cancer treatment. Traditional chemotherapy is designed to kill tumor cells by targeting them directly. In contrast, immunotherapies are designed to stimulate the patient’s immune system to kill the tumor cells. Tumor cells take advantage of a number of different mechanisms to escape immune recognition and killing. Some of these involve activating T-cell inhibitory (checkpoint) pathways. These pathways include programmed cell death-1 (PD-1), programmed cell death ligand-1 (PDL-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4). By inhibiting these escape pathways using checkpoint inhibitors these agents are able to stimulate tumor cell recognition and destruction [97].
Targeting CD70 in combination with chemotherapy to enhance the anti-tumor immune effects in non-small cell lung cancer
Published in OncoImmunology, 2023
Tal Flieswasser, Astrid Van den Eynde, Laurie Freire Boullosa, Jöran Melis, Christophe Hermans, Céline Merlin, Ho Wa Lau, Jonas Van Audenaerde, Filip Lardon, Evelien Smits, Patrick Pauwels, Julie Jacobs
Immunotherapy has been integrated as one of the pillars of cancer treatment in many cancer types7. Immune checkpoint inhibitors aim to treat cancer by either activating the immune system or blocking the immunosuppressive tumor microenvironment. Especially, immune checkpoint inhibitors targeting the PD-1/PD-L1 axis have shown efficacy in a broad range of tumor types, including NSCLC. It should be noted, though, that only a subset of patients responds to single agent treatment, leaving considerable room for improvement8. Inflamed tumors, which have a preexisting CD8+ T cell response to tumor cells, are limited by intra-tumoral PD-L1 expression on those cells and are therefore tackled by antibodies against PD-1/PD-L1. Alternatively, non-inflamed tumors lack the intratumoral cytotoxic T-cells9. A major challenge is how to change a non-inflamed (“cold”) tumor into an inflamed (“hot”) tumor.
Management of trophoblastic tumors : review of evidence, current practice, and future directions
Published in Expert Review of Anticancer Therapy, 2023
Antoine Deleuze, Christophe Massard, Fanny Le Du, Benoit You, Claudia Lefeuvre-Plesse, Pierre-Adrien Bolze, Thibault de la Motte Rouge
Gestational trophoblastic neoplasia (GTN) is a rare group of diseases that arise from abnormal trophoblastic proliferation following any type of pregnancy or after delivery including complete hydatidiform moles (CMH). The incidence of GTN, which includes invasive mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor, varies worldwide, and the lack of evidence-based therapeutic strategies has led to heterogeneous management of this condition. Expert networks, such as The European Organization for Treatment of Trophoblastic Disease, have helped to harmonize management and promote translational research. While chemotherapy has been the backbone of treatment for GTN since the 1970s, the lack of comparative randomized trials has made it challenging to determine the optimal regimen. Nonetheless, the promising effects of immune checkpoint inhibitors have the potential to remodel overall therapeutic strategies. As GTN is relatively unknown to many healthcare professionals, its accurate diagnosis, treatment, and follow-up care remain critical and can present challenges. This review will explore current practices, new evidence, and future directions in the management of GTN.
Optimizing outcomes and managing adverse events in locally advanced or metastatic urothelial cancer: a clinical pharmacology perspective
Published in Expert Review of Clinical Pharmacology, 2023
Pratap Singh, Anand Rotte, Anthony A. Golsorkhi, Sandhya Girish
Distribution of systemically administered immune checkpoint blockers to bladder tissues and bladder tumors is not well elucidated. Recently reported study in humanized mice showed that pembrolizumab uptake into tumors is lower compared to lymphoid tissues suggesting the need for methods to improve tumor distribution of immune checkpoint blockers [96]. Intravesical administration of immune checkpoint blockers could improve the target concentrations of the drug in the bladder and thereby potentially improve patient outcomes. A phase 1 dose escalation trial of intravesically administered pembrolizumab and BCG combination in BCG-unresponsive NMIBC patients (NCT02808143) reported results from 9 patients who completed the therapy. The study noted that intravesical administration of pembrolizumab was safe, feasible and induced anti-tumor immune responses [97]. Further studies could confirm the efficacy and safety of immune checkpoint blockers administered via intravesical route.