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Immune-Related Adverse Events from Cancer Immunotherapy
Published in Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide, Clinical Innovation in Rheumatology, 2023
Currently approved ICI targets CTLA-4 and the interaction between PD-1 and its ligand PD-L1. A CTLA-4 inhibitor was first approved for use in metastatic melanoma in 2011 after Dr. Hodi and colleagues’ seminal paper demonstrating superior survival benefits of ipilimumab over standard therapy.1, 4Anti-PD(L)1 antibodies first received approval for use in 2014 following two pivotal clinical trials, KEYNOTE-001 and CheckMate-037, in unresectable metastatic melanoma (NCT01295827, NCT01721746). Since then, ICIs have gained approval for myriad tumor types including, but not limited to, the following: non-small-cell lung cancer, renal cell carcinoma, and head and neck squamous cell carcinoma.5 In fact, a cross-sectional study estimated that 44% of patients diagnosed with cancer in the United States during 2018 were eligible for checkpoint inhibitor therapy.6 Various adverse events were identified through clinical trials as well as retrospective study and research, and those with an immunological mechanism of action were termed immune-related adverse events. Diffuse rashes, fatal colitis, and unusual endocrinopathies, like hypophysitis, were among the first of the irAEs to be appreciated with CTLA-4 antibodies.1, 7–9 Then with the advent of PD-1/PD-L1 blockers, different irAEs surfaced with more cases of pneumonitis and thyroiditis.3, 10–14 However, it was not until Cappelli et al.’s systematic literature review in 2017 that rheumatology-specific irAEs were brought to light.15, 16
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
Proteins expressed on activated T-cells allow cancers to evade anti-tumour immunity by interfering with activation or effector phases of immune responses. CTLA4 is an important control mechanism that influences the immune response's activation phase, and it can switch off T-cells. MAbs that target CTLA4 are able to block this interaction and enhance T-cell activation against tumour cells. T-cells can be prevented from engaging with and/or killing a tumour cell if the tumour cell expresses PD-L1 on its surface. This negative interaction between T-cell and tumour cell can be interrupted by administration of specific MAbs that block PD-1.
Oncogenesis and Metastasis
Published in Karl H. Pang, Nadir I. Osman, James W.F. Catto, Christopher R. Chapple, Basic Urological Sciences, 2021
Immune checkpoint blockade forms the basis of immunotherapy.PD-L1 (programmed cell death protein ligand 1) on tumour cells.PD-1 (programmed cell death protein 1) on T-cells.PD-L1 and PD-1 binding results in T-cell deactivation.PD-L1 and/or PD-1 inhibitor are used in metastatic bladder/renal cancers.CTLA-4 (cytotoxic T-lymphocyte associated protein 4).Expressed by regulatory T-cells.CTLA-4 inhibitors are used in metastatic renal cancer.Inhibitors restore tumour-specific T-cell immunity.
The prognostic and therapeutic potentials of CTLA-4 in hematological malignancies
Published in Expert Opinion on Therapeutic Targets, 2022
Mohammad Sadeghi, Atefeh Khodakarami, Armin Ahmadi, Mehrdad Fathi, Jamshid Gholizadeh Navashenaq, Hamed Mohammadi, Mehdi Yousefi, Mohammad Hojjat-Farsangi, Ali Akbar Movasaghpour Akbari, Farhad Jadidi-Niaragh
In this study, notable points have been achieved that could be considered to improve CTLA-4 utilization in the future research as well as in clinical practice. It has been found that certain polymorphisms of the CTLA-4 gene could participate in the disease course and could determine the prognosis of HMs. This finding indicates that by determining the type of CTLA-4 gene polymorphisms in certain HMs, their prognosis can be identified, and targeted treatment can be performed faster. This fact also reduces the economic burden for society as well as for the patient, due to the confirmed role of CTLA-4 gene polymorphisms in the prognosis and patients’ response to treatment. Moreover, it has been inferred that CTLA-4 expression is changed in HMs and this change has a prognostic value by itself. Furthermore, the type of expressing cell (tumor or healthy immune T cell) and the type of overexpressed CTLA-4 form (flCTLA-4 or sCTLA-4) are also crucial factors in determining the patients’ prognosis that is needed to be considered to achieve the optimum results. CTLA-4 inhibition strengthens the immune system and enhances anti-tumor responses. Therefore, in each patient, CTLA-4 type and level of expression, its prognosis, and the effectiveness of CTLA-4 inhibition can also be determined in advance, whether inhibition can be beneficial or not, because, CTLA-4 inhibition is not always desirable. For instance, CTLA-4 inhibition is not helpful in CLL and ND MM [16,73]. Meanwhile, lymphomas (HL in particular) respond better to CTLA-4 inhibition.
The evolving landscape of PARP inhibitors in castration-resistant prostate cancer: a spotlight on treatment combinations
Published in Expert Review of Clinical Pharmacology, 2022
Benjamin A. Teply, Emmanuel S. Antonarakis
Immune checkpoint inhibition with anti-CTLA4 and/or anti-PD1/L1 has dramatically changed the treatment paradigm for many cancers over the past decade. However, there is not a currently role nor any FDA-approvals for immune checkpoint inhibitors in prostate cancer despite multiple completed phase III studies [71–73]. The only exceptions are in the cases wherein mCRPC has a characteristic qualifying for pembrolizumab in a tissue-agnostic manner, that is, high tumor mutational burden or microsatellite instability. However, each study shows that there may be a specific patient population that may benefit from immune checkpoint inhibitors. Furthermore, it is an active area of investigation about whether the activity of immune checkpoint inhibitors can be improved in combination with other therapies. Multiple studies of PARP inhibitors in combination with immune checkpoint inhibitors (anti-PD1/L1) are underway.
Evaluation of Expression of LRBA and CTLA-4 Proteins in Common Variable Immunodeficiency Patients
Published in Immunological Investigations, 2022
Fereshte Salami, Saba Fekrvand, Reza Yazdani, Sepideh Shahkarami, Gholamreza Azizi, Yasser Bagheri, Samaneh Delavari, Sahar Shariati, Seyed Alireza Mahdaviani, Mohammamd Nabavi, Afshin Shirkani, Hassan Abolhassani, Morteza Samadi, Asghar Aghamohammadi
LRBA plays a crucial role in maintaining the normal function of Treg cells and its deficiency leads to humoral immunodeficiency associated with immune dysregulation (Wang and Lockey 2014). Patients with LRBA deficiency demonstrate a variety of clinical manifestations such as recurrent infections, autoimmunity, organomegaly, enteropathy, and chronic diarrhea (Azizi et al. 2017a; Azizi et al. 2018a; Habibi et al. 2019). The immunologic profile of these patients consists of hypogammaglobulinemia, CD4+ T-cell abnormalities [mostly Treg cells, T helper 17 (TH17) cells, and follicular helper T (TFH) cells], a decline in the number of natural killer cells as well as B-cell abnormalities (elevated number of CD21low B cells, diminished number of plasmablasts, class-switched and marginal-zone B cells) (Habibi et al. 2019). CTLA-4 is an immunoglobulin- related receptor that is constitutively expressed on Forkhead box P3 (FOXP3)+ Treg cells and activated conventional T cells. CTLA-4 plays an important role in the negative regulation of T cell-mediated immune responses (Rowshanravan et al. 2018). Furthermore, CTLA-4 is crucial in acting as a checkpoint in various immune responses as well as maintenance of self-tolerance so CTLA-4 deficiency results in autoimmunity (Attia et al. 2005; Lo and Abdel-Motal 2017; Tivol et al. 1995).