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Rheumatic Disease
Published in John S. Axford, Chris A. O'Callaghan, Medicine for Finals and Beyond, 2023
T-lymphocyte associated antigen 4 (CTLA4) and programmed cell death receptor 1 (PD-1) are targets for immunological checkpoint inhibition. These treatments have a dramatic impact on the care of patients with advanced melanoma and are rapidly being used for other malignancies. Treatment is associated with immune-related adverse events that may involve the skin, bowel, liver and endocrine system.
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.
Renal Cell Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Immune checkpoint inhibitors are a form of immunotherapy that target mechanisms developed by tumor cells to evade immune destruction. Nivolumab is a human monoclonal antibody against the programmed death receptor 1 (PD1). PD1 is an immunoregulatory receptor expressed on activated T-cells. Nivolumab acts to block T-cell inactivation seen following PD1 ligand (PDL1 and 2) binding and allows the immune system to mount an anti-tumor response. CTLA4 is another immunoregulatory receptor expressed on activated T-cells. The interaction of the CTLA4 with CD80/86 results in T-cell inactivation. Ipilimumab is a monoclonal antibody which acts to block this interaction.
CD29 targeted near-infrared photoimmunotherapy (NIR-PIT) in the treatment of a pigmented melanoma model
Published in OncoImmunology, 2022
Aki Furusawa, Ryuhei Okada, Fuyuki Inagaki, Hiroaki Wakiyama, Takuya Kato, Hideyuki Furumoto, Hiroshi Fukushima, Shuhei Okuyama, Peter L. Choyke, Hisataka Kobayashi
Next, we tested the combination of CD29-PIT and CD44-PIT with an anti-CTLA4 immune checkpoint inhibitor (ICI). Anti-CTLA4 ICI is known to promote anti-cancer T cell activation by blocking the suppression pathway. We expected that a combination of cancer-cell targeted NIR-PIT and anti-CTLA4 ICI would augment the anti-tumor immune activation. Anti-CTLA4 was administrated on days −1, 1 and 3 (Figure 6(a)). With anti-CTLA4 ICI alone, tumor growth was slightly suppressed. With the combination of anti-CTLA4 ICI and CD29-PIT, tumor growth was clearly suppressed compared to control and anti-CTLA4 ICI alone (Figure 6(b,c)). The combination of anti-CTLA4 ICI and CD44-PIT did not show any additional effects compared to anti-CTLA4 ICI alone. The combination therapy of anti-CTLA4 ICI and CD29-PIT significantly extended survival. However, none of the mice achieved CR (Figure 6(d)). We also tested anti-PD-1 ICI in combination with CD29-PIT (supplemental Fig. 8). Although it was not statistically significant, this combination therapy also showed a similar trend of improved tumor growth suppression. However, it did not extend the long-term survival.
Liothyronine could block the programmed death-ligand 1 (PDL1) activity: an e-Pharmacophore modeling and virtual screening study
Published in Journal of Receptors and Signal Transduction, 2022
Navid Pourzardosht, Zahra Sadat Hashemi, Maysam Mard-Soltani, Abolfazl Jahangiri, Mohammad Reza Rahbar, Alireza Zakeri, Ebrahim Mirzajani, Saeed Khalili
Currently, more than 800 clinical trials are recruiting on the PD-1/PD-L1 pathway (the information on clinical trials can be found at https://www.clinicaltrials.gov/). The high numbers of clinical trials represent a clear therapeutic interest targeting this pathway. Blocking immune checkpoint molecules by specific antibodies, which are capable of targeting CTLA-4, PD-1, and PD- L1 molecules, is currently used as monotherapy to treat various types of cancers [1,25]. The licensed antibodies include an antibody against CTLA-4 (ipilimumab in 2011); two antibodies against PD-1 (pembrolizumab and nivolumab in 2014); and an antibody against PD-L1 (atezolizumab in 2016) [26,27]. Moreover, a combination therapy harnessing both CTLA4 and PD-1 blockers have also been approved as the first-line therapy for advanced melanoma patients and other tumor types with different dose levels and intervals [28]. The combination of ICB with conventional therapy, CARs, and epigenetic therapy has also been reported.
Targeting the spectrum of immune checkpoints in prostate cancer
Published in Expert Review of Clinical Pharmacology, 2021
Laura A. Sena, Samuel R. Denmeade, Emmanuel S. Antonarakis
CTLA4 is required for maintenance of immune tolerance. Mice with genetic deletion of CTLA4 exhibit fatal systemic inflammation [4,5]. Similarly, humans with genetic disorders of CTLA4 deficiency (CTLA4 Haploinsufficiency with Autoimmune Infiltration [CHAI] disease, and LRBA deficiency with Autoantibodies, Treg defects, Autoimmune Infiltration, and Enteropathy [LATAIE] disease) exhibit immune dysregulation with autoimmune features [6]. CTLA4 restrains autoimmunity through direct inhibition of effector T cell function and indirect inhibition via activation of regulatory T cells (Tregs) [7]. Effector T cell stimulation leads to rapid upregulation of CTLA4 [8], which subsequently can inhibit T cell activation. Mechanistically, CTLA4 may both inhibit intracellular signaling downstream of the TCR and CD28 [9], as well as compete for binding of B7-1 and B7-2, sequestering them away from binding to CD28 and leading to loss of effective co-stimulation [10]. Tregs constitutively express CTLA4, which is required for their effective immune suppressive function [11,12].