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Use of Immunotherapy in Gynaecological and Breast Cancer
Published in Shazia Rashid, Ankur Saxena, Sabia Rashid, Latest Advances in Diagnosis and Treatment of Women-Associated Cancers, 2022
Showket Hussain, Sandeep Sisodiya, Vishakha Kasherwal, Sonam Tulsyan, Asiya Khan
LAG3 is another potent immunotherapeutic target found on the activated immune cells, especially on NK cells and T-cell lines [30]. LAG3 possesses a higher affinity than CD4 and is shown to be the probable receptor for MHC class II molecules. LAG-3 is claimed to inhibit various cellular processes like homeostasis of T cells, their proliferation and activation and is also known to contribute significantly towards the suppression behaviour of Tregs. A study on the soluble version of LAG-3 IMP321 suggested that no significant adverse events were found to be associated, and it can be used as a future treatment for breast cancer [31]. Till now, no LAG-3–based approved drugs are available in the market, but several clinical trials to ICI are ongoing.
Cardiovascular Complications of Immune Checkpoint Inhibitors
Published in Shyam S. Bansal, Immune Cells, Inflammation, and Cardiovascular Diseases, 2022
Sultan Tousif, Anand Prakash Singh, Prachi Umbarkar, Hind Lal
Immune checkpoint blockades employing antibodies against TIM-3, VISTA, BTLA-B, and LAG-3 are under investigation and have shown promising results in preclinical studies [54]. TIM-3 includes IC inhibitory molecules predominantly expressed on CD4+ helper T cells and CD8+ T cells. TIM-3 binds with its ligand galectin-9 expressed on tumor cells and inhibits T cell proliferation [55]. Its blockade promotes hyperproliferation of T cells and results in improved antitumor immunity [56]. VISTA is primarily expressed on tumor cells and shares homology with PD-L1. Its blockade facilitates the infiltration and activation of T cells in TME and subsequently leads to better antitumor immunity [57]. T cell lymphocyte attenuator (BTLA) is a co-inhibitory molecule expressed on T cells that engage with the B7 superfamily of ligands on APCs and the TNF superfamily. Blocking of BTLA-B leads to better antitumor immune response through enhancement of CD8+ T cell function [58]. Lymphocyte-activation gene 3 (LAG-3), mostly expressed on B cells but to a lesser extent on T cells, induces inhibitory signals in T cells upon MHC-II interaction. Combination treatment employing LAG-3 blockade and anti-PD-1 (nivolumab) has shown promising results in patients with advanced melanoma and those who had no response with anti-PD-1 monotherapy [54]. The therapeutic potential of several other IC targets is currently being investigated in preclinical models and clinical studies. A deeper understanding of the underlying biology of immune checkpoint molecules will aid in the rational development of new inhibitors.
Biologically Targeted Agents in Head and Neck Cancers
Published in John C Watkinson, Raymond W Clarke, Terry M Jones, Vinidh Paleri, Nicholas White, Tim Woolford, Head & Neck Surgery Plastic Surgery, 2018
Kevin J. Harrington, Magnus T. Dillon
In addition to these two pathways, a large number of other checkpoints have been described at the immune checkpoint (e.g. TIM3, LAG3, OX40, GITR). Some of these checkpoints lead to inhibition and others to activation of immune responses. A large number of new therapeutic agents are currently in preclinical or clinical development and it is likely that some of these will reach the clinic in the next few years.
Investigational immunomodulatory drugs for enhancement of triple negative breast cancer (TNBC) immunotherapy: early phase development
Published in Expert Opinion on Investigational Drugs, 2022
Paolo Tarantino, Gabriele Antonarelli, Liliana Ascione, Giuseppe Curigliano
LAG-3 (lymphocyte activation gene-3, CD223) is an inhibitory co-receptor involved in immunotolerance, expressed on activated T-cells, NK cells, dendritic cells and activated B-cells. Its main ligands are the MHC II molecules; after binding, it induces a downregulation of T-cells proliferation and activation while concomitantly stimulating the suppressive function of T regulatory cells [74]. Preclinical data demonstrated a coexpression of LAG-3 and PD-1 on TILs, with dual blockade of both molecules showing to limit tumor growth and activate antitumor immunity [75]. Notably, a strong association between the expression of LAG-3 and PD-1 in TILs was also observed in a cohort of breast cancer specimens; the same study suggested that the presence of LAG-3+ TILs was relatively uncommon, mostly detected in ER-negative tumors [76].
Expression of the immune checkpoint receptors PD-1, LAG3, and TIM3 in the immune context of stage II and III gastric cancer by using single and chromogenic multiplex immunohistochemistry
Published in OncoImmunology, 2021
Yujun Park, An Na Seo, Jiwon Koh, Soo Kyoung Nam, Yoonjin Kwak, Sang-Hoon Ahn, Do Joong Park, Hyung-Ho Kim, Hye Seung Lee
In addition to PD-1, several immune checkpoint receptors (ICRs) control T cell-mediated cytotoxic reactions, including lymphocyte activation gene-3 (LAG3) and T cell immunoglobulin and mucin domain 3 (TIM3). LAG3 is a potential cancer immunotherapeutic target because it regulates T cell activity. It is structurally similar to CD4,7 binds to MHC class II molecules expressed by antigen-presenting cells or aberrantly by cancer cells, and mediates an intrinsic negative inhibitory signal, resulting in immune tolerance and immune evasion of cancer cells.8 LAG3 is expressed on activated human T and NK cells.9 TIM3 is a member of the TIM gene family and plays a role in suppressing T cell responses and inducing peripheral immune tolerance.10 It is predominantly expressed in tumor-infiltrating lymphocytes (TILs) of various cancers including prostate cancer, renal cell carcinoma, colorectal cancer, and cervical cancer.11 However, a comprehensive analysis of the expression of these ICRs in GC is lacking, especially regarding the expression status when considering intratumoral heterogeneity and clinicopathologic implications.
Soluble immune checkpoints and T-cell subsets in blood as biomarkers for resistance to immunotherapy in melanoma patients
Published in OncoImmunology, 2021
Devayani Machiraju, Melanie Wiecken, Nina Lang, Ingrid Hülsmeyer, Jasmin Roth, Timo E. Schank, Rosa Eurich, Niels Halama, Alexander Enk, Jessica C. Hassel
Targeting next generation immune checkpoints such as LAG3 has demonstrated the ability to enhance the efficacy of PD-1 blockade in many models, including a phase 1/2 clinical trial in solid tumors (ESMO 2017).35 Our study results suggest that high circulating sLAG3 in patients might impair effectiveness to anti-PD1 Abs, theoretically these patients might therefore benefit from the combination with a LAG3 inhibitor. Accordingly, nonresponding patients to ipilimumab plus nivolumab combination treatment also had a detectable amount of LAG3 on circulating T cells, which further supports the use of combinational treatment with LAG3 inhibitors for maximum clinical benefit in these patients. However, the impact of neutralizing sLAG3 with LAG3 inhibitors should be further investigated to understand the functional role of sLAG3 in anti-PD1 resistant patients.