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Cancer is associated with higher morbidity and mortality and is the second leading cause of death in the US. Further, in some nations, cancer has overtaken heart disease as the leading cause of mortality. Identification of molecular mechanisms by which cancerous cells evade T cell-mediated cytotoxic damage has led to the modern era of immunotherapy in cancer treatment. Agents that release these immune brakes have shown activity to recover dysfunctional T cells and regress various cancer. Both cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and Programmed Death-1 (PD-1) play their role as physiologic brakes on unrestrained cytotoxic T effector function. CTLA-4 (CD 152) is a B7/CD28 family; it mediates immunosuppression by indirectly diminishing signaling through the co-stimulatory receptor CD28. Ipilimumab is the first and only FDA-approved CTLA-4 inhibitor; PD-1 is an inhibitory transmembrane protein expressed on T cells, B cells, Natural Killer cells (NKs), and Myeloid-Derived Suppressor Cells (MDSCs). Programmed Death-Ligand 1 (PD-L1) is expressed on the surface of multiple tissue types, including many tumor cells and hematopoietic cells. PD-L2 is more restricted to hematopoietic cells. Blockade of the PD-1 /PDL-1 pathway can enhance anti-tumor T cell reactivity and promotes immune control over the cancerous cells. Since the FDA approval of ipilimumab (human IgG1 k anti-CTLA-4 monoclonal antibody) in 2011, six more immune checkpoint inhibitors (ICIs) have been approved for cancer therapy. PD-1 inhibitors nivolumab, pembrolizumab, cemiplimab and PD-L1 inhibitors atezolizumab, avelumab, and durvalumab are in the current list of the approved agents in addition to ipilimumab. In this review paper, we discuss the role of each immune checkpoint inhibitor (ICI), the landmark trials which led to their FDA approval, and the strength of the evidence per National Comprehensive Cancer Network (NCCN), which is broadly utilized by medical oncologists and hematologists in their daily practice.

The development of immune checkpoint inhibitors has changed the treatment paradigm for advanced cancers across many tumor types. Despite encouraging and sometimes durable responses in a subset of patients, most patients do not respond. Tumors have adopted the PD-1/PD-L1 axis for immune escape to facilitate tumor growth, which can be leveraged as a potential target for immune checkpoint inhibitors. On this basis, PD-L1 protein expression on tumor or immune cells emerged as the first potential predictive biomarker for sensitivity to immune checkpoint blockade. The goal of our study was to evaluate PD-L1 as a predictive biomarker based on all US Food and Drug Administration (FDA) drug approvals of immune checkpoint inhibitors. We evaluated the primary studies associated with 45 FDA drug approvals from 2011 until April 2019. In total, there were approvals across 15 tumor types. Across all approvals, PD-L1 was predictive in only 28.9% of cases, and was either not predictive (53.3%) or not tested (17.8%) in the remaining cases. There were 9 FDA approvals linked to a specific PD-L1 threshold and companion diagnostic: bladder cancer (N = 3), non-small cell lung cancer (N = 3), triple-negative breast cancer (N = 1), cervical cancer (N = 1), and gastric/gastroesophageal junction cancer (N = 1) with 8 of 9 (88.9%) with immune checkpoint inhibitor monotherapy. The PD-L1 thresholds were variable both within and across tumor types using several different assays, including approvals at the following PD-L1 thresholds: 1, 5, and 50%. PD-L1 expression was also measured in a variable fashion either on tumor cells, tumor-infiltrating immune cells, or both. In conclusion, our findings indicate that PD-L1 expression as a predictive biomarker has limitations and that the decision to pursue testing must be carefully implemented for clinical decision-making.

The FDA approved a record 59 drugs last year, but the commercial potential of these drugs is lacklustre.The FDA approved a record 59 drugs last year, but the commercial potential of these drugs is lacklustre.

A multidisciplinary team (MDT) is fundamental for properly managing non-melanoma skin cancer (NMSC). Surgery is the first treatment choice for early-stage disease; however, in cases with a high risk of recurrence or when demolitive approaches would not achieve safe margins, radiotherapy (RT) or an MDT approach is required. We retrospectively revised the population evaluated at our weekly MDT meeting, and all patients were discussed. A case series of 130 patients visited from July 2021 to March 2024 was collected. In-person visits were performed. The male/female ratio was 69.5/31.5%. Elderly patients prevailed: the mean age was 79 years (range 29-102 years). Patients affected by Gorlin syndrome were 7, and solid transplant recipients were 4. Among patients, 66 were diagnosed with cutaneous squamous cell carcinoma (SCC) (58%), 52 had basal cell carcinoma (BCC) (40%), and 12 had both SCC and BCC (9.2%). Among patients with SCC, 24 received primary surgery (36.4%), 11 received RT (16.6%), and 25 were candidates for treatment with cemiplimab (37.9%). Six patients (9.1%) were indicated to undertake a dermatological follow-up associated with best supportive care for comorbidities and performance status.

Cutaneous squamous cell carcinoma (cSCC), a non-melanoma skin cancer, is a keratinocyte carcinoma representing one of the most common cancers with an increasing incidence. cSCC could be in situ (e.g., Bowen’s disease) or an invasive form. A significant cSCC risk factor is advanced age, together with cumulative sun exposure, fair skin, prolonged immunosuppression, and previous skin cancer diagnoses. Although most cSCCs can be treated by surgery, a fraction of them recur and metastasize, leading to death. cSCC could arise de novo or be the result of a progression of the actinic keratosis, an in situ carcinoma. The multistage process of cSCC development and progression is characterized by mutations in the genes involved in epidermal homeostasis and by several alterations, such as epigenetic modifications, viral infections, or microenvironmental changes. Thus, cSCC development is a gradual process with several histological- and pathological-defined stages. Dermoscopy and reflectance confocal microscopy enhanced the diagnostic accuracy of cSCC. Surgical excision is the first-line treatment for invasive cSCC. Moreover, radiotherapy may be considered as a primary treatment in patients not candidates for surgery. Extensive studies of cSCC pathogenic mechanisms identified several pharmaceutical targets and allowed the development of new systemic therapies, including immunotherapy with immune checkpoint inhibitors, such as Cemiplimab, and epidermal growth factor receptor inhibitors for metastatic and locally advanced cSCC. Furthermore, the implementation of prevention measures has been useful in patient management.

Immunotherapy has transformed the treatment landscape for a wide range of human cancers. Immune checkpoint inhibitors (ICIs), monoclonal antibodies that block the immune-regulatory \"checkpoint\" receptors CTLA-4, PD-1, or its ligand PD-L1, can produce durable responses in some patients. However, coupled with their success, these treatments commonly evoke a wide range of immune-related adverse events (irAEs) that can affect any organ system and can be treatment-limiting and life-threatening, such as diabetic ketoacidosis, which appears to be more frequent than initially described. The majority of irAEs from checkpoint blockade involve either barrier tissues (e.g., gastrointestinal mucosa or skin) or endocrine organs, although any organ system can be affected. Often, irAEs resemble spontaneous autoimmune diseases, such as inflammatory bowel disease, autoimmune thyroid disease, type 1 diabetes mellitus (T1D), and autoimmune pancreatitis. Yet whether similar molecular or pathologic mechanisms underlie these apparent autoimmune adverse events and classical autoimmune diseases is presently unknown. Interestingly, evidence links HLA alleles associated with high risk for autoimmune disease with ICI-induced T1D and colitis. Understanding the genetic risks and immunologic mechanisms driving ICI-mediated inflammatory toxicities may not only identify therapeutic targets useful for managing irAEs, but may also provide new insights into the pathoetiology and treatment of autoimmune diseases.

Immune checkpoint therapy (ICT) with a monoclonal antibody (MAb) against programmed cell death protein 1 (PD-1) is a powerful clinical treatment for tumors. Cemiplimab is a human IgG4 antibody approved in 2018 and is the first MAb proven to be effective for locally advanced basal cell carcinoma. Here, we report the crystal structure of cemiplimab bound to PD-1 and the effects of PD-1 N-glycosylation on the interactions with cemiplimab. The structure of the cemiplimab/PD-1 complex shows that cemiplimab mainly binds to PD-1 with its heavy chain, whereas the light chain serves as the predominant region to compete with the binding of PD-L1 to PD-1. The interaction network of cemiplimab to PD-1 resembles that of camrelizumab (another PD-1-binding MAb), and the N58 glycan on the BC loop of PD-1 may be involved in the interaction with cemiplimab. The binding affinity of cemiplimab with PD-1 was substantially decreased with N58-glycan-deficient PD-1, whereas the PD-1/PD-L1 blocking efficiency of cemiplimab was attenuated upon binding to the N58-glycosylation-deficient PD-1. These results indicate that both the binding and blocking efficacy of cemiplimab require the N58 glycosylation of PD-1. Taken together, these findings expand our understanding of the significance of PD-1 glycosylation in the interaction with cemiplimab.

Purpose of ReviewThe therapeutic landscape for non-melanoma skin cancer (NMSC) has recently expanded with the development of effective and targeted immunotherapy. Here, we provide an overview of the role of immunotherapy in the management of advanced cutaneous carcinomas.Recent FindingsSeveral agents were recently U.S. Food and Drug Administration (FDA)-approved for the treatment of locally advanced and metastatic cutaneous squamous cell carcinoma, Merkel cell carcinoma, and basal cell carcinoma. However, recent approvals in tissue-agnostic indications may also benefit other NMSCs including cutaneous adnexal solid tumors with high tumor mutation burdens or microsatellite instability. Furthermore, while FDA-approved indications will likely continue to expand, continued studies are needed to support the role of immunotherapy in the neoadjuvant, adjuvant, and refractory settings.SummaryImmunotherapy is emerging as the standard of care for several advanced NMSCs not amenable to surgery and radiation. Ongoing evaluation of the clinical trial landscape is needed to optimize enrollment and ensure continued innovation.

Here we describe an industry-wide collaboration aimed at assessing the binding properties of a comprehensive panel of monoclonal antibodies (mAbs) against programmed cell death protein 1 (PD-1), an important checkpoint protein in cancer immunotherapy and validated therapeutic target, with well over thirty unique mAbs either in clinical development or market-approved in the United States, the European Union or China. The binding kinetics of the PD-1/mAb interactions were measured by surface plasmon resonance (SPR) using a Carterra LSA instrument and the results were compared to data collected on a Biacore 8K. The effect of chip type on the SPR-derived binding rate constants and affinities were explored and the results compared with solution affinities from Meso Scale Discovery (MSD) and Kinetic Exclusion Assay (KinExA) experiments. When using flat chip types, the LSA and 8K platforms yielded near-identical kinetic rate and affinity constants that matched solution phase values more closely than those produced on 3D-hydrogels. Of the anti-PD-1 mAbs tested, which included a portion of those known to be in clinical development or approved, the affinities spanned from single digit picomolar to nearly 425 nM, challenging the dynamic range of our methods. The LSA instrument was also used to perform epitope binning and ligand competition studies which revealed over ten unique competitive binding profiles within this group of mAbs.