Overcoming Resistance to Immunotherapy in Advanced Cutaneous Squamous Cell Carcinoma

Abstract

Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans, and is now responsible for as many deaths as melanoma. Immunotherapy has changed the therapeutic landscape of advanced CSCC after the FDA approval of anti-PD1 molecules for the treatment of locally advanced and metastatic CSCC. However, roughly 50% of patients will not respond to this systemic treatment and even those who do respond can develop resistance over time. The etiologies of primary and secondary resistance to immunotherapy involve changes in the neoplastic cells and the tumor microenvironment. Indirect modulation of immune system activation with new therapies, such as vaccines, oncolytic viruses, and new immunotherapeutic agents, and direct modulation of tumor immunogenicity using other systemic treatments or radiotherapy are now under evaluation in combined regimens. The identification of predictors of response is an important area of research. In this review, we focus on the features associated with the response to immunotherapy, and the evaluation of combination treatments and new molecules, a more thorough knowledge of which is likely to improve the survival of patients with advanced CSCC.

Cemiplimab for Kidney Transplant Recipients With Advanced Cutaneous Squamous Cell Carcinoma

“…Furthermore, we aimed to incorporate potential biomarkers of response and kidney rejection. Similar to previous reports, 19 higher TMB and increased CD8 1 cytotoxic T lymphocytes were potential predictors of response but even patients with low PD-L1-expressing tumors experienced clinical benefit from cemiplimab in this study-acknowledging our limited sample size. It was also interesting to note that baseline tumor-derived ctDNA was not readily detectable in all patients but did seem to track with response when detected.…”

Update on the Molecular Pathology of Cutaneous Squamous Cell Carcinoma

“…Programmed cell death-1 acts as a co-inhibitory receptor because it binds to T cells by binding to the PD-L1 ligand expressed in tumor cells, thereby preventing T cell activation and immunological exhaustion. This process is called immunosurveillance [ 96 ].…”

“…Thus, the tumor markers used may be PD-L1 status, IFN gamma expression, and tumor-infiltrating lymphocytes (TILs). Liquid biopsy markers can be immunophenotypic profile, cytokines and chemokines (IL-6), and soluble markers (sCTLA4 and sPD-L1) [ 96 ].…”

Immunomodulators for Non-Melanoma Skin Cancers: Updated Perspectives

“…It is worthy to note that many immune checkpoint inhibitors have been first approved for melanoma, preceding studies looking into their efficacy for NMSC, and thus future studies are likely to investigate their role in the treatment of these malignancies. 84 , 85 …”

“…It is worthy to note that many immune checkpoint inhibitors have been first approved for melanoma, preceding studies looking into their efficacy for NMSC, and thus future studies are likely to investigate their role in the treatment of these malignancies. 84,85 The current 2.2022 NCCN guidelines recommend cemiplimab or pembrolizumab as first-line therapy for the treatment of locally advanced, recurrent, or metastatic cSCC if curative RT or surgery is not feasible. 1 (Table 1) Other treatments such as carboplatin, paclitaxel, epidermal growth factor receptor inhibitors, capecitabine, cisplatin, and 5-FU are now recommended for cSCC only if patients progress or do not respond to checkpoint inhibitors.…”