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Non-melanoma skin cancer (NMSC) is primarily categorized into basal cell carcinoma (BCC), the most prevalent form of skin cancer, and cutaneous squamous cell carcinoma (cSCC), the second most common type. Both BCC and cSCC represent a significant health burden, particularly in immunocompromised individuals and the elderly. The immune system plays a pivotal role in the development and progression of NMSC, making it a critical focus for therapeutic interventions. This review highlights key immunological targets in BCC and cSCC, with a focus on immune checkpoint molecules such as PD-1/PD-L1 and CTLA-4, which regulate T cell activity and contribute to immune evasion. This review also highlights anti-tumor immune cell subsets within the tumor microenvironment (TME), such as tumor-infiltrating lymphocytes (TILs) and dendritic cells. Additionally, it examines the immunosuppressive elements of the TME, including regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and cancer-associated fibroblasts (CAFs), as well as their roles in NMSC progression and resistance to therapy. Emerging strategies targeting these immune elements, such as monoclonal antibodies, are also discussed for their potential to enhance anti-tumor immune responses and improve clinical outcomes. By elucidating the immunological landscape of BCC and cSCC and drawing comparisons to melanoma, this review highlights the transformative potential of immunotherapy in treating these malignancies. [ABSTRACT FROM AUTHOR]

Uveal melanoma represents a rare and aggressive subtype of melanoma with limited treatment options and poor prognosis, especially in the metastatic setting. Tebentafusp, a bispecific fusion protein, offers a promising therapeutic approach by targeting gp100, an antigen highly expressed in uveal melanoma cells, and redirecting T cell-mediated cytotoxicity towards tumor cells. This review provides an overview of the preclinical and clinical data on tebentafusp in the management of metastatic uveal melanoma. We summarize the mechanism of action, clinical efficacy, safety profile, and ongoing research efforts surrounding this innovative immunotherapy. Preclinical studies have demonstrated the ability of tebentafusp to induce potent and specific anti-tumor immune responses against gp100-expressing uveal melanoma cells. Clinical trials have shown encouraging results, with tebentafusp exhibiting meaningful clinical activity in a subset of patients with metastatic uveal melanoma. Importantly, tebentafusp has also demonstrated a manageable safety profile. By specifically targeting tumor cells expressing gp100, tebentafusp offers a promising therapeutic avenue for individuals with metastatic uveal melanoma, meeting a significant clinical need in this context. Continued clinical trials will provide additional insights into the impact of tebentafusp on treatment-resistant metastatic cutaneous melanoma. Furthermore, we are exploring the potential of T cell engagers directed against the cancer testis antigen PRAME, which could have widespread utility in the treatment of cutaneous melanoma as well as other PRAME-expressing malignancies. [ABSTRACT FROM AUTHOR]

Chemokines and cytokines represent an emerging field of immunotherapy research. They are responsible for the crosstalk and chemoattraction of immune cells and tumor cells. For instance, CXCL9/10/11 chemoattract effector CD8+ T cells to the tumor microenvironment, making an argument for their promising role as biomarkers for a favorable outcome. The cytokine Interleukin-15 (IL-15) can promote the chemokine expression of CXCR3 ligands but also XCL1, contributing to an important DC-T cell interaction. Recruited cytotoxic T cells can be clonally expanded by IL-2. Delivering or inducing these chemokines and cytokines can result in tumor shrinkage and might synergize with immune checkpoint inhibition. In addition, blocking specific chemokine and cytokine receptors such as CCR2, CCR4 or Il-6R can reduce the recruitment of tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs) or regulatory T cells (Tregs). Efforts to target these chemokines and cytokines have the potential to personalize cancer immunotherapy further and address patients that are not yet responsive because of immune cell exclusion. Targeting cytokines such as IL-6 and IL-15 is currently being evaluated in clinical trials in combination with immune checkpoint-blocking antibodies for the treatment of metastatic melanoma. The improved overall survival of melanoma patients might outweigh potential risks such as autoimmunity. However, off-target toxicity needs to be elucidated. [ABSTRACT FROM AUTHOR]

Simple Summary: The effects of immune checkpoint inhibitor (ICI) therapy on 40 melanoma patients who developed immune-related hypophysitis were examined in this study. These patients were compared to 40 matched ones who did not develop hypophysitis. The onset of hypophysitis varied depending on the type of ICI used. Symptoms commonly included fatigue, headaches, and digestive problems. Patients with hypophysitis had low T4 hormone levels regardless of ICI type. However, low T3 and TSH hormone levels were only observed in patients who developed hypophysitis from ipilimumab. A rapid drop in blood sodium levels was also noted at the time of hypophysitis diagnosis. Additionally, the number of eosinophils and lymphocytes in the blood increased consistently in hypophysitis patients. Early diagnosis of hypophysitis is important because of its potential complications. Monitoring patients for specific symptoms and blood value changes could aid in early detection, allowing for prompt intervention and management. Background: Immune checkpoint inhibitors (ICIs) have shown promising anti-tumor activities and are widely used for the treatment of advanced cancers. However, they may lead to immune-related adverse events (irAEs) and some of them, such as hypophysitis, can be life-threatening. Here, early diagnosis is critical. Methods: We retrospectively analyzed 40 melanoma patients who developed hypophysitis during ICI treatment with either ipilimumab and/or anti-PD1 therapy and compared them to 40 control patients who did not develop hypophysitis during the ICI treatment, matched for age, gender, type of immunotherapy, and stage. Clinical data and blood values such as LDH, CRP, TSH, T3, T4, and absolute immune cell counts were retrieved from the medical records. Patient characteristics, laboratory values, progression-free survival, and overall survival were compared between the two groups. Results: Patients with ir-hypophysitis had a median age of 59 years, and most of them were male. Clinically, frequent symptoms were fatigue, headache, dizziness, and gastrointestinal symptoms such as nausea or abdominal pain. The onset of ir-hypophysitis differed much between ipilimumab- (median 8 weeks) and anti-PD1 (median 40 weeks)-induced hypophysitis (p < 0.001). At baseline, besides a slightly increased CRP level (p = 0.06), no differences were observed in patients who later developed hypophysitis compared to the control. After treatment started, hypophysitis patients showed a constant and significant decline in T4 levels from the start of therapy until diagnosis (p < 0.05), independent of the ICI treatment regime. However, a decline in T3 and TSH was only noted in patients with ipilimumab-induced ir-hypophysitis. Furthermore, serum sodium levels declined rapidly at the diagnosis of hypophysitis (p < 0.001). In addition, there was a constant increase in the absolute counts of eosinophils and lymphocytes from baseline in hypophysitis patients (p < 0.05). Conclusion: Ir-hypophysitis reveals different clinical pictures and onset times depending on the ICI regime used. Whereas a drop in T4 levels was indicative of developing hypophysitis independent of the ICI regime, TSH levels only declined in patients under ipilimumab-based ICI regimes. To best monitor our patients, it is important to recognize these differences. [ABSTRACT FROM AUTHOR]

Simple Summary: Platelets express the C-type lectin-like receptor 2 (CLEC-2) that enables binding to podoplanin (PDPN)-expressing tumor cells and, thereby, promote metastatic spread. An increased level of soluble CLEC-2 was reported in patients with thromboinflammatory and malignant disease, presumably released from activated platelets. In our study, we show that in vitro platelet activation leads to a significant decrease in CLEC-2 on platelets and in the plasma. We also found decreased levels of soluble CLEC-2 in plasma samples of patients with colorectal carcinoma (stages I to IV), breast cancer or melanoma (stages I to III) compared to healthy donors. Interestingly, in patients with glioblastoma, the plasma level of soluble CLEC-2 was significantly higher. We concluded that an increased plasma level of soluble CLEC-2 is not a suitable biomarker of platelet activation and tumor progression in most types of cancer. The C-type lectin-like receptor 2 (CLEC-2) is expressed on platelets and mediates binding to podoplanin (PDPN) on various cell types. The binding to circulating tumor cells (CTCs) leads to platelet activation and promotes metastatic spread. An increased level of soluble CLEC-2 (sCLEC-2), presumably released from activated platelets, was shown in patients with thromboinflammatory and malignant disease. However, the functional role of sCLEC-2 and the mechanism of sCLEC-2 release are not known. In this study, we focused on the effect of platelet activation on CLEC-2 expression and the sCLEC-2 plasma level in patients with cancer. First, citrated blood from healthy volunteer donors (n = 20) was used to measure the effect of platelet stimulation by classical agonists and PDPN on aggregation, CLEC-2 expression on platelets with flow cytometry, sCLEC-2 release to the plasma with ELISA and total CLEC-2 expression with Western blot analysis. Second, sCLEC-2 was determined in plasma samples from healthy donors (285) and patients with colorectal carcinoma (CRC; 194), melanoma (160), breast cancer (BC; 99) or glioblastoma (49). PDPN caused a significant increase in the aggregation response induced by classical agonists. ADP or PDPN stimulation of platelets caused a significant decrease in CLEC-2 on platelets and sCLEC-2 in the plasma, whereas total CLEC-2 in platelet lysates remained the same. Thus, the increased plasma level of sCLEC-2 is not a suitable biomarker of platelet activation. In patients with CRC (median 0.9 ng/mL), melanoma (0.9 ng/mL) or BC (0.7 ng/mL), we found significantly lower sCLEC-2 levels (p < 0.0001), whereas patients with glioblastoma displayed higher levels (2.6 ng/mL; p = 0.0233) compared to healthy controls (2.1 ng/mL). The low sCLEC-2 plasma level observed in most of the tumor entities of our study presumably results from the internalization of sCLEC-2 by activated platelets or binding of sCLEC-2 to CTCs. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint blockade has dramatically improved the outcomes of patients with melanoma. Available long-term updates of clinical studies show a sustained clinical benefit for patients treated with PD-1 inhibitors such as nivolumab or pembrolizumab or for those treated with a combination of nivolumab and ipilimumab. However, about 40–50% of patients acquire resistance to therapy within five years from the start of anti-PD-1 therapy. This review assesses available definitions of the resistance and patterns of response to PD-1 immunotherapy and summarizes the potential underlying mechanisms. The available data on resistance to PD-1 therapy, medical needs and therapeutic options for melanoma patients resistant to ICI are discussed for the metastatic setting, including brain metastases, as well as for the adjuvant and neo-adjuvant settings. Available 4- and 5-year updates for progression-free and for overall survival demonstrate a lasting clinical benefit for melanoma patients receiving anti-PD-directed immune checkpoint inhibitor therapy. However, at least one-half of the patients either do not respond to therapy or relapse early or late following the initial response to therapy. Little is known about the reasons for primary and/or secondary resistance to immunotherapy and the patterns of relapse. This review, prepared by an interdisciplinary expert panel, describes the assessment of the response and classification of resistance to PD-1 therapy, briefly summarizes the potential mechanisms of resistance, and analyzes the medical needs of and therapeutic options for melanoma patients resistant to immune checkpoint inhibitors. We appraised clinical data from trials in the metastatic, adjuvant and neo-adjuvant settings to tabulate frequencies of resistance. For these three settings, the role of predictive biomarkers for resistance is critically discussed, as well as are multimodal therapeutic options or novel immunotherapeutic approaches which may help patients overcome resistance to immune checkpoint therapy. The lack of suitable biomarkers and the currently modest outcomes of novel therapeutic regimens for overcoming resistance, most of them with a PD-1 backbone, support our recommendation to include as many patients as possible in novel or ongoing clinical trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients suffering from metastasized melanoma can be treated with three different combinations of tablets ("targeted therapy"), with similar efficacy but different side effect profiles. When one of the combinations is not tolerated well, their physicians may switch to a different combination; however, it has not been evaluated whether the second combination is actually tolerated better. In this work, we collected data on 94 patients from six German cancer centers who received two different combinations of targeted melanoma therapy to figure out whether the second combination was tolerated better. We found that indeed many side effects did not occur again and the novel combination was overall tolerated better, which justifies switching the combination when a patient experiences severe side effects. However, new side effects may occur. We believe our results are important for oncologists to adequately counsel patients with poor tolerability of this commonly used melanoma treatment. Targeted therapy with BRAF and MEK inhibitors (BRAFi, MEKi) is one of the mainstays of melanoma treatment. When dose-limiting toxicity (DLT) is observed, an option represents the intra-class switch to a different BRAFi+MEKi combination. Currently, there is scarce evidence for this procedure. This is a multicenter, retrospective analysis from six German skin cancer centers of patients who received two different combinations of BRAFi and MEKi. In total, 94 patients were included: 38 patients (40%) were re-exposed with a different combination because of previous unacceptable toxicity, 51 (54%) were re-exposed after progression, and 5 (5%) were included for other reasons. Of the 44 patients with a DLT during their first BRAFi+MEKi combination, only five (11%) experienced the same DLT during their second combination. A new DLT was experienced by 13 patients (30%). Six patients (14%) had to discontinue the second BRAFi treatment due to its toxicity. Compound-specific adverse events were avoided in the majority of patients by switching to a different combination. Efficacy data were similar to historical cohorts of BRAFi+MEKi rechallenge, with an overall response rate of 31% for patients who had previously progressed to treatment. We conclude that switching to a different BRAFi+MEKi combination if dose-limiting toxicity occurs is a feasible and rational approach in patients with metastatic melanoma. [ABSTRACT FROM AUTHOR]

Simple Summary: Our study looked at the usefulness of a protein called S100 in monitoring the progression of uveal melanoma, a type of black skin cancer first growing in the eye. We found that only a small number of patients had high levels of S100 in their blood when the cancer had first spread to other organs. However, in over half of the patients, S100 levels increased as the disease progressed. Our study also looked at the expression of S100 in melanoma metastases, which are cancer cells that have spread to other parts of the body. We found that patients with strong expression of S100 in metastases always had rising levels of S100 in their blood during the course of the disease, while patients without S100 expression in metastases never showed rising S100 levels. Therefore, we concluded that S100 serum levels can be predicted by examining the expression of S100 in metastases and may be useful in monitoring disease progression, but it is not a reliable marker for early detection of the cancer. S100 protein is routinely used as a serum tumor marker in advanced cutaneous melanoma. However, there is scarce and inconclusive evidence on its value in monitoring disease progression of uveal melanoma. In this monocenter study, we retrospectively assessed the connection between documented S100 protein levels of patients suffering from stage IV uveal melanoma and the clinical course of disease. Where available, we analyzed expression of S100 in melanoma metastases by immunohistochemistry. A total of 101 patients were included, 98 had available serum S100 levels, and in 83 cases, sufficient data were available to assess a potential link of S100 with the clinical course of the uveal melanoma. Only 12 of 58 (20.7%) patients had elevated serum levels at first diagnosis of stage IV disease. During progressive disease, 54% of patients showed rising serum S100 levels, while 46% of patients did not. Tumor material of 56 patients was stained for S100. Here, 26 (46.4%) showed expression, 19 (33.9%) weak expression, and 11 (19.6%) no expression of S100. Serum S100 levels rose invariably in all patients with strong expression throughout the course of disease, while patients without S100 expression in metastases never showed rising S100 levels. Thus, the value of S100 serum levels in monitoring disease progression can be predicted by immunohistochemistry of metastases. It is not a reliable marker for early detection of advanced disease. [ABSTRACT FROM AUTHOR]

Simple Summary: Merkel cell carcinoma (MCC) is a rare, malignant primary skin tumor with high rates of recurrence and stage adapted 5-year overall survival rates around 66–75% at stage I, 50–60% at stage II, 42–52% at stage III and 17–18% at stage IV. Wide local tumor excision is indicated for localized disease, usually followed by postoperative radiotherapy of the tumor bed. A positive sentinel lymph node biopsy (SLNB) is considered a poor prognostic factor, but the only randomized controlled trial on elective lymph node irradiation was in times before introduction of SLNB in MCC, hence the management of the regional lymph nodes with respect to SLNB is currently not clear. The aim of this study was to analyze the pattern of relapse of patients with MCC that underwent surgery and postoperative radiotherapy at our institution and to determine the role of elective radiotherapy to regional lymph nodes with respect to SLNB results. The aim of this study was to analyze the pattern of relapse of patients with Merkel cell carcinoma (MCC) that underwent resection of the primary tumor site and postoperative radiotherapy at the Department of Radiation Oncology of Heidelberg University and to determine the role of the elective radiotherapy of regional lymph nodes with respect to SLNB results. A total of 57 patients were included in the present retrospective analysis. A total of 33 patients had additional lymph node irradiation (LNI); 24 had postoperative radiotherapy of the tumor bed only. Median follow-up was 43 months. Recurrence rate of the total cohort was 22.8%. Most relapses (69%) occurred in the regional nodes. Cumulative infield-tumor recurrence rate was low with 5.3%. Regional recurrence was more frequent in the cohort without LNI with 85.7% versus 37.5% with LNI. These results were similar for patients with negative sentinel lymph node (SLN) only with 80% regional relapses for those without LNI versus 33% with LNI. In conclusion, our data show that regional recurrence is the most frequent site of relapse in stage I-III MCC treated with curative intended postoperative radiotherapy and that elective irradiation of the regional lymph nodes reduces the risk of regional relapse even if the SLN was negative. [ABSTRACT FROM AUTHOR]

Simple Summary: For patients with advanced basal cell carcinoma (aBCC) limited treatment options are available. In this situation, hedgehog inhibitors (HHIs) are approved as first-line treatment. Upon treatment failure or intolerance, a second-line treatment with PD1 inhibitors (PD1i) is an option. However, no third-line treatment is established. Therefore, we collected data of patients with aBCC, who received HHI reinduction following PD1i-failure. In our cohort of 12 patients, initial HHI treatment led to partial response in 8 and disease stabilization in 4 patients. Eventual HHI discontinuation was mostly due to tumor progression. Second-line PD1i resulted in a partial response in only one patient. Four out of the twelve patients responded to HHI reinduction, with the longest follow-up period being 29 months. Thus, a sequential treatment with HHI reinduction can be a feasible treatment option in a subgroup of patients with aBCC after treatment failure of first-line HHIs as well as of second-line PD1i. For patients with advanced basal cell carcinoma (aBCC) first-line treatment with hedgehog inhibitors (HHIs) and second-line treatment with PD1 inhibitors (PD1i) is available, offering combination and sequencing options. Here, we focus on the efficacy and safety of HHI reinduction after PD1i failure. Retrospective data analysis was performed with 12 patients with aBCC (locally advanced (n = 8)/metastatic (n = 4)). These patients (male:female 6:6, median age 68 years) initially received HHIs, leading to complete/partial response (66%) or stable disease (33%). Median treatment duration was 20.8 (2–64.5) months until discontinuation due to progression (n = 8), adverse events (n = 3), or patient request (n = 1). Subsequent PD1 inhibition (pembrolizumab 42%, cemiplimab 58%) yielded a partial response (8%), stable disease (33%), or progression (59%). Median treatment duration was 4.1 (0.8–16.3) months until discontinuation due to progression (n = 9), adverse events (n = 1), patient request (n = 1), or missing drug approval (n = 1). HHI reinduction resulted in complete/partial response (33%), stable disease (50%), or progression (17%). Median treatment duration was 3.6 (1–29) months. Response duration in the four responding patients was 2–29+ months. Thus, a subgroup of patients with aBCC responded to reinduction of HHI following PD1i failure. Therefore, this sequential treatment represents a feasible treatment option. [ABSTRACT FROM AUTHOR]

Simple Summary: Cutaneous B-cell lymphomas (CBCL) are a heterogeneous group of mature B-cells neoplasms that present in the skin without evidence of nodal or systemic involvement. Despite being indolent in nature, they tend to recur in a third of patients after treatment. As repetitive treatments may be necessary for patients with CBCL, there is a need for gentle non-invasive therapy. Rituximab is a medication that targets CD20, a receptor regularly expressed on CBCL, and thereby destroys the cancerous cells. This medication can be given as an infusion into the vein or as an injection directly into the skin tumors. In this study, we found that rituximab injections have a similar efficacy compared to infusions for patients with limited CBCL lesions. Indolent cutaneous B-cell lymphomas (CBCL) are a rare disease for which the therapeutic recommendations are based on clinical reports. Recommendations for solitary lesions include surgery or irradiation. However, the high relapse rates may require less invasive repeatable therapy. This study seeks to retrospectively assess the efficacy of intralesional rituximab (ILR) for indolent CBCL when compared with intravenous rituximab (IVR). Patients treated for indolent CBCL with ILR or IVR at the Division of DermatoOncology of the University Hospital Heidelberg were eligible for this study. Characteristics of lymphoma, treatment response, and adverse events were assessed. Twenty-one patients, 67% male at a median age of 52 (range 17–80), were included. Nineteen (90%) had only localized lymphoma (stage T1 and T2). Complete response was achieved in 92% (11/12) of ILR after a median of one cycle (three injections) and 78% (7/8) of IVR patients after a median of six cycles. Half of ILR patients and 78% of IVR patients showed relapse after a median of 15 and 23 months, respectively. Adverse reactions were usually mild and were limited to the first injection of ILR. One patient with IVR contracted a pulmonary infection. ILR may be an alternative to the intravenous administration of rituximab for localized indolent CBCL. [ABSTRACT FROM AUTHOR]

Simple Summary: Local therapies are no longer an option for locally advanced basal cell carcinoma. Abnormal activation of the hedgehog signaling pathway leads to uncontrolled tumor growth. Hedgehog pathway inhibitors are an effective treatment option for this kind of tumor. However, treatment-related toxicity under long-term treatment may lead to limitations in quality of life, and thus to therapy interruption or even discontinuation. This review summarizes pertinent treatment adjustments and novel therapeutic strategies for effective treatment of locally advanced basal cell carcinoma. The first-line therapy for locally advanced basal cell carcinoma (laBCC) is Hedgehog pathway inhibitors (HHIs), as they achieve good efficacy and duration of response. However, toxicity in the course of long-term treatment may lead to a decrease in the quality of life, and consequently to interruption or even discontinuation of therapy. As HHI therapy is a balancing act between effectiveness, adverse events, quality of life, and adherence, numerous successful treatment strategies have evolved, such as dose reduction and dose interruptions with on-off treatment schedules or interruptions with re-challenge after progression. As a small percentage of patients show primary or acquired resistance to HHIs, the inhibition of programmed cell death protein 1 (PD-1) has been approved as a second-line therapy, which may also be accompanied by immune-related toxicities and non-response. Thus, optimization of current treatment schedules, novel agents, and combination strategies are urgently needed for laBCC. Here, we narratively model the treatment sequence for patients with laBCC and summarize the current state of approved treatment regimens and therapeutic strategies to optimize the long-term management of laBCC. [ABSTRACT FROM AUTHOR]

Simple Summary: Knowledge on the real-world outcomes of patients with advanced melanoma and the value of different endpoints for evaluating survival benefits is limited. We investigated the outcomes and different surrogate endpoints for overall survival (OS) in 664 pembrolizumab-treated patients with advanced melanoma in Germany. Our findings support the effectiveness of pembrolizumab in real-world clinical practice. The real-world time to next treatment was most strongly correlated with OS, suggesting it as a valuable surrogate endpoint to assess treatment effectiveness. Real-world studies assessing time to next treatment could support clinical and payer decision making. Knowledge on the real-world characteristics and outcomes of pembrolizumab-treated advanced melanoma patients in Germany and on the value of different real-world endpoints as surrogates for overall survival (OS) is limited. A sample of 664 pembrolizumab-treated patients with advanced melanoma from the German registry ADOReg was used. We examined OS, real-world progression-free survival (rwPFS), real-world time to next treatment (rwTtNT), and real-world time on treatment (rwToT). Spearman's rank and iterative multiple imputation (IMI)-based correlation coefficients were computed between the OS and the rwPFS, rwTtNT, and rwToT and reported for the first line of therapy and the overall sample. The median OS was 30.5 (95%CI 25.0–35.4) months, the rwPFS was 3.9 months (95%CI 3.5–4.9), the rwTtNT was 10.7 months (95%CI 9.0–12.9), and the rwToT was 6.2 months (95%CI 5.1–6.8). The rwTtNT showed the highest correlation with the OS based on the IMI (rIMI = 0.83), Spearman rank correlations (rs = 0.74), followed by the rwToT (rIMI = 0.74 and rs = 0.65) and rwPFS (rIMI = 0.69 and rs = 0.56). The estimates for the outcomes and correlations were similar for the overall sample and those in first-line therapy. The median OS was higher compared to recent real-world studies, supporting the effectiveness of pembrolizumab in regular clinical practice. The rwTtNT may be a valuable OS surrogate, considering the highest correlation was observed with the OS among the investigated real-world endpoints. [ABSTRACT FROM AUTHOR]

Simple Summary: Technical advances in immunotherapies have led to the development of novel T cell receptor (TCR)-based approaches to fight cancer. One of these therapies, tebentafusp, has shown a significant benefit in the overall survival of uveal melanoma patients for the first time. This review focuses on TCR-directed therapies in the treatment of uveal melanoma. Metastatic uveal melanoma (mUM) is one of the most rapidly progressing tumors, with a bad prognosis and no standard-of-care treatment. Immune checkpoint inhibitors have revolutionized cancer therapy and improved overall survival in patients with metastatic cutaneous melanoma (mCM). However, this approach has been largely unimpressive, with no significant impact on the survival of mUM patients. Technical advances in immunotherapies have led to the development of novel T cell receptor (TCR)-based approaches to fight cancer. For the first time in over 50 years, compelling evidence demonstrates the power of TCR-based approaches for survival in mUM patients. Hence, this review summarizes novel TCR-based immunotherapeutic strategies currently in clinical studies for mUM treatment. We also discuss the potential combinational treatments to these strategies to maximize the clinical benefits. [ABSTRACT FROM AUTHOR]

The impact of age on the clinical benefit of anti-PD1 immunotherapy in advanced melanoma patients has been evolving recently. Due to a reduced immune function in elderly patients, young patients with a robust immune system are theoretically expected to benefit more from the treatment approach. However, in contrast to this hypothesis, recent studies in patients with metastatic melanoma have demonstrated that immunotherapy, especially with anti-PD1 treatment, is less effective in patients below 65 years, on average, with significantly lower responses and reduced overall survival compared to patients above 65 years of age. Besides, data on young patients are even more sparse. Hence, in this review, we will focus on age-dependent differences in the previously described resistance mechanisms to the treatment and discuss the development of potential combination treatment strategies for enhancing the anti-tumor efficacy of anti-PD1 or PDL1 treatment in young melanoma patients. [ABSTRACT FROM AUTHOR]

Simple Summary: The fractal dimension (FD) and the multifractal spectrum (MFS) are nonlinear quantitative measures which express the heterogeneity in the distribution of the tracer, F-18-fluorodeoxyglucose, (18F-FDG), in the body of patients suffering from metastatic melanoma. Given the well-documented, high accumulation of the tracer in tumor/metastatic sites, the measures expressing the tracer distribution also express the extent of metastases in the body. As such, FD and MFS can be employed to detect the presence of melanoma and to monitor the therapeutic outcome using the PET-CT follow-up digitized scans of the patients. In the present study, the FD and MFS measures of patients are evaluated before and during treatment with PD-1 inhibitors and are compared with the corresponding values of healthy controls. The MFS predictions agree with the PET Response Evaluation Criteria for Immunotherapy (PERCIMT) in 81% of the cases, while the FD agrees in 77% of all cases. Therefore, the quantitative MFS is proposed as an additional, alternative biomarker for monitoring the immunotherapy outcome in melanoma patients, after treatment with PD-1 inhibitors. Longitudinal whole-body PET-CT scans with F-18-fluorodeoxyglucose (18F-FDG) in patients suffering from metastatic melanoma were analyzed and the tracer distribution in patients was compared with that of healthy controls. Nineteen patients with metastatic melanoma were scanned before, after two and after four cycles of treatment with PD-1 inhibitors (pembrolizumab, nivolumab) applied as monotherapy or as combination treatment with ipilimumab. For comparison eight healthy controls were analyzed. As quantitative measures for the comparison between controls and patients, the nonlinear fractal dimension (FD) and multifractal spectrum (MFS) were calculated from the digitized PET-CT scans. The FD and MFS measures, which capture the dispersion of the tracer in the body, decreased with disease progression, since the tracer particles tended to accumulate around metastatic sites in patients, while the measures increased when the patients' clinical condition ameliorate. The MFS measure gave better predictions and were consistent with the PET Response Evaluation Criteria for Immunotherapy (PERCIMT) in 81% of the cases, while FD agreed in 77% of all cases. These results agree, qualitatively, with a previous study of our group when treatment with ipilimumab monotherapy was considered. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy is the standard of care in patients harboring metastasized melanoma. However, once further tumor growth is stopped it remains unclear when immunotherapy can be safely ceased. This clinical question is increasingly raised especially in patients with a strong desire to discontinue therapy or in patients who are forced to pause treatment due to severe immune-related side effects. With our study we aim to provide data which may be helpful for clinicians and patients when treatment discontinuation is considered. Further prospective, multicenter studies are needed to further address this important clinical issue. Checkpoint inhibitors have revolutionized the treatment of patients with metastasized melanoma. However, it remains unclear when to stop treatment. We retrospectively analyzed 45 patients (median age 64 years; 58% male) with metastasized melanoma from 3 cancer centers that received checkpoint inhibitors and discontinued therapy due to either immune-related adverse events or patient decision after an (18F)2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) combined with a low-dose CT scan (FDG-PET-CT) scan without signs for disease progression. After a median of 21 (range 1–42) months of immunotherapy an FDG-PET-CT scan was performed to evaluate disease activity. In these, 32 patients (71%) showed a complete metabolic response (CMR) and 13 were classified as non-CMR. After a median follow-up of 34 (range 1–70) months, 3/32 (9%) of CMR patients and 6/13 (46%) of non-CMR patients had progressed (p = 0.007). Progression-free survival (PFS), as estimated from the date of last drug administration, was significantly longer among CMR patients than non-CMR (log-rank: p = 0.001; hazard ratio: 0.127; 95% CI: 0.032–0.511). Two-year PFS was 94% among CMR patients and 62% among non-CMR patients. Univariable Cox regression showed that metabolic response was the only parameter which predicted PFS (p = 0.004). Multivariate analysis revealed that metabolic response predicted disease progression (p = 0.008). In conclusion, our findings suggest that patients with CMR in an FDG-PET-CT scan may have a favorable outcome even if checkpoint inhibition is discontinued. [ABSTRACT FROM AUTHOR]

Simple Summary: The potential interference at the immune response level between COVID-19 and cancer therapy raises key clinical questions and points out scientific issues that need to be promptly addressed. Among the therapeutic strategies available in oncological clinics, major concerns are raised by immunomodulatory drugs and, particularly, by immune checkpoint inhibitors (ICIs), which currently constitute a crucial drug in the management of several types of advanced and metastatic solid tumors. To date, the debate about the real impact of ICIs on the clinical outcome of COVID infection is still open. Here, we report and review the results of pertinent studies designed to evaluate the relationships between ICI treatment and COVID-19. Since the start of the global spread of coronavirus disease (COVID-19) pandemic, cancer patients were identified as a specifically susceptible subgroup of the patient population. Several reports have shown that cancer patients have an increased risk of both contracting the infection and of experiencing a more severe disease course, with a rapidly evolving picture associated with higher mortality. The assumption of cancer patients as "COVID-19 vulnerable" has led, irretrievably, to profound changes in the decision making of oncological treatments. Potential justifications for such concerns encompass the cancer-dependent suppression of the immune response, as well as the influence of administration of systemic anticancer treatments, including chemotherapy and immunotherapy. Nevertheless, to date, it is not clear whether the use of immune checkpoint inhibitors (ICIs) in cancer patients is safe, given their modulating effects on the immune system, or that they may rather conceal detrimental consequences. Theoretically, on the one hand, ICIs may enhance the immunological control of viral infections through their immunostimulating mechanisms; on the other hand, they could contribute to the hyper-inflammatory phase of COVID-19, worsening its clinical outcomes. In this study, we report the foremost clinical observations on the safety of ICI administration in cancer patients affected by COVID-19. [ABSTRACT FROM AUTHOR]

Tumor antigen-specific redirection of cytotoxic T cells (CTLs) or natural killer (NK) cells including chimeric antigen receptor (CAR-) and T cell receptor (TCR-) cell therapy is currently being evaluated in different tumor entities including melanoma. Expression of melanoma-specific antigen recognized by the respective CAR or TCR directly or presented by HLA molecules is an indispensable prerequisite for this innovative therapy. In this study, we investigated in 168 FFPE tumor specimens of patients with stage I-IV melanoma the protein expression of HER2, TRP2, ABCB5, gp100, p53, and GD2 by immunohistochemistry (IHC). These results were correlated with clinical parameters. Membrane expression of HER2 and GD2 was also investigated in ten melanoma cell lines by flow cytometry for which corresponding tumors were analyzed by IHC. Our results demonstrated that gp100 was the most frequently overexpressed protein (61%), followed by TRP2 (50%), GD2 (38%), p53 (37%), ABCB5 (17%), and HER2 (3%). TRP2 expression was higher in primary tumors compared to metastases (p = 0.005). Accordingly, TRP2 and ABCB5 expression was significantly associated with lower tumor thickness of the primary (p = 0.013 and p = 0.025). There was no association between protein expression levels and survival in advanced melanoma patients. Flow cytometric analysis revealed abundant surface expression of GD2 and HER2 in all melanoma cell lines. The discordant HER2 expression in situ and in vitro suggests a tissue culture associated induction. In summary, our data support the use of gp100 and GD2 as a potential target for developing engineered TCR- or CAR-cell therapies, respectively, against melanoma. [ABSTRACT FROM AUTHOR]

Simple Summary: The reliable and early during-the-course-of-treatment assessment of tumor response to the novel immunotherapeutic agents is a matter of debate, posing relevant challenges to conventional imaging modalities. In this prospective study, including 25 metastatic melanoma patients, we explored the prognostic significance of quantitative, dynamic 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) performed early during programmed cell death protein 1 (PD-1) blockade. At a median follow-up of 24.2 months, several semiquantitative and quantitative PET/CT parameters derived from tumor lesions and reference tissues had an impact on progression-free survival (PFS). In particular, 18F-FDG standardized uptake value (SUVmean, SUVmax) and fractal dimension (FD) of melanoma lesions adversely affected PFS, while FD of the thyroid, as well as SUVmax and k3 of the bone marrow, positively affected PFS. These findings underline the potential predictive role of quantitative, dynamic, interim PET/CT—performed in combination with conventional, static, whole-body PET/CT—in metastatic melanoma patients under PD-1 blockade. The advent of novel immune checkpoint inhibitors has led to unprecedented survival rates in advanced melanoma. At the same time, it has raised relevant challenges in the interpretation of treatment response by conventional imaging approaches. In the present prospective study, we explored the predictive role of quantitative, dynamic 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) performed early during immunotherapy in metastatic melanoma patients receiving treatment with programmed cell death protein 1 (PD-1) inhibitors. Twenty-five patients under PD-1 blockade underwent dynamic and static 18F-FDG PET/CT before the start of treatment (baseline PET/CT) and after the initial two cycles of therapy (interim PET/CT). The impact of semiquantitatively (standardized uptake value, SUV) and quantitatively (based on compartment modeling and fractal analysis) derived PET/CT parameters, both from melanoma lesions and different reference tissues, on progression-free survival (PFS) was analyzed. At a median follow-up of 24.2 months, survival analysis revealed that the interim PET/CT parameters SUVmean, SUVmax and fractal dimension (FD) of the hottest melanoma lesions adversely affected PFS, while the parameters FD of the thyroid, as well as SUVmax and k3 of the bone marrow positively affected PFS. The herein presented findings highlight the potential predictive role of quantitative, dynamic, interim PET/CT in metastatic melanoma under PD-1 blockade. Therefore, dynamic PET/CT could be performed in selected oncological cases in combination with static, whole-body PET/CT in order to enhance the diagnostic certainty offered by conventional imaging and yield additional information regarding specific molecular and pathophysiological mechanisms involved in tumor biology and response to treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: BRAF inhibitors (BRAFi) are standard of care for BRAF-mutated metastatic melanoma (MM). One of the most common side effects is arthralgia, for which a high incidence has been described, but whose clinical presentation and management have not yet been characterized. The aim of this retrospective study was to assess the patterns and clinical course of this drug-induced joint pain and to discuss a potential pathogenesis based on our clinical findings. In our cohort of patients treated with BRAFi between 2010 and 2018, 48 of 154 (31%) patients suffered from new-onset joint pain, which primarily affected small joints with a symmetrical pattern, as can be observed in patients affected by rheumatoid arthritis, the most frequent rheumatic and musculoskeletal disease. Most cases were sufficiently treated by non-steroidal anti-inflammatory drugs; however, some patients required dose reduction or permanent discontinuation of the BRAFi. Interestingly, we found that the occurrence of arthralgia was associated with better tumor control. Introduction: BRAF inhibitors (BRAFi), commonly used in BRAF-mutated metastatic melanoma (MM) treatment, frequently cause arthralgia. Although this is one of the most common side effects, it has not been characterized yet. Methods: We retrospectively included all patients treated with BRAFi +/− MEK inhibitors (MEKi) for MM at the National Center for Tumor Diseases (Heidelberg) between 2010 and 2018 and reviewed patient charts for the occurrence and management of arthralgia. The evaluation was supplemented by an analysis of frozen sera. Results: We included 154 patients (63% males); 31% (48/154) of them reported arthralgia with a median onset of 21 days after the start of the therapy. Arthralgia mostly affected small joints (27/36, 75%) and less frequently large joints (19/36, 53%). The most commonly affected joints were in fingers (19/36, 53%), wrists (16/36, 44%), and knees (12/36, 33%). In 67% (24/36) of the patients, arthralgia occurred with a symmetrical polyarthritis, mainly of small joints, resembling the pattern typically observed in patients affected by rheumatoid arthritis (RA), for which a role of the MAPK signaling pathway was previously described. Patients were negative for antinuclear antibodies, anti-citrullinated protein antibodies, and rheumatoid factor; arthritis was visible in 10 of 13 available PET–CT scans. The development of arthralgia was linked to better progression-free survival and overall survival. Conclusion: Arthralgia is a common side effect in patients receiving BRAFi +/− MEKi therapy and often presents a clinical pattern similar to that observed in RA patients. Its occurrence was associated with longer-lasting tumor control. [ABSTRACT FROM AUTHOR]

Simple Summary: There is currently no consensus on a widely accepted algorithm for imaging Merkel cell carcinoma (MCC) patients. Baseline, tomographic imaging is not generally recommended in early-stage disease, but its value in locally advanced and/or distant metastatic MCC has been well established. In this context, the hybrid imaging modality positron emission tomography/computed tomography (PET/CT) is increasingly applied in the workup of metastatic or unresectable MCC, providing essential information for staging, restaging, and treatment monitoring of the disease. Although the role of PET/CT in the management of loco-regional MCC is still limited and less well-defined, current evidence suggests its important contribution also in cases of localized MCC. Herein, we provide a structured literature review summarizing the most important studies on the role of PET or PET/CT with different radiopharmaceuticals in the clinical care of MCC. Merkel cell carcinoma (MCC) is a rare neuroendocrine skin malignancy usually arising as a nonspecific nodule on sun-exposed areas of the head and neck. Given the poor prognosis of this aggressive tumor, assessment of disease burden in pre- and post-treatment care may ensure an optimal management with significant implications for patient surveillance and prognosis. Although imaging has established its role in locally advanced or distant metastatic MCC, a standard imaging algorithm is yet to be determined and respective recommendations are mainly based on melanoma. Positron emission tomography/computed tomography (PET/CT) is increasingly evolving as a valuable imaging tool in metastatic or unresectable MCC, mostly utilizing the glucose analogue 18F-fluorodeoxyglucose (18F-FDG) as a radiotracer. Despite being inferior in detecting the disease in its early stages compared to the "gold standard" of sentinel lymph node biopsy, recent evidence suggests an important role for 18F-FDG PET/CT in the routine workup of localized MCC. Moreover, 68Ga-labeled somatostatin analogues have been employed as PET tracers in the field of MCC with promising, yet comparable to 18F-FDG, results. This article provides a structured literature review of the most important studies investigating the role of PET or PET/CT in the clinical practice of MCC. [ABSTRACT FROM AUTHOR]

Patient-centered motives and expectations of the treatment of actinic keratoses (AK) have received little attention until now. Hence, we aimed to profile and cluster treatment motivations and expectations among patients with AK in a nationwide multicenter, cross-sectional study including patients from 14 German skin cancer centers. Patients were asked to complete a self-administered questionnaire. Treatment motives and expectations towards AK management were measured on a visual analogue scale from 1–10. Specific patient profiles were investigated with subgroup and correlation analysis. Overall, 403 patients were included. The highest motivation values were obtained for the items "avoid transition to invasive squamous cell carcinoma" (mean ± standard deviation; 8.98 ± 1.46), "AK are considered precancerous lesions" (8.72 ± 1.34) and "treating physician recommends treatment" (8.10 ± 2.37; p < 0.0001). The highest expectation values were observed for the items "effective lesion clearance" (8.36 ± 1.99), "safety" (8.20 ± 2.03) and "treatment-related costs are covered by health insurance" (8.00 ± 2.41; p < 0.0001). Patients aged ≥77 years and those with ≥7 lesions were identified at high risk of not undergoing any treatment due to intrinsic and extrinsic motivation deficits. Heat mapping of correlation analysis revealed four clusters with distinct motivation and expectation profiles. This study provides a patient-based heuristic tool for a personalized treatment decision in patients with AK. [ABSTRACT FROM AUTHOR]

Background: Uveal melanoma is the most common primary intraocular malignancy among adults. It is, nevertheless, a rare disease, with an incidence of approximately one case per 100,000 individuals per year in Europe. Approximately half of tumors will eventually metastasize, and the liver is the organ usually affected. No standard-of-care treatment exists for metastasized uveal melanoma. Chemotherapies or liver-directed treatments do not usually result in long-term tumor control. Immunotherapies are currently the most promising therapy option available. Methods: We reviewed both relevant recent literature on PubMed concerning the treatment of uveal melanoma with immunotherapies, and currently investigated drugs on ClinicalTrials.gov. Our own experiences with immune checkpoint blockers are included in a case series of 20 patients. Results: Because few clinical trials have been conducted for metastasized uveal melanoma, no definitive treatment strategy exists for this rare disease. The outcomes of most immunotherapies are poor, especially compared with cutaneous melanoma. However, encouraging results have been found for some very recently investigated agents such as the bispecific tebentafusp, for which a remarkably increased one-year overall survival rate, and similarly increased disease control rate, were observed in early phase studies. Conclusions: The treatment of metastatic uveal melanoma remains challenging, and almost all patients still die from the disease. Long-term responses might be achievable by means of new immunological strategies. Patients should therefore be referred to large medical centers where they can take part in controlled clinical studies. [ABSTRACT FROM AUTHOR]

Recent studies suggest that combining nivolumab with ipilimumab is a more effective treatment for melanoma patients, compared to using ipilimumab or nivolumab alone. However, treatment with these immunotherapeutic agents is frequently associated with increased risk of toxicity, and (auto-) immune-related adverse events. The precise pathophysiologic mechanisms of these events are not yet clear, and evidence from clinical trials and translational studies remains limited. Our retrospective analysis of ~7700 metastatic melanoma patients treated with ipilimumab and/or nivolumab from the FDA Adverse Event Reporting System (FAERS) demonstrates that the identified immune-related reactions are specific to ipilimumab and/or nivolumab, and that when the two agents are administered together, their safety profile combines reactions from each drug alone. While more prospective studies are needed to characterize the safety of ipilimumab and nivolumab, the present work constitutes perhaps the first effort to examine the safety of these drugs and their combination based on computational evidence from real world post marketing data. [ABSTRACT FROM AUTHOR]

Re-induction with immune checkpoint blockade (ICB) needs to be considered in many patients with uveal melanoma (UM) due to limited systemic treatment options. Here, we provide hitherto the first analysis of ICB re-induction in UM. A total of 177 patients with metastatic UM treated with ICB were included from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of ICB re-induction, two cohorts were compared: patients who received at least one ICB re-induction (cohort A, n = 52) versus those who received only one treatment line of ICB (cohort B, n = 125). In cohort A, a transient benefit of overall survival (OS) was observed at 6 and 12 months after the treatment start of ICB. There was no significant difference in OS between both groups ( p = 0.1) with a median OS of 16.2 months (cohort A, 95% CI: 11.1-23.8) versus 9.4 months (cohort B, 95% CI: 6.1-14.9). Patients receiving re-induction of ICB (cohort A) had similar response rates compared to those receiving ICB once. Re-induction of ICB may yield a clinical benefit for a small subgroup of patients even after resistance or development of toxicities.

Background: Since there is no standardized and effective treatment for advanced uveal melanoma (UM), the prognosis is dismal once metastases develop. Due to the availability of immune checkpoint blockade (ICB) in the real-world setting, the prognosis of metastatic UM has improved. However, it is unclear how the presence of hepatic and extrahepatic metastasis impacts the response and survival after ICB., Methods: A total of 178 patients with metastatic UM treated with ICB were included in this analysis. Patients were recruited from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of hepatic metastasis, two cohorts were compared: patients with liver metastasis only (cohort A, n = 55) versus those with both liver and extra-hepatic metastasis (cohort B, n = 123). Data were analyzed in both cohorts for response to treatment, progression-free survival (PFS), and overall survival (OS). The survival and progression probabilities were calculated with the Kaplan-Meier method. Log-rank tests, χ 2 tests, and t-tests were performed to detect significant differences between both cohorts., Results: The median OS of the overall population was 16 months (95% CI 13.4-23.7) and the median PFS, 2.8 months (95% CI 2.5-3.0). The median OS was longer in cohort B than in cohort A (18.2 vs. 6.1 months; p = 0.071). The best objective response rate to dual ICB was 13.8% and to anti-PD-1 monotherapy 8.9% in the entire population. Patients with liver metastases only had a lower response to dual ICB, yet without significance (cohort A 8.7% vs. cohort B 16.7%; p = 0.45). Adverse events (AE) occurred in 41.6%. Severe AE were observed in 26.3% and evenly distributed between both cohorts., Conclusion: The survival of this large cohort of patients with advanced UM was more favorable than reported in previous benchmark studies. Patients with both hepatic and extrahepatic metastasis showed more favorable survival and higher response to dual ICB than those with hepatic metastasis only.