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UVA1 therapy is effective in the treatment of inflammatory and autoimmune skin diseases. The mode of action of UVA1 therapy is not completely understood and especially data on cells of the innate immune system like monocytes, which are critically involved in many inflammatory processes, are sparse. We wanted to answer the question whether UVA1 irradiation alters functional properties of human monocytes. We treated human peripheral blood monocytes in vitro with 2 J/cm

Purpose: Metastatic malignant melanoma is a devastating disease with a poor prognosis. Recent therapeutic trials have focused on immunotherapy to induce development of endogenous antitumor immune responses. To date, such protocols have shown success in activation of tumor-specific CTL but no overall improvement in survival. To kill tumor, antigen-specific CTL must efficiently target and enter tumor tissue. The purpose of this study was to examine the pathway of leukocyte migration to metastatic melanoma.Experimental design: Peripheral blood and metastatic melanoma tissues (n = 65) were evaluated for expression of adhesion molecules using immunohistochemistry of tumor sections and flow cytometry of tumor-associated and peripheral blood CTL and compared with healthy controls. CTL expressing T-cell receptors for the melanoma antigen MART-1 were identified in a subset of samples by reactivity with HLA-A2 tetramers loaded with MART-1 peptide.Results: Results show that the majority of metastatic melanoma samples examined do not express the vascular adhesion receptors E-selectin (CD62E), P-selectin (CD62P), and intercellular adhesion molecule-1 (CD54) on vessels within the tumor boundaries. Strong adhesion receptor expression was noted on vessels within adjacent tissue. Tumor-associated T lymphocytes accumulate preferentially in these adjacent areas and are not enriched for skin- or lymph node–homing receptor phenotype.Conclusion: Expression of leukocyte homing receptors is dysregulated on the vasculature of metastatic melanoma. This results in a block to recruitment of activated tumor-specific CTL to melanoma metastases and is a likely factor limiting the effectiveness of current immunotherapy protocols.

Supplementary Figures S1-S4 from T-Cell Distribution and Adhesion Receptor Expression in Metastatic Melanoma

Superficial leiomyosarcomas (LMS) are rare skin cancers (2–3% of cutaneous sarcomas) that originate from dermally located hair follicle muscles, dartos or areolar muscles (cutaneous/dermal LMS), or from vascular muscle cells of the subcutaneous adipose tissue (subcutaneous LMS). These superficial LMS are distinct from LMS of the deep soft tissues. Leiomyosarcomas are typically localized at the lower extremities, trunk or capillitium, and present as painful, erythematous to brownish nodules. Diagnosis is made by histopathology. The treatment of choice for primary LMS is complete (R0) microscopically controlled excision, with safety margins of 1 cm in dermal LMS, and 2 cm in subcutaneous LMS, if possible. Non-resectable or metastatic LMS require individual treatment decisions. After R0 resection with 1 cm safety margins, the local recurrence rate of dermal LMS is very low, and metastasis is very rare. Subcutaneous LMS, very large, or incompletely excised LMS recur and metastasize more frequently. For this reason, clinical follow-up examinations are recommended every six months for cutaneous LMS, and every three months for subcutaneous LMS within the first two years (in subcutaneous LMS including locoregional lymph node sonography). Imaging such as CT/MRI is indicated only in primary tumors with special features, recurrences, or already metastasized tumors.

BackgroundDespite the availability of effective systemic therapies, a significant number of advanced melanoma patients develops brain metastases. This study investigated differences in incidence and time to diagnosis of brain metastasis and survival outcomes dependent on the type of first-line therapy.MethodsPatients with metastatic, non-resectable melanoma (AJCCv8 stage IIIC–V) without brain metastasis at start of first-line therapy (1L-therapy) were identified from the prospective multicenter real-world skin cancer registry ADOREG. Study endpoints were incidence of brain metastasis, brain metastasis-free survival (BMFS), progression-free survival (PFS), and overall survival (OS).ResultsOf 1704 patients, 916 were BRAF wild-type (BRAFwt) and 788 were BRAF V600 mutant (BRAFmut). Median follow-up time after start of 1L-therapy was 40.4 months. BRAFwtpatients received 1L-therapy with immune checkpoint inhibitors (ICI) against CTLA-4+PD-1 (n=281) or PD-1 (n=544). In BRAFmutpatients, 1L-therapy was ICI in 415 patients (CTLA-4+PD-1, n=108; PD-1, n=264), and BRAF+MEK targeted therapy (TT) in 373 patients. After 24 months, 1L-therapy with BRAF+MEK resulted in a higher incidence of brain metastasis compared with PD-1±CTLA-4 (BRAF+MEK, 30.3%; CTLA-4+PD-1, 22.2%; PD-1, 14.0%). In multivariate analysis, BRAFmutpatients developed brain metastases earlier on 1L-therapy with BRAF+MEK than with PD-1±CTLA-4 (CTLA-4+PD-1: HR 0.560, 95% CI 0.332 to 0.945, p=0.030; PD-1: HR 0.575, 95% CI 0.372 to 0.888, p=0.013). Type of 1L-therapy, tumor stage, and age were independent prognostic factors for BMFS in BRAFmutpatients. In BRAFwtpatients, tumor stage was independently associated with longer BMFS; ECOG Performance status (ECOG-PS), lactate dehydrogenase (LDH), and tumor stage with OS. CTLA-4+PD-1 did not result in better BMFS, PFS, or OS than PD-1 in BRAFwtpatients. For BRAFmutpatients, multivariate Cox regression revealed ECOG-PS, type of 1L-therapy, tumor stage, and LDH as independent prognostic factors for PFS and OS. 1L-therapy with CTLA-4+PD-1 led to longer OS than PD-1 (HR 1.97, 95% CI 1.122 to 3.455, p=0.018) or BRAF+MEK (HR 2.41, 95% CI 1.432 to 4.054, p=0.001), without PD-1 being superior to BRAF+MEK.ConclusionsIn BRAFmutpatients 1L-therapy with PD-1±CTLA-4 ICI resulted in a delayed and less frequent development of brain metastasis compared with BRAF+MEK TT. 1L-therapy with CTLA-4+PD-1 showed superior OS compared with PD-1 and BRAF+MEK. In BRAFwtpatients, no differences in brain metastasis and survival outcomes were detected for CTLA-4+PD-1 compared with PD-1.

in press

Cutaneous T-cell lymphomas (CTCL) are rare types of non-Hodgkin lymphoma, which present in skin. Mycosis fungoides (MF) and Sézary syndrome (SS) are subtypes which make up two-thirds of all CTCL cases. The phase 3 MAVORIC study (NCT01728805) compared mogamulizumab to vorinostat in MF and SS patients, with post hoc data showing a trend for higher efficacy in mogamulizumab-treated patients as baseline blood tumour burden increases.The aim of this study was to use updated post hoc analyses in order to examine the efficacy of mogamulizumab and vorinostat in MF patients when stratified by baseline blood involvement and to determine what factors affect time-to-global and time-to-skin response to inform clinical follow-up.Post hoc analyses were carried out using data from MAVORIC. Overall response rate (ORR), progression-free survival (PFS) and time-to-next-treatment (TTNT) data were used to assess efficacy in patients with MF. Time-to-global response (TTR) was examined by disease subtype, by blood involvement in MF patients, and time-to-skin response was examined by blood involvement in MF patients.Numerically superior results were seen for ORR, PFS and TTNT in mogamulizumab-treated patients with MF compared with vorinostat, with a trend for outcomes improving with increasing baseline blood class. Statistically significant results for mogamulizumab compared with vorinostat were seen for MF B1 pts for PFS (8.43 vs. 2.83 months, p = 0.003) and TTNT (11.9 vs. 3.13 months, p = 0.002), and for MF B2 pts for ORR (46.2 vs. 9.1 months, p = 0.033).In mogamulizumab-treated MF patients, ORR and PFS were seen to improve with increasing blood involvement, which led to improved TTNT. TTR was more predictable for mogamulizumab-treated MF patients with blood involvement, and skin response may take longer than previously reported in some patients.

Objectives: Forty to sixty percent of patients with advanced melanoma show primary resistance to PD-1-based immunotherapy, 30–40% of initial responders also progress. Here, we evaluated the outcome of second-line targeted therapy (TT) after progression on PD-1-based immune checkpoint inhibition (ICI) in BRAFV600-mutated melanoma. In addition, we report data on the activity of re-exposure with PD-1-based regimes. Methods: Patients with advanced (non-resectable stage III or IV, AJCC 2017, 8th edition) melanoma progressing on PD-1-based ICI (nivolumab, pembrolizumab or ipilimumab plus nivolumab) and receiving second-line BRAF plus MEK inhibition were identified from the prospective multicenter skin cancer registry ADOREG. Results: We identified 108 patients with unresectable stage III or stage IV melanoma progressing on first-line ICI (nivolumab, pembrolizumab or ipilimumab plus nivolumab) and receiving second-line combined BRAF/MEK inhibition. Seventy-three percent of the cohort presented with primary PD-1 resistant disease. Median progression-free survival (PFS) on ICI was 2.6 (95% CI 2.2–2.9) months. Median PFS on subsequent TT was 6.6 (95% CI 5.4–7.8) months. Median OS from start of second-line TT was 16.0 (95% CI 11.2–20.8) months. The 3-year PFS and OS rates on second-line TT were 16% and 30%. The objective response rate (ORR) and disease control rate (DCR) to TT were 42.6% and 55.6%. In patients with brain metastases, the ORR and DCR were 31.4% and 43.1%. Patients without brain metastases showed an ORR and DCR of 52.6% and 66.7%, respectively. Response to first-line ICI was associated with a numerically higher ORR and DCR to second-line TT and improved OS on TT. Twenty-three patients received third-line ICI of whom two patients showed an objective response. Conclusions: BRAF plus MEK inhibition shows meaningful activity and outcome in patients with advanced melanoma resistant to anti-PD-1-based immunotherapy. Rates of long-term benefit and survival in our study were similar to those reported for treatment-naïve patients receiving first-line MAPKi.

BackgroundDespite of various therapeutic strategies, treatment of patients with melanoma brain metastasis (MBM) still is a major challenge. This study aimed at investigating the impact of type and sequence of immune checkpoint blockade (ICB) and targeted therapy (TT), radiotherapy, and surgery on the survival outcome of patients with MBM.MethodWe assessed data of 450 patients collected within the prospective multicenter real-world skin cancer registry ADOREG who were diagnosed with MBM before start of the first non-adjuvant systemic therapy. Study endpoints were progression-free survival (PFS) and overall survival (OS).ResultsOf 450 MBM patients, 175 (38.9%) received CTLA-4+PD-1 ICB, 161 (35.8%) PD-1 ICB, and 114 (25.3%) BRAF+MEK TT as first-line treatment. Additional to systemic therapy, 67.3% of the patients received radiotherapy (stereotactic radiosurgery (SRS); conventional radiotherapy (CRT)) and 24.4% had surgery of MBM. 199 patients (42.2%) received a second-line systemic therapy. Multivariate Cox regression analysis revealed the application of radiotherapy (HR for SRS: 0.213, 95% CI 0.094 to 0.485, p1 cm: 1.977, 95% CI 1.117 to 3.500, p=0.019), age (HR for age >65 years: 1.802, 95% CI 1.016 to 3.197, p=0.044), and ECOG performance status (HR for ECOG ≥2: HR: 2.615, 95% CI 1.024 to 6.676, p=0.044) as independent prognostic factors of OS on first-line therapy. The type of first-line therapy (ICB vs TT) was not independently prognostic. As second-line therapy BRAF+MEK showed the best survival outcome compared with ICB and other therapies (HR for CTLA-4+PD-1 compared with BRAF+MEK: 13.964, 95% CI 3.6 to 54.4, pConclusionsIn patients with MBM, the addition of radiotherapy resulted in a favorable OS on systemic therapy. In BRAF-mutated MBM patients, ICB as first-line therapy and BRAF+MEK as second-line therapy were associated with a significantly prolonged OS.

Background and objectives The aim of the present study was to determine the prevalence and incidence of skin cancer. Patients and methods We calculated prevalence and incidence for cutaneous melanoma (CM) and non-melanoma skin cancer (NMSC) in 2012 in Germany, using claims data of 2.1 million insured persons. In order to allow statements concerning differences between subgroups, we calculated 95 % confidence intervals. Finally, we standardized prevalence and incidence with regard to the German population. Results The prevalence and incidence of CM amounted to 0.12 % and 0.04 % and increased with age. For NMSC these measures were 0.65 % and 0.15 %. Of the prevalent and incident patients, 88.9 % and 87.4 % (CM) and 99.4 % and 98.8 % (NMSC) respectively were at early stages. A projection on the whole population resulted in 75,419 persons affected by CM and 376,004 persons affected by NMSC, including 24,075 (CM) and 84,618 (NMSC) incident patients. Conclusions In this study, we defined epidemiological measures according to the number of patients affected by skin cancer and having a medical consultation indicating a need for treatment. These results can serve in future research as a data basis for analysis of health service demand in skin cancer patients and the associated costs.

Total skin electron beam therapy (TSEBT) has proved to be a safe and effective treatment for cutaneous T‑cell lymphomas. Here, we examined the impact of this treatment on patient quality of life and outcome. Forty-four patients with mycosis fungoides (MF) or Sezary syndrome (SS) received 48 TSEBT courses with a median dose of 12 Gy within the past 8 years at our institute. Patient and treatment characteristics for these cases as well as the impact of TSEBT on quality of life and duration of response were retrospectively analyzed and compared. The median modified Severity-Weighted Assessment Tool score before the start of TSEBT was 44. The overall response rate was 88%, with a complete response (CR) rate of 33%. The median follow-up period was 13 months. The median duration of response (DOR) and progression-free survival (PFS) for the entire cohort were 10 months and 9 months, respectively. Patient-reported symptom burden was measured with the Dermatological Life Quality Index and Skindex-29 questionnaires. The mean symptom reductions were 6 ± 8 (P = 0.005) and 21 ± 24 (P = 0.002), respectively. In the Functional Assessment of Cancer Therapy-General Assessment, significant improvements in the emotional (P = 0.03) domains were observed after TSEBT. Patients who received maintenance or adjuvant treatments had a longer PFS (P = 0.01). TSEBT improved disease symptoms and significantly improved emotional domains of patients’ quality of life in patients with MF or SS. In addition, our results indicate that maintenance or adjuvant therapy after TSEBT may improve the PFS.

Lymphocytic infiltration into melanoma tissue is an important prerequisite for effective antitumoral immunity. However, analysis of human metastatic melanoma has shown that leucocyte adhesion receptor expression on melanoma blood vessels is very low or absent, thereby impairing the entry of cytotoxic lymphocytes into tumor tissue. We hypothesized that adhesion molecules can be induced on melanoma vasculature allowing better infiltration of cytotoxic lymphocytes. Quantitative real-time PCR and immunofluorescence staining indicated that the adhesion molecules ICAM-1 (CD54) and E-selectin (CD62E) can be significantly induced by intralesional application of TNF alpha in tissue from human melanoma metastases either in vitro or in vivo when grafted onto immunodeficient NSG (NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ) mice that preserved human vessels. Furthermore, activated human autologous CD3+ lymphocytes were injected intravenously into mice bearing melanoma xenografts treated with TNF-α or PBS in addition to the leucocyte chemoattractant TARC (CCL17). Significantly increased numbers of CD8+ cells were detected in TNF-α-treated melanoma metastases compared with PBS-treated controls. In addition, tumor cell apoptosis was enhanced and melanoma cell proliferation reduced as shown by TUNEL assay and KI-67 staining. We conclude that adhesion molecules can be induced on human melanoma vasculature resulting in significantly improved homing of activated autologous cytotoxic T cells to melanoma tissue and inhibition of melanoma cell proliferation. These observations should be considered when designing protocols for immunotherapy of malignant melanoma.

PD-1 inhibition (PD-1i) is the standard of care in melanoma and other malignancies. In patients with bone metastases of solid tumors, the monoclonal antibody denosumab directed against RANKL is approved for the prevention of skeletal-related events. However, RANKL is not only relevant in osteoclastogenesis, but also has immunological effects. Hence, we aimed at investigating, whether the combination of PD-1i and denosumab produces synergistic effects in metastatic melanoma treatment. We retrospectively collected and analyzed clinical data of metastatic melanoma patients with bone metastases, who received PD-1i and denosumab therapy. 29 patients were identified with a median age of 60.7 years: 20 were male and 9 were female. 20 patients (69%) were in stage IV M1c and 9 (31%) in stage IV M1d; 52% had an increased serum LDH. 24 patients (83%) received PD-1i as first-line therapy and five patients (17%) as second- or third-line therapy. 13 patients received the triple combination nivolumab, ipilimumab and denosumab (N + I+D), 16 patients received PD-1i and denosumab (PD-1i + D). Within a median follow-up time of 19.8 months, 17 patients progressed with a median time to progression of 6 months. The objective response rate was 54% in the N + I + D group and 50% in the PD-1i + D group. Recalcification of bone metastases was radiologically observed in 18 (62%) patients. No unexpected treatment-related adverse events emerged. The combination therapy of metastatic melanoma with PD-1i and denosumab was feasible without unexpected safety issues and showed a promising efficacy signal. Further investigation in prospective studies is needed.

Introduction Talimogene laherparepvec is a first-in-class oncolytic immunotherapy for intratumoral injection with proven efficacy and tolerability in patients with unresectable early metastatic melanoma (stage IIIB–IVM1a) in the pivotal phase III OPTiM study. The objective was to characterize melanoma patients treated with talimogene laherparepvec in routine clinical practice in Germany. Methods A retrospective chart review was conducted in unresectable stage IIIB–IVM1a melanoma patients. Data on demographics, disease and medical history, and use of talimogene laherparepvec were collected. A survey was also conducted to understand physician treatment decisions. Results Data for 27 patients who initiated talimogene laherparepvec between June 2016 and July 2017 were analyzed (median age 68; stage IIIB/C disease 56%). All patients had prior surgery, and over half had repeated resections for recurrent disease (median 3). Overall, 48% of patients received at least one prior local treatment, mainly radiation therapy or electrochemotherapy. Talimogene laherparepvec was first-line systemic therapy in 63% of patients. The most frequent prior systemic treatment was immunotherapy (7/27 patients). At end of follow-up, 13 patients were still on talimogene laherparepvec and 14 patients had discontinued treatment. Among those who discontinued, 8 (57%) did not receive subsequent systemic therapy. Only one patient receiving first-line talimogene laherparepvec received a subsequent systemic therapy. Three patients stopped treatment because of no remaining injectable lesions. Median treatment duration was 22.1 weeks overall and 27.9 weeks in stage IIIB/C disease patients. Nearly all cutaneous lesions (93%) were injected with talimogene laherparepvec compared to subcutaneous (83%) and nodal lesions (77%). No new safety signals were reported. The main reasons given in the physician survey for treating with talimogene laherparepvec were good tolerability, overall efficacy, and lack of contraindications. Conclusion Talimogene laherparepvec is now included as a routine treatment option for unresectable early metastatic melanoma in Germany. This study characterizes the first patients treated with talimogene laherparepvec in Europe and confirms the good tolerability observed in clinical trials. Trial Registration EUPAS registry, EUPAS17410. Funding Amgen Inc. Electronic supplementary material The online version of this article (10.1007/s12325-018-0850-6) contains supplementary material, which is available to authorized users.

Introduction Cutaneous melanoma is notorious for the development of in-transit metastases (ITM). For unknown biological reasons, ITM remain the leading tumour manifestation without progression to distant sites in some patients. Methods In total, 191 patients with initially unresectable stage III ITM and satellite metastases from 16 skin cancer centres were retrospectively evaluated for their tumour characteristics, survival and therapy response. Three groups according to disease kinetics (no distant progress, slow (>6 months) and fast ( Results Median follow-up time was 30.5 (range 0.8–154.0) months from unresectable ITM. Progression to stage IV was observed in 56.5% of cases. Patients without distant metastasis were more often female, older (>70 years) and presented as stage III with lymph node or ITM at initial diagnosis in 45.7% of cases. Melanoma located on the leg had a significantly better overall survival (OS) from time of initial diagnosis compared to non-leg localised primaries (hazard ratio [HR] = 0.61, 95% confidence interval [CI] 0.40–0.91; p = 0.017), but not from diagnosis of unresectable stage III (HR = 0.67, 95% CI 0.45–1.02; p = 0.06). Forty percent of patients received local therapy for satellite and ITM. Overall response rate (ORR) to all local first-line treatments was 38%; disease control rate (DCR) was 49%. In total, 72.3% of patients received systemic therapy for unresectable stage IIIB-D. ORR for targeted therapy (n = 19) was highest with 63.2% and DCR was 84.2% compared to an ORR of 31.4% and a DCR of 54.3% in PD-1 treated patients (n = 70). Patients receiving PD-1 and intralesional talimogene laherparepvec (n = 12) had an ORR of 41.7% and a DCR of 75%. Conclusion Patients with unresectable ITM and without distant progression are more often female, older, and have a primary on the leg. Response to PD-1 inhibitors in this cohort was lower than expected, but further investigation is required to elucidate the biology of ITM development and the interplay with the immune system.

Advanced nanoBiomed research 1(1), 2000029 (2021). doi:10.1002/anbr.202000029, Published by Wiley-VCH, Weinheim

Background Elevated lactate dehydrogenase (LDH) is a known predictive and prognostic factor for a poor outcome in patients with metastatic melanoma. It is unclear whether first-line targeted therapy (TT) or immune checkpoint inhibition (ICI) is more beneficial in melanoma patients with elevated LDH because prospective studies in this area are lacking. Methods This multicentre retrospective cohort study was conducted at 25 melanoma centres worldwide to analyse progression-free survival (PFS) and overall survival (OS) among melanoma patients with elevated LDH. The role of confounders was addressed by using inverse probability of treatment weighting. Results Among 173 BRAFV600-mutant patients, PFS at 12 months in the TT group was 22% compared with 52% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.6, 95% CI 0.4–1.0, p = 0.07) and 18% in the anti-PD-1 monotherapy group (HR 1.8, 95% CI 1.2–2.8, p = 0.003). Twelve months' OS was 48% in the TT group compared with 83% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.5, 95% CI 0.3–1.0, p = 0.03) and 50% in the anti-PD-1 monotherapy group (HR 1.2, 95% CI 0.8–2.0, p = 0.37). The ORR in the TT group was 63%, compared with 55% and 20% in the combined anti-PD-1 and anti-CTLA-4 and anti-PD-1 monotherapy group, respectively. Among 314 patients receiving ICI first-line, PFS at 12 months was 33% in the anti-PD-1 group versus 38% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.8, 95% CI 0.6–1.0; p = 0.07). OS at 12 months was 54% in the anti-PD-1 group versus 66% in the combined ICI group (HR 0.7, 95% CI 0.5–1.0; p = 0.03). The ORR was 30% in the anti-PD-1 monotherapy group and 43% in the combined anti-PD-1 and anti-CTLA-4 group. Results from multivariate analysis confirmed the absence of qualitative confounding. Conclusions Among BRAF-mutant patients with elevated LDH, combined anti-PD-1 and anti-CTLA-4 blockade seems to be associated with prolonged OS compared with first-line TT. Among patients receiving ICI as a first-line treatment, OS appears to be longer for the combination of anti-PD-1 and anti-CTLA-4 than for anti-PD-1 alone.

Background CV8102 is a non-coding, non-capped RNA complexed with a carrier peptide activating the innate (via TLR7/8, RIG-I) and adaptive immune system.1 2 An ongoing phase I trial is investigating i.t. CV8102 either as a single agent or in combination with systemic anti-PD-1 antibodies in patients with advanced melanoma (MEL), squamous cell carcinoma of the skin (cSCC) or head and neck (hnSCC) and adenoid cystic carcinoma (ACC). Methods An open-label, cohort-based, dose escalation and expansion study in patients with advanced cutaneous melanoma (cMEL), cutaneous squamous cell carcinoma (cSCC), head and neck squamous cell carcinoma (hnSCC) or adenoid cystic carcinoma (ACC) is ongoing investigating i.t. CV8102 as single agent and in combination with anti-PD-1 antibodies. 8 intratumoral injections of CV8102 are being administered initially over a 12 week period, while patients benefiting from the single agent therapy may receive further treatment. In an initial dose escalation part the maximum tolerated dose and recommended phase 2 dose for subsequent cohort expansion will be defined. Results As of September 16, 2020, 29 patients have been treated with CV8102 as a single agent (25-900 µg) and 21 patients have received CV8102 (25-900 µg) in combination with anti-PD-1 antibodies. Most frequent treatment related adverse events were mild to moderate fever, fatigue, chills and headache. One patient treated at the 900 µg single agent experienced a dose limiting toxicity (G3 transaminase increase in the context of G2 cytokine release syndrome). Regression of injected and distant noninjected lesions was observed in several patients in the single agent and the anti-PD-1 combination cohorts. Updated safety and efficacy results will be presented. Conclusions CV8102 showed an acceptable tolerability and preliminary evidence of clinical efficacy as single agent and in combination with anti-PD-1- antibodies. Trial Registration NCT03291002 Ethics Approval The study was approved by the Central Ethics Committees in Tuebingen, Germany under 785/2016AMG1, in France under 19.05.17.64111, in Barcelona, Spain under the EudraCT number. Consent Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal. References Ziegler A, Soldner C, Lienenklaus S, Spanier J, Trittel S, Riese P, Kramps T, Weiss S, Heidenreich R, Jasny E, Guzman CA, Kallen KJ, Fotin-Mleczek M, Kalinke U. A new RNA-based adjuvant enhances virus-specific vaccine responses by locally triggering TLR- and RLH-dependent effects. J Immunol 2017;198(4):1595-1605. doi:10.4049/jimmunol.1601129 Heidenreich R, Jasny E, Kowalczyk A, Lutz J, Probst J, Baumhof P, Scheel B, Voss S, Kallen KJ, Fotin-Mleczek M. A novel RNA-based adjuvant combines strong immunostimulatory capacities with a favorable safety profile. Int J Cancer 2015 Jul 15;137(2):372-84. doi: 10.1002/ijc.29402

Introduction Talimogene laherparepvec (T-VEC; IMLYGIC®, Amgen Inc.) is an oncolytic immunotherapy approved in Europe for the treatment of unresectable metastatic melanoma (stage IIIB–IVM1a). This study characterised real-world use of T-VEC in four European countries. Methods Data on demographics, treatment pattern, safety, and clinical effectiveness were examined in a retrospective chart review of patients with stage IIIB–IVM1a unresectable melanoma treated with T-VEC in surgical (the Netherlands) and medical (Austria, Germany, UK) oncology settings. Results Overall, 66 patients were included (the Netherlands: n = 31; Austria, Germany, UK: n = 35). The median age was 69 years and 59.1% were female. At the time of T-VEC initiation, 47 patients (71.2%) had stage IIIB/C disease; of these, 30 were from the Netherlands. Although 72.7% patients overall received T-VEC as first-line therapy, this was higher in the Netherlands than the other countries (93.5% vs 54.3%). Of the 47 patients who discontinued T-VEC, 26 (55.3%) had no remaining injectable lesions (potentially indicating complete response); 20/26 of these patients were from the Netherlands. One patient discontinued T-VEC due to toxicity. Conclusion This study is the first comprehensive multinational evaluation of the use of T-VEC to treat unresectable stage IIIB/C–IVM1a melanoma in real-world clinical practice in Europe. The differences between European countries were apparent, with physicians in the Netherlands using T-VEC in patients with earlier advanced disease stage and in the first-line setting compared with other countries. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-020-01590-w.

Metastatic melanoma is a devastating disease with a marginal-albeit increasing-hope for cure. Melanoma has a high mutation rate which correlates to the expression of numerous neo-antigens and thus is associated with the potential to induce and strengthen effective antitumoral immunity. However, the incomplete and potentially insufficient response to established immunotherapies (response rates usually do not markedly exceed 60%) already points to the need of further studies to improve treatment strategies. Multiple tumor escape mechanisms that allow melanoma to evade from antitumoral immune responses have been characterized and must be overcome to achieve a better clinical efficacy of immunotherapies. Recently, promising progress has been made in targeting tumor vasculature to control and increase the infiltration of tumors with effector lymphocytes. It has been hypothesized that amplified lymphocytic infiltrates in melanoma metastases result in a switch of the tumor microenvironment from a non-inflammatory to an inflammatory state. In this view point essay, we discuss the requirements for successful homing of lymphocytes to melanoma tissue and we present a mouse melanoma xenograft model that allows the investigation of human tumor vessels in vivo. Furthermore, current clinical studies dealing with the activation of melanoma vasculature for enhanced effectiveness of immunotherapy protocols are presented and open questions for routine clinical application are addressed.

Purpose Cold atmospheric plasma was intensively investigated for medical applications in the last decade and a new field of plasma medicine emerged. Methods Basic components of cold plasma and their biomedical effects were deciphered and mainly relate to redox-biologic effects. With regard to wound treatment, cold plasma already reached standard medical care status. In terms of plasma effects in oncology, only preliminary research data are available. Results This emerging and highly dynamic field of plasma medicine in oncology shows several promising applications. As the skin is most easily accessible and a need for further therapies of skin cancers like metastasized melanoma and squamous cell carcinoma exists, translational approaches are urgently needed. Conclusion To this end, we introduce a first Leibniz professorship for plasmabiotechnology in dermatology world-wide and establish a scientific network for the investigation of the efficacy and safety of cold atmospheric plasma in dermato-oncology.

Background: Concomitant radiation with BRAF inhibitor (BRAFi) therapy may increase radiation-induced side effects but also potentially improve tumour control in melanoma patients. Methods: A total of 155 patients with BRAF-mutated melanoma from 17 European skin cancer centres were retrospectively analysed. Out of these, 87 patients received concomitant radiotherapy and BRAFi (59 vemurafenib, 28 dabrafenib), while in 68 patients BRAFi therapy was interrupted during radiation (51 vemurafenib, 17 dabrafenib). Overall survival was calculated from the first radiation (OSRT) and from start of BRAFi therapy (OSBRAFi). Results: The median duration of BRAFi treatment interruption prior to radiotherapy was 4 days and lasted for 17 days. Median OSRT and OSBRAFi in the entire cohort were 9.8 and 12.6 months in the interrupted group and 7.3 and 11.5 months in the concomitant group (P=0.075/P=0.217), respectively. Interrupted vemurafenib treatment with a median OSRT and OSBRAFi of 10.1 and 13.1 months, respectively, was superior to concomitant vemurafenib treatment with a median OSRT and OSBRAFi of 6.6 and 10.9 months (P=0.004/P=0.067). Interrupted dabrafenib treatment with a median OSRT and OSBRAFi of 7.7 and 9.8 months, respectively, did not differ from concomitant dabrafenib treatment with a median OSRT and OSBRAFi of 9.9 and 11.6 months (P=0.132/P=0.404). Median local control of the irradiated area did not differ in the interrupted and concomitant BRAFi treatment groups (P=0.619). Skin toxicity of grade ≥2 (CTCAE) was significantly increased in patients with concomitant vemurafenib compared to the group with treatment interruption (P=0.002). Conclusions: Interruption of vemurafenib treatment during radiation was associated with better survival and less toxicity compared to concomitant treatment. Due to lower number of patients, the relevance of treatment interruption in dabrafenib treated patients should be further investigated. The results of this analysis indicate that treatment with the BRAFi vemurafenib should be interrupted during radiotherapy. Prospective studies are desperately needed.

BackgroundCV8102 is a non-coding, non-capped RNA complexed with a carrier peptide activating the innate (via TLR7/8, RIG-I) and adaptive immune system.1 2 An ongoing phase I trial is investigating the intratumoral (i.t.) administration of CV8102 in patients with advanced cutaneous melanoma (cMEL), squamous cell carcinoma of the skin (cSCC) or head and neck (hnSCC) and adenoid cystic carcinoma (ACC), either as a single agent or in combination with systemic anti-PD-1 antibodies. Preliminary immune profiling results will be reported.MethodsAn open-label, cohort-based, dose escalation and expansion study in patients with advanced cMEL, cSCC, hnSCC or ACC is ongoing investigating CV8102 i.t. as single agent and in combination with anti-PD-1 antibodies. Eight i.t. injections of CV8102 were administered over a 12 week period with optional continuing treatment in case of clinical benefit. In the initial dose escalation part, the recommended phase II dose for subsequent cohort expansion was defined. Blood samples for immune cell phenotyping, RNA sequencing (RNAseq) and serum cytokine/chemokine analysis were collected at baseline and multiple time points during the treatment period. For characterization of the tumor microenvironment (TME), optional core needle biopsies of injected and/or non-injected lesions were taken before, during and after treatment. Changes on various tumor-infiltrating immune cells were assessed by multiplex immunofluorescence (MultiOmyx < sup >TM ) and immune-related gene expression profiling using nCounter® Pan Cancer IO360 < sup >TM panel (NanoString).ResultsDuring the dose escalation part, 33 patients received CV8102 (dose range of 25–900 µg) as single agent and 25 patients received CV8102 in combination with an anti-PD-1 antibody. A dose of 600 µg was selected as recommended phase II dose. Serum cytokine/chemokine and blood RNAseq analysis showed transient increases in several markers like interferons alpha and gamma after the first dose. First analyses of paired biopsies showed changes in the TME of injected and non-injected lesions. Complete results of cytokine and chemokine analysis in serum and blood RNAseq for the dose escalation cohorts will be presented. Multiplex immunofluorescence and gene expression profiling from paired biopsies from individual patients will be also included.ConclusionsIntratumoral injection of CV8102 activated several cytokine/chemokine pathways in the peripheral blood and showed immunological changes in the tumor microenvironment of injected and non-injected lesions.Trial RegistrationNCT03291002ReferencesZiegler A, Soldner C, Lienenklaus S, Spanier J, Trittel S, Riese P, Kramps T, Weiss S, Heidenreich R, Jasny E, Guzmán CA, Kallen KJ, Fotin-Mleczek M, Kalinke U. A New RNA-Based Adjuvant Enhances Virus-Specific Vaccine Responses by Locally Triggering TLR- and RLH-Dependent Effects. J Immunol 2017;198(4):1595–1605. doi: 10.4049/jimmunol.1601129.Heidenreich R, Jasny E, Kowalczyk A, Lutz J, Probst J, Baumhof P, Scheel B, Voss S, Kallen KJ, Fotin-Mleczek M. A novel RNA-based adjuvant combines strong immunostimulatory capacities with a favorable safety profile. Int J Cancer 2015 Jul 15;137(2):372–84. doi: 10.1002/ijc.29402.Ethics ApprovalThe study was approved by the Central Ethics Committees in Tuebingen, Germany under 785/2016AMG1, in France by the COMITE DE PROTECTION DES PERSONNES SUD-EST I under 2019–49, approval dated 17-May-2019, in Barcelona, Spain by the CEC COMITÉ DE ÉTICA DE INVESTIGACIÓN CLÍNICA CON MEDICAMENTOS del Hospital Universitari Vall d’Hebron, approval date 28-Nov-2019 under the EUdraCT number, in Austria by the Central Ethics Committee in Graz under 31–426 ex 18/19 approved on 19-Sep-2019.ConsentWritten informed consent from the patient was obtained for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

To evaluate clinical, histopathologic, and radiation (RT) dose parameters in patients with extranodal low-grade (ENLG) non-Hodgkin lymphoma (NHL) and their possible impact on local control (LC) and survival. The medical records of 159 patients with 181 histologically confirmed ENLG-NHL lesions treated at our institution were reviewed retrospectively. The predominant histological subtype (73%) was marginal zone lymphoma (MZL). Common lesion sites were the gastrointestinal tract (GIT; 33%), skin (26%), and orbit (21%). The majority of patients (88%) presented with stage I/II disease. Thirty-three (20%) lesions were treated with reduced-dose RT (≤30.6 Gy) and 148 lesions (80%) with conventional-dose RT (>30.6 Gy), with an overall median dose of 39.6 Gy (range 4–63). The median follow-up period was 72 months. The 10-year local control (LC), Progression-free survival (PFS), and overall survival (OS) rates were 96, 65, and 82%, respectively. Higher overall response rate (ORR; 98% vs. 94%, p = 0.001) and complete response rate (CRR; 95% vs. 73%, p = 0.001) were observed in patients treated with conventional-dose regimens than in those treated with reduced-dose regimens. Ten-year PFS (p = 0.90) and OS (p = 0.40) was similar between the two dose groups. RT was well tolerated in both dose groups, with no grade 4/5 toxicities. In the multivariate analysis, RT dose and timing (upfront or salvage) were related to LC, whereas age, histology, and complete response (CR) to RT were associated with PFS. Patient age and radiation field size impacted OS. RT is an effective and curative local treatment for early-stage FL and MZL at conventional and reduced radiation doses. Conventional-doses seems to be associated with local response improvement, without significant differences in PFS rates. Age, histology, and response to RT may influence the PFS.

Radiotherapy (RT) has an established role in the curative treatment of indolent primary cutaneous B‑cell lymphoma (PCBCL). With the role of low-dose regimens such as 2 × 2 Gy being uncertain, we compared conventional-dose RT to a low-dose approach and investigated outcome and toxicities.We retrospectively reviewed the medical records of 26 patients with 44 cutaneous lesions treated at our institution between 2007 and 2017, comprising 22 marginal zone lymphoma (PCMZL) lesions and 22 follicle center lymphoma (PCFCL) lesions. Seven lesions (16%) were treated with low-dose RT (LDRT) (4 Gy) and 37 (84%) with conventional-dose RT (≥24 Gy, median 40 Gy). Median follow-up duration was 76 months.The overall response rate (ORR) was 91% (complete response rate [CRR]: 75%). The 5‑year local control rate (LCR) was 88% and the 10-year LCR was 84%. The response rates were significantly higher following conventional-dose RT (ORR: 92% vs. 86%; CRR: 84% vs. 29%; P = 0.007). In terms of radiation dose, the rate of infield relapses (14% vs. 11%, P = 0.4) and the 5‑year LCR (86% vs. 90%, P = 0.4) were comparable in the LDRT and conventional-dose RT groups. During RT courses, about two-thirds of patients experienced mild toxicities, with grade I and II acute toxicity rates of 61% and 9%, respectively, with lower incidences of grade I (14% vs. 70%) and grade II (0% vs. 8%, P = 0.004) toxicities following LDRT.This long-term analysis confirms the excellent outcome of RT in the management of PCBCL. The LDRT concept with 4 Gy was associated with a comparable LCR and reduced rates of acute toxicity. However, the response rates were significantly lower for this group and LDRT may therefore not be recommended as standard treatment.ZIELSETZUNG: Die Strahlentherapie (RT) hat eine etablierte Rolle in der kurativen Behandlung indolenter primär kutaner B‑Zell-Lymphome (PCBCL). Die Rolle einer Niedrigdosis-Behandlung (z. B. 2 × 2 Gy) wird kontrovers diskutiert, sodass in der folgenden Studie ein Vergleich der konventionellen RT-Dosis mit einem Niedrigdosis-Konzept erfolgte und hierbei Effektivität und Toxizitäten analysiert wurden.In einer retrospektiven Analyse wurden 26 Patienten mit 44 kutanen Läsionen identifiziert, die zwischen 2007 und 2017 an unserer Klinik behandelt wurden. Hierunter waren 22 Läsionen von Marginalzonenlymphomen (PCMZL) und 22 Läsionen von Follikelzentrumslymphomen (PCFCL). Es wurden 7 Läsionen (16 %) mit Niedrigdosis-RT (LDRT) (4 Gy) behandelt und 37 Läsionen (84 %) mit einer RT in konventioneller Dosis (≥24 Gy, im Median 40 Gy). Das mediane Follow-up betrug 76 Monate.Die Gesamtansprechrate (ORR) lag bei 91 % (komplette Ansprechrate [CRR]: 75 %). Die 5‑Jahres-Lokalkontrollrate (LCR) war 88 % und die 10-Jahres-LCR 84 %. Die Ansprechraten waren nach Bestrahlung in konventioneller Dosis signifikant höher (ORR: 92 % vs. 86 %; CRR: 84 % vs. 29 %; P = 0,007). Im Hinblick auf die Rate an „Infield“-Rezidiven (14 % vs. 11 %; P = 0,4) und die 5‑Jahres-LCR (86 % vs. 90 %; P = 0,4) waren die Gruppen der LDRT und der konventionellen Bestrahlung vergleichbar. Während der RT traten Grad-I-Toxizitäten bei 61 % und Grad-2-Toxizitäten bei 9 % der Patienten auf, mit signifikant weniger Akuttoxizitäten vom Grad I (14 % vs. 70 %) und vom Grad II (0 % vs. 8 %; P = 0,004) in der LDRT-Gruppe.Diese Langzeitanalyse bestätigt die exzellenten Ergebnisse der RT in der Behandlung von PCBCL. Die LDRT mit 4 Gy war mit einer vergleichbaren LCR und niedrigeren Toxizitäten verbunden. Allerdings waren die Ansprechraten signifikant niedriger, sodass die LDRT nicht als Standard empfohlen werden kann.

Anti-programmed cell death 1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma and other cancer entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects can involve skin, gastrointestinal tract, liver, the endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential.In total, 496 patients with metastatic melanoma from 15 skin cancer centres were treated with pembrolizumab or nivolumab. Two hundred forty two side-effects in 138 patients have been analysed. In 77 of the 138 patients side-effects affected the nervous system, respiratory tract, musculoskeletal system, heart, blood and eyes. Not yet reported side-effects such as meningo-(radiculitis), polyradiculitis, cardiac arrhythmia, asystolia, and paresis have been observed. Rare and difficult to manage side-effects such as myasthenia gravis are described in detail.Anti-PD-1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.

Purpose Recent trials with low-dose total skin electron beam (TSEB) therapy demonstrated encouraging results for treating primary cutaneous T-cell lymphoma (PCTCL). In this study, we assessed the feasibility of different radiation doses and estimated survival rates of different pathologic entities and stages. Methods and Materials We retrospectively identified 45 patients with PCTCL undergoing TSEB therapy between 2000 and 2015. Clinical characteristics, treatment outcomes, and toxicity were assessed. Results A total of 49 courses of TSEB therapy were administered to the 45 patients. There were 26 pathologically confirmed cases of mycosis fungoides (MF) lymphoma, 10 cases of Sezary syndrome (SS), and 9 non-MF/SS PCTCL patients. In the MF patients, the overall response rate (ORR) was 92% (50% complete remission [CR]), 70% ORR in SS patients (50% CR), and 89% ORR in non-MF/SS patients (78% CR). The ORR for MF/SS patients treated with conventional dose (30-36 Gy) regimens was 92% (63% CR) and 75% (25% CR) for low-dose ( P =.09). In MF patients, the overall survival (OS) was 77 months with conventional dose regimens versus 14 months with low-dose regimens ( P =.553). In SS patients, the median OS was 48 versus 16 months ( P =.219), respectively. Median event-free survival (EFS) for MF in conventional dose patients versus low-dose patients was 15 versus 8 months, respectively ( P =.264) and 19 versus 3 months for SS patients ( P =.457). Low-dose regimens had shorter treatment time ( P =.009) and lower grade 2 adverse events ( P =.043). A second TSEB course was administered in 4 MF patients with 100% ORR. There is a possible prognostic impact of supplemental/boost radiation ( P P P =.021) were detected. Conclusions TSEB therapy is an efficacious treatment modality in the treatment of several forms of cutaneous T-cell lymphoma. There is a nonsignificant trend to higher and longer clinical benefit for MF and SS patients receiving conventional dose. Low-dose TSEB regimens are well tolerated and achieve short-term palliation.

BackgroundImmune checkpoint inhibition (ICI) is an essential treatment option in melanoma. Its outcome may be improved by a preceding radiation of metastases. This study aimed to investigate the impact of a preceding radiotherapy on the clinical outcome of ICI treatment.MethodsThis multicenter retrospective cohort study included patients who received anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or anti-programmed cell death protein 1 (PD-1) ICI with or without preceding radiotherapy for unresectable metastatic melanoma. ICI therapy outcome was measured as best overall response (BOR), progression-free (PFS) and overall survival (OS). Response and survival analyses were adjusted for confounders identified by directed acyclic graphs. Adjusted survival curves were calculated using inverse probability treatment weighting.Results835 patients who received ICI (anti-CTLA-4, n=596; anti-PD-1, n=239) at 16 centers were analyzed, whereof 235 received a preceding radiotherapy of metastatic lesions in stage IV disease. The most frequent organ sites irradiated prior to ICI therapy were brain (51.1%), lymph nodes (17.9%) and bone (17.9%). After multivariable adjustment for confounders, no relevant differences in ICI therapy outcome were observed between cohorts with and without preceding radiotherapy. BOR was 8.7% vs 13.0% for anti-CTLA-4 (adjusted relative risk (RR)=1.47; 95% CI=0.81 to 2.65; p=0.20), and 16.5% vs 25.3% for anti-PD-1 (RR=0.93; 95% CI=0.49 to 1.77; p=0.82). Survival probabilities were similar for cohorts with and without preceding radiotherapy, for anti-CTLA-4 (PFS, adjusted HR=1.02, 95% CI=0.86 to 1.25, p=0.74; OS, HR=1.08, 95% CI=0.81 to 1.44, p=0.61) and for anti-PD-1 (PFS, HR=0.84, 95% CI=0.57 to 1.26, p=0.41; OS, HR=0.73, 95% CI=0.43 to 1.25, p=0.26). Patients who received radiation last before ICI (n=137) revealed no better survival than those who had one or more treatment lines between radiation and start of ICI (n=86). In 223 patients with brain metastases, we found no relevant survival differences on ICI with and without preceding radiotherapy.ConclusionsThis study detected no evidence for a relevant favorable impact of a preceding radiotherapy on anti-CTLA-4 or anti-PD-1 ICI treatment outcome in metastatic melanoma.