Chemokines and Cytokines in Immunotherapy of Melanoma and Other Tumors: From Biomarkers to Therapeutic Targets.

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.

Distinct Immune Signatures Indicative of Treatment Response and Immune-Related Adverse Events in Melanoma Patients under Immune Checkpoint Inhibitor Therapy.

To identify potential early biomarkers of treatment response and immune-related adverse events (irAE), a pilot immune monitoring study was performed in stage IV melanoma patients by flow cytometric analysis of peripheral blood mononuclear cells (PBMC). Overall, 17 patients were treated with either nivolumab or pembrolizumab alone, or with a combination of nivolumab and ipilimumab every three weeks. Of 15 patients for which complete response assessment was available, treatment responders (n = 10) as compared to non-responders (n = 5) were characterized by enhanced PD-1 expression on CD8+ T cells immediately before treatment (median ± median absolute deviation/MAD 26.7 ± 10.4% vs. 17.2 ± 5.3%). Responders showed a higher T cell responsiveness after T cell receptor ex vivo stimulation as determined by measurement of programmed cell death 1 (PD-1) expression on CD3+ T cells before the second cycle of treatment. The percentage of CD8+ effector memory (CD8+CD45RA-CD45RO+CCR7-) T cells was higher in responders compared to non-responders before and immediately after the first cycle of treatment (median ± MAD 39.2 ± 7.3% vs. 30.5 ± 4.1% and 37.7 ± 4.6 vs. 24.0 ± 6.4). Immune-related adverse events (irAE) were accompanied by a higher percentage of activated CD4+ (CD4+CD38+HLADR+) T cells before the second treatment cycle (median ± MAD 14.9 ± 3.9% vs. 5.3 ± 0.4%). In summary, PBMC immune monitoring of immune-checkpoint inhibition (ICI) treatment in melanoma appears to be a promising approach to identify early markers of treatment response and irAEs.

Therapy understanding and health related quality of life in stage III/IV melanoma patients treated with novel adjuvant therapies.

OBJECTIVE: Our aims were to investigate the motivation for therapy, the understanding and valuation of potential treatment toxicities in melanoma patients offered adjuvant therapies. METHODS: Between September 2018 and September 2019 49 adjuvant patients with stage III and IV melanoma received a self-created, pre-treatment questionnaire. Furthermore, the patients were handed out the REPERES-G, EQ-5D-3L and EORTC QLQ C-30 questionnaires. RESULTS: Eight patients (18.3 %) decided against adjuvant therapy (mean age 71.6 years). Four of these had stage IIIA melanoma. The majority of patients (73.4 %) decided for adjuvant treatment with PD1-inhibitors despite their potential high grade, persistent, irreversible or even fatal toxicities. About a third of patients with BRAF V600 mutated melanoma who decided for therapy chose targeted therapy (31.3 %). These patients were younger (mean age 49 years), still working and had families with children. The REPERES-G questionnaire showed that our patients were generally satisfied with medical care. The average scores in the EQ-5D-3L and EORTC QLQ C-30 questionnaires indicated good subjective general health. CONCLUSIONS: Despite the associated toxicities as well as the required time and effort for a one-year treatment the majority of patients decided for adjuvant treatments.

Rechallenge with checkpoint inhibitors in metastatic melanoma.

To date, there have been only few studies investigating rechallenge with checkpoint inhibitors in melanoma patients. Herein, we present the first review of all internationally published, English-language articles. A total of 570 patients were included in our analysis, divided into four groups: 1) rechallenge with anti-PD1 following disease progression on anti-PD1 therapy; 2) rechallenge with anti-PD1 and anti-CTLA4 following disease progression on anti-PD1 therapy; 3) rechallenge with anti-CLTA-4 following disease progression on anti-CTLA-4 therapy; and 4) rechallenge following toxicity-related treatment discontinuation. In the first group (85 patients), the mean disease control rate (DCR) was 45.8 %, with a mean overall response rate (ORR) of 15.5 %. The second group (114 patients) showed a mean DCR of 40.6 % and an ORR of 20 %. In the third group (182 patients), the mean DCR was 50.9 %, with an ORR of 20.4 %. Thus, even patients with a history of disease progression on initial checkpoint inhibitor therapy may benefit from rechallenge. Patients in the fourth group (189 patients) showed a mean DCR of 89.5 % and an ORR of 70.2 %. Of these individuals, 18 % saw recurrence of the same toxicity; 23 % were affected by adverse events different from the ones previously experienced.

[Rare form of a segmental neurofibromatosis with giant plexiform neurofibroma]. / Seltene Form einer segmentalen Neurofibromatose mit monströsem plexiformem Neurofibrom.

The case of segmental neurofibromatosis (NF) with a monstrous plexiform neurofibroma in a 53-year-old female patient is described. Segmental NF is a rare form of NF, which is caused by a postzygotic mutation in the NF1 gene. In this mosaic form the typical cutaneous symptoms of NF are limited to certain unilateral dermatomes. Plexiform neurofibromas are clinically and histologically in contrast to locally delimited neurofibromas. They involve the catchment area of a peripheral nerve, affect many fascicles and nerve branches, do not respect growth limits and spread in a reticulated fashion. Plexiform neurofibromas can become malignant. In the presented case large parts of the monstrous plexiform cutaneous neurofibroma were excised and the patient did not wish any further measures to be carried out for the time being.

[Pitfall cryothermic dermatitis artefacta]. / Fallstrick kryothermische Dermatitis artefacta.

We present four clinicopathological correlated cases of young patients with cryothermic dermatitis artefacta. They were initially misdiagnosed as primary bullous dermatoses or fixed drug eruptions. Cryothermic dermatitis artefacta can imitate authentic dermatoses such as linear IgA bullous dermatosis, herpes virus infection, bullous pemphigoid or fixed drug eruption. It should be considered as differential diagnosis in uncommon cases of recurrent bullae in adolescent and young adult patients. We summarize helpful clinical and histopathological criteria for correct diagnosis and therewith causative treatment.

Rechallenge of targeted therapy in metastatic melanoma.

Rechallenge of targeted therapy in patients with BRAFV600 -mutated melanoma plays an important role, because of the prolonged overall survival of melanoma patients. Patients may be rechallenged after a drug-free interval following adverse drug reactions, after radiation therapy or surgery, following disease progression on subsequent immunotherapy or chemotherapy, or after disease progression without interim therapeutic intervention. To date, only few data has been published on treatment outcomes associated with rechallenge. The articles published on this topic included a total of 238 patients. In general, it was shown that patients did respond to rechallenge, even if they had previously experienced disease progression on targeted therapy. Patient response varied from stable disease to partial response and even complete remission in some cases. Our analysis showed overall response rates to rechallenge of 47 %, with disease control rates of 67 %. While mean progression-free survival was 6.4 months, this was shorter than after the first round of targeted therapy (mean progression-free survival of 9.2 months). Rechallenge of targeted therapy offers another option in the management of melanoma patients who have received extensive prior treatment. In particular, it will be important to clarify whether the type of interim treatment has an impact on the response to rechallenge.

Correction: Reschke, R.; Olson, D.J. Leveraging STING, Batf3 Dendritic Cells, CXCR3 Ligands, and Other Components Related to Innate Immunity to Induce a "Hot" Tumor Microenvironment That Is Responsive to Immunotherapy. Cancers 2022, 14, 2458.

The authors would like to make the following corrections to their published paper [...].

The role of tissue-resident memory T cells as mediators for response and toxicity in immunotherapy-treated melanoma-two sides of the same coin?

Tissue-resident memory T cells (TRM cells) have become an interesting subject of study for antitumor immunity in melanoma and other solid tumors. In the initial phases of antitumor immunity, they maintain an immune equilibrium and protect against challenges with tumor cells and the formation of primary melanomas. In metastatic settings, they are a prime target cell population for immune checkpoint inhibition (ICI) because they highly express inhibitory checkpoint molecules such as PD-1, CTLA-4, or LAG-3. Once melanoma patients are treated with ICI, TRM cells residing in the tumor are reactivated and expand. Tumor killing is achieved by secreting effector molecules such as IFN-γ. However, off-target effects are also observed. Immune-related adverse events, such as those affecting barrier organs like the skin, can be mediated by ICI-induced TRM cells. Therefore, a detailed understanding of this memory T-cell type is obligatory to better guide and improve immunotherapy regimens.

Predictive Value of Dual-Energy CT-Derived Metrics for the Use of Bone Substitutes in Distal Radius Fracture Surgery.

(1) Background: Low bone mineral density (BMD) is a significant risk factor for complicated surgery and leads to the increased use of bone substitutes in patients with distal radius fractures (DRFs). No accepted model has yet been established to predict the use of bone substitutes to facilitate preoperative planning. (2) Methods: Unenhanced dual-energy CT (DECT) images of DRFs were retrospectively acquired between March 2016 and September 2020 using the internal PACS system. Available follow-up imaging and medical health records were reviewed to determine the use of bone substitutes. DECT-based BMD, trabecular Hounsfield units (HU), cortical HU, and cortical thickness ratio were measured in non-fractured segments of the distal radius. Diagnostic accuracy parameters were calculated for all metrics using receiver-operating characteristic (ROC) curves and associations of all metrics with the use of bone substitutes were evaluated using logistic regression models. (3) The final study population comprised 262 patients (median age 55 years [IQR 43-67 years]; 159 females, 103 males). According to logistic regression analysis, DECT-based BMD was the only metric significantly associated with the use of bone substitutes (odds ratio 0.96, p = 0.003). However, no significant associations were found for cortical HU (p = 0.06), trabecular HU (p = 0.33), or cortical thickness ratio (p = 0.21). ROC-curve analysis revealed that a combined model of all four metrics had the highest diagnostic accuracy with an area under the curve (AUC) of 0.76. (4) Conclusions: DECT-based BMD measurements performed better than HU-based measurements and cortical thickness ratio. The diagnostic performance of all four metrics combined was superior to that of the individual parameters.

Tissue-resident memory T cells in immune-related adverse events: friend or foe?

Many cancer patients experience toxicity during checkpoint blockade immunotherapy, which often leads to treatment discontinuation. To this end, understanding the mechanisms mediating immune-related adverse events (irAE) should ultimately enable improvement in clinical outcomes. Recent work has revealed that tissue-resident memory T (TRM) cells are locally expanded in irAE-dermatitis and -colitis.