Exploring the clinical significance of specific immune-related adverse events in melanoma patients undergoing immune checkpoint inhibitor therapy.

Several studies have demonstrated that patients who experience immune-related adverse events (irAE) as a result of immunotherapy treatment, exhibit significantly improved outcomes compared to patients without toxicity. Data regarding the impact of specific irAE is, however, currently lacking. This is a real-world single-site cohort of 415 advanced melanoma patients who were treated with immunotherapy as first-line between 2014 and 2020, with a median follow-up of 24.5 months. The most frequent irAEs were cutaneous (classified as non-vitiligo, n  = 110, 26.5% and vitiligo, n  = 48, 11.6%), rheumatologic ( n  = 68, 16.4%), gastrointestinal ( n  = 66, 15.9%), endocrine ( n  = 61, 14.7%), and hepatitis ( n  = 50, 12%). Specific irAE that were significantly associated with survival benefit were rheumatologic (hazard ratio 0.34 for PFS, P  < 0.001; hazard ratio 0.38 for OS, P  < 0.001), non-vitiligo cutaneous (hazard ratio 0.58 for PFS, P  < 0.001; hazard ratio 0.54 for OS, P  = 0.001), vitiligo (hazard ratio 0.30 for PFS, P  < 0.001; hazard ratio 0.29 for OS, P  < 0.001), and endocrine (hazard ratio 0.6 for PFS, P  = 0.01; hazard ratio 0.52 for OS, P  < 0.001). Other types if irAEs, such as colitis, hepatitis and others - do not present this correlation. . The occurrence of these specific irAEs may reflect a hyperactivated immune response and thus can serve as meaningful clinical biomarkers.

PET-CT underestimates the true pathological extent of disease at lymphadenectomy for melanoma patients after systemic therapy.

INTRODUCTION: Modern systemic therapy has revolutionized the treatment of melanoma. Currently, patients with clinically involved lymph nodes require lymphadenectomy with associated morbidities. Positron Emission Tomography - Computed Tomography (PET-CT) has demonstrated accuracy in melanoma detection and response to therapy. We aimed to identify whether a PET-CT directed lymphatic resection after systemic therapy is oncologically sound. MATERIALS AND METHODS: Retrospective review of patients who underwent lymphadenectomy after systemic therapy for melanoma with a preoperative PET-CT. Examined demographic, clinical, and perioperative parameters including extent of disease, systemic therapy and response, and PET-CT findings compared to pathological outcomes. We compared patients with "as or less than expected" outcomes on pathology against those with "more than expected" pathological outcomes. RESULTS: Thirty-nine patients met inclusion criteria. In 28 (71.8%), pathological outcomes were "as or less than expected" by PET-CT, and in 11 (28.2%) pathological outcome were "more than expected". "More than expected" occurred more frequently with advanced disease at presentation with 75% presenting with regional/metastatic disease versus only 42.9% in the "as or less than expected" group (p = 0.015). Poor response to therapy also trended towards the "more than expected" group with only 27.3% favorable response versus 53.6% favorable response in the "as or less than expected" group, not statistically significant. Extent of disease on imaging failed to predict pathological concordance. CONCLUSION: PET-CT underestimates pathological extent of disease in the lymphatic basin in 30% of patients after systemic therapy. We failed to identify predictors of more extensive disease and warn against limited PET-CT directed lymphatic resections.

Systemic dysregulation of CEACAM1 in melanoma patients.

It was previously shown that CEACAM1 on melanoma cells strongly predicts poor outcome. Here, we show a statistically significant increase of serum CEACAM1 in 64 active melanoma patients, as compared to 48 patients with no evidence of disease and 37 healthy donors. Among active patients, higher serum CEACAM1 correlated with LDH values and with decreased survival. Multivariate analysis with neutralization of LDH showed that increased serum CEACAM1 carries a hazard ratio of 2.40. In vitro, soluble CEACAM1 was derived from CEACAM1(+), but neither from CEACAM1(-) melanoma cells nor from CEACAM1(+) lymphocytes, and directly correlated with the number of CEACAM1(+) melanoma cells. Production of soluble CEACAM1 depended on intact de novo protein synthesis and secretion machineries, but not on metalloproteinase function. An unusually high percentage of CEACAM1(+) circulating NK and T lymphocytes was demonstrated in melanoma patients. CEACAM1 inhibited killing activity in functional assays. CEACAM1 expression could not be induced on lymphocytes by serum from patients with high CEACAM1 expression. Further, expression of other NK receptors was impaired, which collectively indicate on a general abnormality. In conclusion, the systemic dysregulation of CEACAM1 in melanoma patients further denotes the role of CEACAM1 in melanoma and may provide a basis for new tumor monitoring and prognostic platforms.

Metabolic assessment of Merkel cell carcinoma: the role of 18F-FDG PET/CT.

OBJECTIVES: Merkel cell carcinoma (MCC) is a rare aggressive skin tumor associated with a high mortality rate. The present study evaluated the role of fluorine-18 fluorodeoxyglucose (F-FDG) PET/computed tomography (CT) in subsequent management of patients with MCC. METHODS: A total of 101 consecutive F-FDG PET/CT studies of 46 patients with MCC (28 men, 68±15.4 years) were retrospectively evaluated and the role in clinical care was documented. RESULTS: There were 40 positive studies (40%) in 28 patients (61%); of these, 33 studies (33%) in 27 patients (59%) showed metastatic disease. Fifty-two PET/CT studies (51%) in 23/46 (50%) patients were negative. Fifty-three studies (52%) were performed for staging or restaging in 41 patients, 29 scans (29%) were performed for routine follow-up in 10 patients, nine studies were carried out for suspected recurrent disease in eight patients, and 10 studies were carried out for assessment of response to therapy in seven patients. On the basis of PET/CT results, there was a change in disease stage in 12 studies in 12 patients (26%) and further change in the management of seven patients (15%). Overall, 2/29 routine follow-up studies were positive with further impact on management in one patient. CONCLUSION: F-FDG PET-CT altered the stage of one of four patients and changed the management of one of seven MCC patients. In the majority of patients, a negative F-FDG PET-CT study excluded active MCC with a high degree of confidence. PET-CT contributed toward patient management when performed for staging and restaging, monitoring response to treatment, and suspected recurrent disease, but not in the routine follow-up of asymptomatic patients with MCC.

Natural killer lysis receptor (NKLR)/NKLR-ligand matching as a novel approach for enhancing anti-tumor activity of allogeneic NK cells.

BACKGROUND: NK cells are key players in anti tumor immune response, which can be employed in cell-based therapeutic modalities. One of the suggested ways to amplify their anti tumor effect, especially in the field of stem cell transplantation, is by selecting donor/recipient mismatches in specific HLA, to reduce the inhibitory effect of killer Ig-like receptors (KIRs). Here we suggest an alternative approach for augmentation of anti tumor effect of allogeneic NK cells, which is founded on profile matching of donor NK lysis receptors (NKLR) phenotype with tumor lysis-ligands. METHODOLOGY/PRINCIPAL FINDINGS: We show that an NKLR-mediated killing directly correlates with the NKLR expression intensity on NK cells. Considerable donor variability in the expression of CD16, NKp46, NKG2D and NKp30 on circulating NK cells, combined with the stability of phenotype in several independently performed tests over two months, indicates that NKLR-guided selection of donors is feasible. As a proof of concept, we show that melanoma cells are dominantly recognized by three NKLRs: NKG2D, NKp30 and NKp44. Notably, the expression of NKp30 on circulating NK cells among metastatic melanoma patients was significantly decreased, which diminishes their ability to kill melanoma cells. Ex vivo expansion of NK cells results not only in increased amount of cells but also in a consistently superior and predictable expression of NKG2D, NKp30 and NKp44. Moreover, expanded NK cultures with high expression of NKG2D or NKp30 were mostly derived from the corresponding NKG2D(high) or NK30(high) donors. These NK cultures subsequently displayed an improved cytotoxic activity against melanoma in a HLA/KIR-ligand mismatched setup, which was NKLR-dependent, as demonstrated with blocking anti-NKG2D antibodies. CONCLUSIONS/SIGNIFICANCE: NKLR/NKLR-ligand matching reproducibly elicits enhanced NK anti-tumor response. Common NKLR recognition patterns of tumors, as demonstrated here in melanoma, would allow implementation of this approach in solid malignancies and potentially in hematological malignancies, either independently or in adjunction to other modalities.