Background
Since a non-negligible fraction of patients with metastatic melanoma does not experience long-term disease control, even with immunotherapy and targeted therapy, new biomarkers for patient ...stratification and treatment tailoring are needed in this setting.
Objective
We investigated the association of a novel immune-inflammatory blood-based biomarker, the Pan-Immune-Inflammation Value (PIV), with clinical outcomes of patients with metastatic melanoma receiving first-line therapy.
Patients and Methods
We retrospectively included patients treated at the Fondazione IRCCS Istituto Nazionale dei Tumori of Milan and having an available baseline complete blood cell count (CBC). PIV was calculated as: neutrophil count (10
3
/mm
3
) × platelet count (10
3
/mm
3
) × monocyte count (10
3
/mm
3
)/lymphocyte count (10
3
/mm
3
).
Results
A total of 228 patients were included: 119 (52%) had been treated with immunotherapy and 109 (48%) with targeted therapy. PIV was significantly higher in patients with ECOG PS ≥ 1, high disease burden, synchronous metastases, and elevated baseline LDH level. High baseline PIV was independently associated with poor overall survival (adjusted hazard ratio HR: 2.06; 95% confidence interval CI: 1.30–3.29; adjusted
P =
0.002) and progression-free survival (adjusted HR 1.56; 95% CI 1.01–2.41; adjusted
P =
0.044). High PIV was also associated with primary resistance to both immunotherapy (odds ratio OR: 3.98; 95% CI 1.45–12.32;
P =
0.005) and targeted therapy (OR: 8.42; 95% CI 2.50–34.5;
P
< 0.001). PIV showed a promising discrimination ability in terms of AIC and c-index when compared with other CBC-based biomarkers.
Conclusions
PIV may guide the treatment decision process and the development of novel first-line treatment strategies in melanoma, but warrants further study and validation.
immunotherapy with immune checkpoint inhibitors has become one of the standard therapeutic modalities for patients with advanced melanoma. Melanoma of the female lower genital tract is a rare and ...aggressive disease, with poor long-term clinical outcomes. To date, no study evaluated the role of immunotherapy in metastatic melanoma of the lower genital tract.
Data of women with metastatic melanoma of the lower genital tract were prospectively collected. Survival outcomes over time was assessed using Kaplan-Meier model.
Seven cases of metastatic melanoma of the lower genital tract (vulva n=2, vagina n=4, and uterine cervix n=1) treated with immune checkpoint inhibitors are reviewed. Two patients had metastatic disease at diagnosis, while 5 patients developed metastatic disease at a mean (standard deviation) time of 9.9 (±3.0) months from primary diagnosis. Four patients received an anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA4) (ipilimumab) and 3 received an anti-programmed cell death 1 (PD-1) (pembrolizumab n=2, nivolumab n=1) therapy. The response rate to immunotherapy was 28.5%. Patients receiving an anti-PD-1 experienced a better progression-free survival than patients treated with anti-CTLA4 (p=0.01, log-rank test). Although not reaching statistical significance, overall survival was better in patients having an anti-PD-1 therapy in comparison to anti-CTLA4 (p=0.15, log-rank test).
Results from our series confirm the poor prognosis of women with metastatic melanoma of the lower genital tract, thus supporting the need of exploring new treatment modalities. Further studies are warranted to improve knowledge on the role of immunotherapy in metastatic melanoma of the lower genital tract.
Metastatic melanoma was the first malignancy in which immune checkpoint inhibitors demonstrated their successful efficacy. Currently, the knowledge on the interaction between the immune system and ...malignant disease is steadily increasing and new drugs and therapeutic strategies are overlooking in the clinical scenario. To provide a comprehensive overview of immune modulating drugs currently available in the treatment of melanoma as well as to discuss of possible future strategies in the metastatic melanoma setting, the present review aims at analyzing controversial aspects about the optimal immunomodulating treatment sequences, the search for biomarkers of efficacy of immunocheckpoint inhibitors, and innovative combinations of drugs currently under investigation.
Background
Neurological immune-related adverse events (nirAEs) are rare toxicities of immune-checkpoint inhibitors (ICI). With the increase of ICI oncological indications, their incidence is growing. ...Their recognition and management remain nevertheless challenging.
Methods
A national, web-based database was built to collect cases of neurological symptoms in patients receiving ICI and not attributable to other causes after an adequate workup.
Results
We identified 27 patients who developed nirAEs (20 males, median age 69 years). Patients received anti-PD1/PDL1 (78%), anti-CTLA4 (4%), or both (19%). Most common cancers were melanoma (30%) and non-small cell lung cancer (26%). Peripheral nervous system was mostly affected (78%). Median time to onset was 43.5 days and was shorter for peripheral versus central nervous system toxicities (36 versus 144.5 days,
p
= 0.045). Common manifestations were myositis (33%), inflammatory polyradiculoneuropathies (33%), and myasthenia gravis (19%), alone or in combination, but the spectrum of diagnoses was broad. Most patients received first-line glucocorticoids (85%) or IVIg (15%). Seven patients (26%) needed second-line treatments. At last follow-up, four (15%) patients were deceased (encephalitis, 1; myositis/myasthenia with concomitant myocarditis, 2; acute polyradiculoneuropathy, 1), while seven (26%) had a complete remission, eight (30%) partial improvement, and six (22%) stable/progressing symptoms. ICI treatment was discontinued in most patients (78%).
Conclusions
Neurological irAEs are rare but potentially fatal. They primarily affect neuromuscular structures but encompass a broad range of presentations. A prompt recognition is mandatory to timely withheld immunotherapy and administrate glucocorticoids. In corticoresistant or severely affected patients, second-line treatments with IVIg or plasmapheresis may result in additional benefit.
Administration of NGR-TNF, a tumor vessel-targeting and tumor necrosis factor α TNFα) peptide conjugate, with immunotherapy has been shown to inhibit tumor growth in mice. Thus, we planned a Phase I ...pilot clinical trial to assess safety, immune and clinical response of this combination treatment for advanced melanoma. NA17.A2 and MAGE-3.A1 peptides were used as vaccine. HLA-A*0201 or HLA-A*01 metastatic melanoma patients received human NGR-hTNF i.v. alternating with s.c. weekly injections of either of the peptides emulsified in Montanide. The T-cell response was assessed ex-vivo using peripheral blood mononuclear cells (PBMCs) before, during and after therapy. The serum level of chromogranin A (CgA), soluble TNF receptors (sTNFR1/2), vascular endothelial growth factor (VEGF), and MIP-1β and MCP-1 chemokines, was determined. In 3 subjects, pre- and post-treatment tumor lesions were examined by immunohistochemistry. Clinically, chills were observed in 4 patients during NGR-hTNF infusion and erythema at vaccination site was seen in 7 patients. T-cell response against the vaccine or against other melanoma-associated antigens was detectable after treatment in 6 out of 7 tested patients. Low level or reduction of CgA and sTNFR and increase of MIP-1β and MCP-1 were found in patients sera. In the lesions examined the immune infiltrate was scanty but macrophage number increased in post-therapy lesions. From a clinical standpoint, a long term survival (>4 months) was found in 6 out of 8 evaluable patients (4, 4, 7, 11, 23+, 25+, 25+, 29+ months). The combination of NGR-hTNF and vaccine in metastatic melanoma patients was well tolerated, often associated with an ex-vivo T cell response and long-term overall survival. These findings warrant confirmation in a larger group of patients.
The most frequently reported skin tumours during treatment with targeted therapies for BRAF (B type Rapidly Accelerated Fibrosarcoma kinase) mutated metastatic melanoma are squamous cell carcinomas ...(SCCs). Basal cell carcinomas (BCCs) have been described in such setting, but no cases of multiple and recurring tumours have been reported so far. A patient with a history of chronic sun exposure and more than 10 BCCs removed since 1998 started treatment with vemurafenib for BRAF mutated metastatic melanoma. Therapy was complicated by sporadic episodes of atrial fibrillation and by the development of recurrent, multiple and diffuse BCCs. So, vemurafenib was discontinued and dabrafenib and trametinib were started. Since then, only four BCCs occurred in the patient. Histopathological re-examination showed that most BCCs occurred under vemurafenib presented with squamous features. Such characteristic was significantly less evident before therapy start and in lesions removed under treatment with dabrafenib and trametinib. BRAF inhibition (BRAFi) without MEK inhibition induces mitogen activated kinases overactivation, with consequent skin toxicity and acquired drug resistance. The BCCs removed from our patient showed squamous features, more evident during vemurafenib monotherapy. Both the switch from vemurafenib to dabrafenib and the addition of MEK inhibitor (MEKi) might have reduced the incidence of BCCs and their squamous differentiation.
Abstract Cancer stem cells (CSCs) represent a minor subpopulation of tumour cells that share some features with the normal stem cells of the tissue from which tumour derives and have the properties ...of self-renewal, multiple differentiation and tumour initiation (tumour-initiating cells, TICs). Thus CSCs/TICs need to survive cancer therapies in order to provide new, more differentiated, metastatic-prone tumour cells. This occurs through different signals delivered within the tumour microenvironment. The immune system of cancer patients may recognise CSCs/TICs and kill them though it is unclear whether this may occur in vivo during spontaneous tumour growth. This review summarises findings on the immunological profile of CSCs/TICs as compared with neoplastic non-stem cells and discusses the possible antigens recognised by the patients’ immune system, the in vitro and the potential in vivo immunogenicity of such antigens and the ability of human CSCs/TICs to down-regulate the immune response by the release of a variety of suppressive factors. We conclude that available data on immunological characterisation of CSCs/TICs may be useful in the perspective of designing new translational immunotherapy protocols targeting CSCs/TICs.
Background
Therapeutic chances for metastatic melanoma have consistently changed over the last years with the advent of antibodies targeting the programmed cell death protein-1 (PD-1). Onset of ...immune-related adverse events (irAEs) during treatment can be a source of concern, and the association with survival outcome is yet to be defined.
Patients and methods
Data of consecutive patients treated with anti-PD1 (nivolumab or pembrolizumab) for metastatic melanoma between July 2013 and January 2018 were retrospectively reviewed. Baseline factors, together with onset of irAEs and vitiligo during treatment, were evaluated to identify predictors of progression-free (PFS) and overall (OS) survival. PFS and OS were assessed using Kaplan–Meier and Cox models.
Results
Overall, 173 patients were included in the present analysis, and 102 patients (59%) experienced irAEs. Disease control rate was 51%. Median (interquartile range) PFS and OS were 4.9 (2.6–13.3) and 8.6 (3.5–18.3) months, respectively. At multivariate analysis, irAEs occurrence was independently associated with improved PFS HR 0.47 (95% CI 0.26, 0.86);
p
= 0.016, and correlated with better OS HR 0.39 (95% CI 0.18, 0.81);
p
= 0.007. Among various irAEs, the occurrence of vitiligo was associated with a trend toward a non-significant improved OS in comparison with other irAEs (
p
= 0.061). Median OS was undefined for patients experiencing vitiligo vs. 21.9 months for patients with other irAEs vs. 9.7 months for patients who had no irAEs (
p
= 0.003).
Conclusions
Our study underlines the association between irAEs and survival outcomes from anti-PD1 therapy. Careful management of treatment-related toxicity can lead to achieve maximum clinical benefit from this therapy.
Prognosis of patients with metastatic melanoma has dramatically improved over recent years because of the advent of antibodies targeting programmed cell death protein-1 (PD1). However, the response ...rate is ~40% and baseline biomarkers for the outcome are yet to be identified. Here, we aimed to determine whether artificial intelligence might be useful in weighting the importance of baseline variables in predicting response to anti-PD1.
This is a retrospective study evaluating 173 patients receiving anti-PD1 for melanoma. Using an artificial neuronal network analysis, the importance of different variables was estimated and used in predicting response rate and overall survival.
After a mean follow-up of 12.8 (±11.9) months, disease control rate was 51%. Using artificial neuronal network, we observed that 3 factors predicted response to anti-PD1: neutrophil-to-lymphocyte ratio (NLR) (importance: 0.195), presence of ≥3 metastatic sites (importance: 0.156), and baseline lactate dehydrogenase (LDH) > upper limit of normal (importance: 0.154). Looking at connections between different covariates and overall survival, the most important variables influencing survival were: presence of ≥3 metastatic sites (importance: 0.202), age (importance: 0.189), NLR (importance: 0.164), site of primary melanoma (cutaneous vs. noncutaneous) (importance: 0.112), and LDH > upper limit of normal (importance: 0.108).
NLR, presence of ≥3 metastatic sites, LDH levels, age, and site of primary melanoma are important baseline factors influencing response and survival. Further studies are warranted to estimate a model to drive the choice to administered anti-PD1 treatments in patients with melanoma.
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