Is single versus combination therapy problematic in the treatment of cutaneous melanoma?

Krattinger, Regina; Ramelyte, Egle; Dornbierer, Joëlle; Dummer, Reinhard

doi:10.1080/17512433.2019.1650641

Cited by 6 publications

(6 citation statements)

References 107 publications

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“…En conclusion, les immunothérapies sont très prometteuses mais nécessitent encore des recherches pour optimiser les limites de chacune d'entre elles. Les solutions aujourd'hui largement envisagées sont l'utilisation de différentes stratégies thérapeutiques simultanément afin de prévenir au mieux la mise en place de résistance par les cellules de mélanome (Krattinger et al, 2019). Une autre approche également envisagée est le ciblage de nouveaux immune checkpoint (Tundo et al, 2019).…”

Section: Le Transfert Adoptif De Ltunclassified

Ultrarapid lytic granule release from CTLs activates Ca ²⁺ -dependent synaptic resistance pathways in melanoma cells

et al. 2022

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Human cytotoxic T lymphocytes (CTLs) exhibit ultrarapid lytic granule secretion, but whether melanoma cells mobilize defense mechanisms with commensurate rapidity remains unknown. We used single-cell time-lapse microscopy to offer high spatiotemporal resolution analyses of subcellular events in melanoma cells upon CTL attack. Target cell perforation initiated an intracellular Ca 2+ wave that propagated outward from the synapse within milliseconds and triggered lysosomal mobilization to the synapse, facilitating membrane repair and conferring resistance to CTL induced cytotoxicity. Inhibition of Ca 2+ flux and silencing of synaptotagmin VII limited synaptic lysosomal exposure and enhanced cytotoxicity. Multiplexed immunohistochemistry of patient melanoma nodules combined with automated image analysis showed that melanoma cells facing CD8 + CTLs in the tumor periphery or peritumoral area exhibited significant lysosomal enrichment. Our results identified synaptic Ca 2+ entry as the definitive trigger for lysosomal deployment to the synapse upon CTL attack and highlighted an unpredicted defensive topology of lysosome distribution in melanoma nodules.

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Ultrarapid lytic granule release from CTLs activates Ca ²⁺ -dependent synaptic resistance pathways in melanoma cells

et al. 2022

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“…However, despite the performance of the AJCC classification, the prognosis of patients within each risk group remains heterogeneous. New prognostic factors are needed to assess the risk for each patient and to determine the best treatment option, especially among the new and recently validated therapeutic options in stage IV melanoma, such as: (i) single anti-PD1 immunotherapy versus combination with anti-CTLA4 immunotherapy [ 1 ]; (ii) first-line targeted therapy versus first-line immunotherapy in BRAF -mutated melanoma [ 2 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

Circulating Tumour DNA Is an Independent Prognostic Biomarker for Survival in Metastatic BRAF or NRAS-Mutated Melanoma Patients

Herbreteau

Vallée

Knol

et al. 2020

Cancers

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Circulating tumour DNA (ctDNA) can be used to identify gene alterations. The purpose of this study was to determine whether the detection of ctDNA, based on the identification of BRAF and NRAS mutations before systemic treatment initiation, was associated with the prognosis of metastatic melanoma. In total, 68 BRAF or NRAS-mutated stage IV or unresectable stage III metastatic cutaneous melanoma patients were included and tested for the presence of BRAF and NRAS mutations in circulating DNA before treatment initiation, using the Cobas BRAF/NRAS Mutation Test (Roche). The expected mutation was detected in the plasma of 34/68 patients (50% sensitivity). ctDNA detection was associated with AJCC stage, along with the number and nature of metastases. ctDNA was less frequently detected in NRAS-mutated than in BRAF-mutated melanoma (36% and 66%, respectively). At initiation of first-line treatment, ctDNA detection was associated with poor prognosis in Progression Free Survival (PFS) and Overall Survival (OS) in univariate analysis (log-rank: p = 0.002 and p < 0.0001, respectively). In multivariate analysis, ctDNA detection was an independent factor of poor prognosis in OS, after adjustment for AJCC stage, number and nature of metastases and gender (HR = 4.384; 95% CI: (1.308; 14.699); p = 0.017).

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“…Another interesting observation of our study was that although patients with low and high SMI values did not differ regarding disease severity as indicated by AJCC stages, we observed that patients with high SMI values more frequently received combination immune checkpoint inhibitor therapy. Since patients with high SMI values were also younger in our cohort, possibly this observation may be explained by the fact that in advanced melanoma, it was recently recommended to use combination immune checkpoint inhibitor therapy preferably in younger patients, while immune checkpoint inhibitor monotherapy should be applied in elderly subjects [ 23 ]. This issue may be further addressed in future studies.…”

Section: Discussionmentioning

confidence: 99%

Deep Learning-Based Body Composition Analysis Predicts Outcome in Melanoma Patients Treated with Immune Checkpoint Inhibitors

et al. 2021

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Previous studies suggest an impact of body composition on outcome in melanoma patients. We aimed to determine the prognostic value of CT-based body composition assessment in patients receiving immune checkpoint inhibitor therapy for treatment of metastatic disease using a deep learning approach. One hundred seven patients with staging CT examinations prior to initiation of checkpoint inhibition between January 2013 and August 2019 were retrospectively evaluated. Using an automated deep learning-based body composition analysis pipeline, parameters for estimation of skeletal muscle mass (skeletal muscle index, SMI) and adipose tissue compartments (visceral adipose tissue index, VAI; subcutaneous adipose tissue index, SAI) were derived from staging CT. The cohort was binarized according to gender-specific median cut-off values. Patients below the median were defined as having low SMI, VAI, or SAI, respectively. The impact on outcome was assessed using the Kaplan–Meier method with log-rank tests. A multivariable logistic regression model was built to test the impact of body composition parameters on 3-year mortality. Patients with low SMI displayed significantly increased 1-year (25% versus 9%, p = 0.035), 2-year (32% versus 13%, p = 0.017), and 3-year mortality (38% versus 19%, p = 0.016). No significant differences with regard to adipose tissue compartments were observed (3-year mortality: VAI, p = 0.448; SAI, p = 0.731). On multivariable analysis, low SMI (hazard ratio (HR), 2.245; 95% confidence interval (CI), 1.005–5.017; p = 0.049), neutrophil-to-lymphocyte ratio (HR, 1.170; 95% CI, 1.076–1.273; p < 0.001), and Karnofsky index (HR, 0.965; 95% CI, 0.945–0.985; p = 0.001) remained as significant predictors of 3-year mortality. Lowered skeletal muscle index as an indicator of sarcopenia was associated with worse outcome in patients with metastatic melanoma receiving immune checkpoint inhibitor therapy.

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Is single versus combination therapy problematic in the treatment of cutaneous melanoma?

Cited by 6 publications

References 107 publications

Ultrarapid lytic granule release from CTLs activates Ca ²⁺ -dependent synaptic resistance pathways in melanoma cells

Ultrarapid lytic granule release from CTLs activates Ca ²⁺ -dependent synaptic resistance pathways in melanoma cells

Circulating Tumour DNA Is an Independent Prognostic Biomarker for Survival in Metastatic BRAF or NRAS-Mutated Melanoma Patients

Deep Learning-Based Body Composition Analysis Predicts Outcome in Melanoma Patients Treated with Immune Checkpoint Inhibitors

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Is single versus combination therapy problematic in the treatment of cutaneous melanoma?

Cited by 6 publications

References 107 publications

Ultrarapid lytic granule release from CTLs activates Ca 2+ -dependent synaptic resistance pathways in melanoma cells

Ultrarapid lytic granule release from CTLs activates Ca 2+ -dependent synaptic resistance pathways in melanoma cells

Circulating Tumour DNA Is an Independent Prognostic Biomarker for Survival in Metastatic BRAF or NRAS-Mutated Melanoma Patients

Deep Learning-Based Body Composition Analysis Predicts Outcome in Melanoma Patients Treated with Immune Checkpoint Inhibitors

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Ultrarapid lytic granule release from CTLs activates Ca ²⁺ -dependent synaptic resistance pathways in melanoma cells

Ultrarapid lytic granule release from CTLs activates Ca ²⁺ -dependent synaptic resistance pathways in melanoma cells