Long-Term Outcomes and Responses to Retreatment in Patients With Melanoma Treated With PD-1 Blockade

Warner, Allison Betof; Palmer, Jessica; Shoushtari, Alexander N.; Goldman, Debra A.; Panageas, Katherine S.; Hayes, Sara A.; Bajwa, Raazi; Momtaz, Parisa; Callahan, Margaret K.; Wolchok, Jedd D.; Postow, Michael A.; Chapman, Paul B.

doi:10.1200/jco.19.01464

Cited by 138 publications

(114 citation statements)

References 19 publications

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“…Most CRs were durable, but the probability of treatment failure 3 years after best overall response was 27%. 61 The appropriate time to stop treatment has been the subject of much debate, particularly because different agents were developed with different stopping rules. For example, in the pembrolizumab KEYNOTE-006 trial, patients received up to 2 years of treatment 5 ; whereas, in the CheckMate 067 trial, patients continued until progression, unacceptable toxicity, or withdrawal of consent.…”

Section: Long-term Survival Outcomesmentioning

confidence: 99%

Evolving impact of long-term survival results on metastatic melanoma treatment

Michielin

Atkins

Koon

et al. 2020

J Immunother Cancer

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Melanoma treatment has been revolutionized over the past decade. Long-term results with immuno-oncology (I-O) agents and targeted therapies are providing evidence of durable survival for a substantial number of patients. These results have prompted consideration of how best to define long-term benefit and cure. Now more than ever, oncologists should be aware of the long-term outcomes demonstrated with these newer agents and their relevance to treatment decision-making. As the first tumor type for which I-O agents were approved, melanoma has served as a model for other diseases. Accordingly, discussions regarding the value and impact of long-term survival data in patients with melanoma may be relevant in the future to other tumor types. Current findings indicate that, depending on the treatment, over 50% of patients with melanoma may gain durable survival benefit. The best survival outcomes are generally observed in patients with favorable prognostic factors, particularly normal baseline lactate dehydrogenase and/or a low volume of disease. Survival curves from melanoma clinical studies show a plateau at 3 to 4 years, suggesting that patients who are alive at the 3-year landmark (especially in cases in which treatment had been stopped) will likely experience prolonged cancer remission. Quality-of-life and mixture-cure modeling data, as well as metrics such as treatment-free survival, are helping to define the value of this long-term survival. In this review, we describe the current treatment landscape for melanoma and discuss the long-term survival data with immunotherapies and targeted therapies, discussing how to best evaluate the value of long-term survival. We propose that some patients might be considered functionally cured if they have responded to treatment and remained treatment-free for at least 2 years without disease progression. Finally, we consider that, while there have been major advances in the treatment of melanoma in the past decade, there remains a need to improve outcomes for the patients with melanoma who do not experience durable survival.

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Section: Long-term Survival Outcomesmentioning

confidence: 99%

Evolving impact of long-term survival results on metastatic melanoma treatment

Michielin

Atkins

Koon

et al. 2020

J Immunother Cancer

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“…In recent years, immune checkpoint blockade has demonstrated that targeting the immune system by activating previously exhausted or dysfunctional T cells can lead to long-term control of various cancers, including melanoma ( 57 – 59 ). In particular, cytotoxic CD8+ T cells are important for tumor cell killing and memory CD8+ T cells are important for durable anti-tumor immunity ( 60 ).…”

Section: Tumor Microenvironment Of Neuroblastomamentioning

confidence: 99%

“Re-educating” Tumor Associated Macrophages as a Novel Immunotherapy Strategy for Neuroblastoma

Liu

Joshi

2020

Front. Immunol.

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Neuroblastoma is the most common extracranial pediatric tumor and often presents with metastatic disease, and patients with high-risk neuroblastoma have survival rates of ~50%. Neuroblastoma tumorigenesis is associated with the infiltration of various types of immune cells, including myeloid derived suppressor cells, tumor associated macrophages (TAMs), and regulatory T cells, which foster tumor growth and harbor immunosuppressive functions. In particular, TAMs predict poor clinical outcomes in neuroblastoma, and among these immune cells, TAMs with an M2 phenotype comprise an immune cell population that promotes tumor metastasis, contributes to immunosuppression, and leads to failure of radiation or checkpoint inhibitor therapy. This review article summarizes the role of macrophages in tumor angiogenesis, metastasis, and immunosuppression in neuroblastoma and discusses the recent advances in “macrophage-targeting strategies” in neuroblastoma with a focus on three aspects: (1) inhibition of macrophage recruitment, (2) targeting macrophage survival, and (3) reprogramming of macrophages into an immunostimulatory phenotype.

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“…Recent advances in immunotherapeutic approaches have raised unprecedented clinical achievements in the treatment of cancer, particularly in melanoma [ 47 ]. However, a considerable fraction of treated patients remain as non-responders and/or acquire resistance to immunotherapy [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Hypoxic Melanoma Cells Deliver microRNAs to Dendritic Cells and Cytotoxic T Lymphocytes through Connexin-43 Channels

Tittarelli

Navarrete

Lizana

et al. 2020

IJMS

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Alterations in microRNA (miRNA) profiles, induced by tumor microenvironment stressors, like hypoxia, allow cancer cells to acquire immune-resistance phenotypes. Indeed, hypoxia-induced miRNAs have been implicated in cancer progression through numerous cancer cell non-autonomous mechanisms, including the direct transfer of hypoxia-responsive miRNA from cancer to immune cells via extracellular vesicles. Connexin-43 (Cx43)-constituted gap junctions (GJs) have also been involved in miRNA intercellular mobilization, in other biological processes. In this report, we aimed to evaluate the involvement of Cx43-GJs in the shift of miRNAs induced by hypoxia, from hypoxic melanoma cells to dendritic cells and melanoma-specific cytotoxic T lymphocytes (CTLs). Using qRT-PCR arrays, we identified that miR-192-5p was strongly induced in hypoxic melanoma cells. Immune cells acquired this miRNA after co-culture with hypoxic melanoma cells. The transfer of miR-192-5p was inhibited when hypoxic melanoma cells expressed a dominant negative Cx43 mutant or when Cx43 expression was silenced using specific short-hairpin RNAs. Interestingly, miR-192-5p levels on CTLs after co-culture with hypoxic melanoma cells were inversely correlated with the cytotoxic activity of T cells and with ZEB2 mRNA expression, a validated immune-related target of miR-192-5p, which is also observed in vivo. Altogether, our data suggest that hypoxic melanoma cells may suppress CTLs cytotoxic activity by transferring hypoxia-induced miR-192-5p through a Cx43-GJs driven mechanism, constituting a resistance strategy for immunological tumor escape.

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Long-Term Outcomes and Responses to Retreatment in Patients With Melanoma Treated With PD-1 Blockade

Cited by 138 publications

References 19 publications

Evolving impact of long-term survival results on metastatic melanoma treatment

Evolving impact of long-term survival results on metastatic melanoma treatment

“Re-educating” Tumor Associated Macrophages as a Novel Immunotherapy Strategy for Neuroblastoma

Hypoxic Melanoma Cells Deliver microRNAs to Dendritic Cells and Cytotoxic T Lymphocytes through Connexin-43 Channels

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