Cancer is a systemic heterogeneous disease that can undergo several rounds of latency and activation. Tumor progression evolves by increasing diversity, adaptation to signals from the microenvironment and escape mechanisms from therapy. These dynamic processes indicate necessity for cell plasticity. Epithelial-mesenchymal transition (EMT) plays a major role in facilitating cell plasticity in solid tumors by inducing dedifferentiation and cell type transitions. These two practices, plasticity and dedifferentiation enhance tumor heterogeneity creating a key challenge in cancer treatment. In this review we will explore cancer cell plasticity and elaborate treatment modalities that aspire to overcome such dynamic processes in solid tumors. We will further discuss the therapeutic potential of utilizing enhanced cell plasticity for differentiation therapy.
Background: Successful treatment with Immune Checkpoint Inhibitors (ICI) requires the balanced activation of the immune system. Over-activation may result in immune-related adverse events (irAEs), which often require steroidal treatment. This study examined the possible impact of steroids on treatment efficacy in melanoma patients concerning initiation timing and dosage. Methods: A retrospective, single-center analysis of patients with advanced melanoma who underwent first-line ICI therapy during 2014–2020 was conducted. Results: Among the 415 patients, two-hundred patients (48.3%) were exposed to steroids during the first line, most of them due to irAEs (n = 169, 84.5%). Nearly a quarter of them were exposed to steroids within the first four weeks of treatment. Surprisingly, steroidal exposure was associated with better progression-free survival (PFS; HR = 0.74, p = 0.015); however, early exposure (within four weeks of treatment) resulted in a significantly shorter PFS compared to late exposure (adjusted HR 3.2, p < 0.001). Conclusions: Early exposure to corticosteroids during the priming phase of ICI therapy could impede the establishment of an effective immune response. These results suggest that caution should be exercised when considering the use of steroids for the management of early-onset irAEs.
9544 Background: The immune-system manipulation by immune-checkpoint inhibitors (ICI) has led to unprecedented clinical advances in melanoma. The management of the consequent immune-related adverse events (irAEs) is based mostly on steroids and other immune-modulators. Methods: A real world single-site cohort of metastatic melanoma patients who were treated with immunotherapy as first line between 2014 and 2020. This study explores the effect of dose, timing, and duration of steroid exposure on treatment efficacy. Results: Four hundred and forty patients were treated with either anti PD-1 (n = 285, 65%) or combination of anti PD-1 and ipilimumab ICI (n = 112, 25%), or ipilimumab alone (n = 43, 10%). The median age was 68 years [12-99y], and 57% were male. Any-grade irAEs were seen in 71% of the patients, and 49% were exposed to steroids. The median steroid dose was 0.75mg/kg prednisolone equivalent [0.03- 80mg/kg], the median duration of steroidal treatment was 11.2 weeks [0.1-316w] and the median time to onset of steroids was 7.6 weeks [0-193w]. Both experiencing irAEs, and the associated steroid exposure were associated with a significant progression free survival (PFS) benefit [HR 0.47, p < 0.001; 95%CI 0.39-0.6 and HR 0.77, p = 0.026; 95%CI 0.60-0.97, respectively], regardless of dose and duration. Notably, within those who were exposed to steroids, an earlier onset of < 4 weeks from immunotherapy initiation was significantly associated with a shorter PFS [HR = 3.5, p < 0.001 (95%CI 2.32-5.45)]. This observation resulted significant also on multivariable analysis including other prognostic variables – ECOG PS, M-stage, LDH and protocol. Conclusions: Steroidal treatment during the immunotherapy priming phase (first 4 weeks) might have a deleterious effect on its’ efficacy and should be explored in larger prospective cohorts.
9566 Background: Several studies have demonstrated that patients who experience irAE as a result of ICI treatment, exhibit significantly improved outcomes compared to patients without toxicity. However, data regarding the impact of specific irAE is currently lacking. Methods: This is a real world single-site cohort of advanced melanoma patients who were treated with ICI as first line between 2014 and 2020. This study explores the effects of specific irAE on treatment efficacy. Results: Three hundred and ninety-five (395) patients were treated with either monotherapy anti PD-1 (65.4%), combination ICI (24.3%), or anti CTLA-4 (10.3%). Median age was 68 years (12-99y), and 57% were male. The median follow up was 24.5m. Any-grade irAEs were seen in 72% (n = 299), and 26% experienced high-grade irAE (n = 104). The most frequent irAE were dermatologic (n = 110, 27.8%), vitiligo (n = 48, 12.1%), rheumatologic (n = 68, 17.2%), gastro-intestinal (n = 66, 16.7%), and endocrine (n = 61, 15.4%). The development of irAE was associated with a significantly longer median PFS (19.3m vs 4.5m; HR 0.46, p < 0.001) and median OS (55m vs 16.9m; HR 0.44, p < 0.001). Specific irAE that were significantly associated with survival benefic were rheumatologic (HR 0.34 for PFS, p < 0.001; HR 0.38 for OS, p < 0.001), dermatologic (HR 0.58 for PFS, p < 0.001; HR 0.54 for OS, p = 0.001), vitiligo (HR 0.30 for PFS, p < 0.001; HR 0.29 for OS, p < 0.001) and endocrine (HR 0.6 for PFS, p = 0.01; HR 0.52 for OS, p < 0.001). After adjustment for ECOG performance status, LDH level, type of ICI protocol and M-substage - the rheumatologic, dermatologic and vitiligo irAE remained significant on multivariate analysis for both PFS and OS. Conclusions: The development of rheumatologic, vitiligo and other dermatologic irAE during ICI treatment, is correlated with a noteworthy survival advantage. These irAE may reflect a hyper-activated immune response and thus can serve as meaningful clinical biomarkers.
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