Activation of immune responses in patients with relapsed-metastatic head and neck cancer (CONFRONT phase I-II trial): Multimodality immunotherapy with avelumab, short-course radiotherapy, and cyclophosphamide

Merlano, Marco; Merlotti, Anna; Licitra, Lisa; Denaro, Nerina; Fea, Elena; Galizia, Danilo; Maïo, Massimo Di; Fruttero, Claudia; Curcio, Paola; Vecchio, Stefania; Russi, Elvio; Corvò, Renzo

doi:10.1016/j.ctro.2018.08.001

Cited by 12 publications

(13 citation statements)

References 42 publications

(42 reference statements)

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“…Similar results were obtained in the murine colorectal cancer model where oxaliplatin augmented the amounts of CTLs and activated dendritic cells (DCs) potentiating the efficacy of anti-PD-L1 therapy (42). Enhanced infiltration of CD8+ and CD4+FoxP3T along with suppression of the CD4+ CD25+ FoxP3+ regulatory T cell function have seen after low dose cyclophosphamide with an anti-PD1 agent and improved tumor-free survival in a model of cervical cancer (43,44). There are clinical studies ongoing, combining a metronomic dose of cyclophosphamide along with ICIs as depicted in Table 2.…”

Section: Metronomic Therapysupporting

confidence: 59%

Combination Strategies to Augment Immune Check Point Inhibitors Efficacy - Implications for Translational Research

et al. 2021

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Immune checkpoint inhibitor therapy has revolutionized the field of cancer immunotherapy. Even though it has shown a durable response in some solid tumors, several patients do not respond to these agents, irrespective of predictive biomarker (PD-L1, MSI, TMB) status. Multiple preclinical, as well as early-phase clinical studies are ongoing for combining immune checkpoint inhibitors with anti-cancer and/or non-anti-cancer drugs for beneficial therapeutic interactions. In this review, we discuss the mechanistic basis behind the combination of immune checkpoint inhibitors with other drugs currently being studied in early phase clinical studies including conventional chemotherapy drugs, metronomic chemotherapy, thalidomide and its derivatives, epigenetic therapy, targeted therapy, inhibitors of DNA damage repair, other small molecule inhibitors, anti-tumor antibodies hormonal therapy, multiple checkpoint Inhibitors, microbiome therapeutics, oncolytic viruses, radiotherapy, drugs targeting myeloid-derived suppressor cells, drugs targeting Tregs, drugs targeting renin-angiotensin system, drugs targeting the autonomic nervous system, metformin, etc. We also highlight how translational research strategies can help better understand the true therapeutic potential of such combinations.

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Section: Metronomic Therapysupporting

confidence: 59%

Combination Strategies to Augment Immune Check Point Inhibitors Efficacy - Implications for Translational Research

et al. 2021

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“…To date, only the following two anti-PD-1 monoclonal antibodies, pembrolizumab and nivolumab, and two anti-PD-L1 monoclonal antibodies, durvalumab, and atezolizumab (anti-PD-L1), have been tested in R/M HNSCC ( Table 2). As yet, there is only one published phase I study regarding avelumab, a PD-L1 inhibitor, in R/M HNSCC (27)(28)(29).…”

Section: Scope Of Problemsmentioning

confidence: 99%

Current Understanding of the Mechanisms Underlying Immune Evasion From PD-1/PD-L1 Immune Checkpoint Blockade in Head and Neck Cancer

Kok

2020

Front. Oncol.

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Starting in 2014, large phase III clinical trials began to disclose the study results of using programmed death (PD)-1 immune checkpoint inhibitors (ICIs) (pembrolizumab, nivolumab) and PD-ligand (L)1 (atezolizumab, durvalumab, avelumab) ICIs immunotherapy in patients with advanced head and neck squamous cell carcinoma (HNSCC). In the recurrent and metastatic (R/M), cisplatin-refractory setting, nivolumab achieved a 2.2-fold increase of the median 1-year overall survival as compared with investigators' choice of salvage chemotherapy (36.0 vs. 16.6%). A paradigm shift to the winning regimen, pembrolizumab combined with platinum and infusional fluorouracil, has outperformed the past gold standard of cetuximab-based platinum and fluorouracil combination in terms of overall survival (median, 13.6 vs. 10.1 mo) when administered as the first-line treatment for R/M HNSCC. Nevertheless, many patients still did not respond to the PD-1/PD-L1 checkpoint inhibitor treatment, indicating innate, adapted, or quickly acquired resistance to the immunotherapy. The mechanisms of resistance to ICIs targeting the PD-1/PD-L1 signaling pathway in the context of HNSCC are the focus of this review. The past 5 years have seen improved understanding of the mechanisms underlying checkpoint inhibition resistance in tumor cells, such as: tumor cell adaption with malfunction of the antigen-presenting machinery via class I human leukocyte antigen (HLA), reintroduction of cyclin D-cyclin-dependent kinase (CDK) 4 complex to cell cycles, enrichment of CD44+ cancer stem-like cells, or development of inactivating mutation in IKZF1 gene; impairment of T-cell functions and proliferation through mutations in the interferon-γ-regulating genes, suppression of the stimulator of interferon genes (STING) pathway, or resulted from constitutional nutritional iron deficiency state; metabolic reprogramming by cancer cells with changes in metabolites such as GTP cyclohydrolase 1, tetrahydrobiopterin, kynurenine, indoleamine 2,3-dioxygenase, and arginase 1; defective dendritic cells, CD-69 sufficient state; and the upregulation or activation of the alternative immune checkpoints, including lymphocyte activation gene-3 (LAG3), T-cell Kok Immune Evasion From PD-1/PD-L1 Immunotherapy immunoglobulin and ITIM domain (TIGIT)/CD155 pathway, T-cell immunoglobulin mucin-3 (TIM-3), and V domain-containing Ig suppressor of T-cell activation (VISTA). Several potential biomarkers or biosignatures, which could predict the response or resistance to the PD-1/PD-L1 checkpoint immunotherapy, are also discussed.

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“…Lastly, we cannot speculate that the effects seen in the patients treated with this combination are similar to those achievable with other immunotherapies. Ongoing studies from our group, using a similar combination but replacing IL-2 with an anti-PD-L1 [ 36 ] will partially clarify this point. However, it is possible that different immune drugs, targeting other immune check-points, such as LAG-3, TIM-3 and VISTA, or other immune targets may induce different effects on the circulating cytokines.…”

Section: Discussionmentioning

confidence: 99%

Cytokine Profiling of End Stage Cancer Patients Treated with Immunotherapy

Merlano

Abbona²,

Paccagnella³

et al. 2021

Vaccines

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Published data suggest that immunotherapy plays a role even in patients with very advanced tumours. We investigated the immune profile of end-stage cancer patients treated with immunotherapy to identify changes induced by treatment. Breast, colon, renal and prostate cancer patients were eligible. Treatment consisted of metronomic cyclophosphamide, low-dose interleukin-2 (IL-2) and a single radiation shot. A panel of 16 cytokines was assessed using automated ELISA before treatment (T0), after radiation (RT; T1), at cycle 2 (T2) and at disease progression (TPD). Receiving operating characteristic (ROC) analysis was used to identify cytokine cut-off related to overall survival (OS). Principal component analysis (PCA) was used to identify the immune profile correlating better with OS and progression-free survival. Twenty-three patients were enrolled. High IL-2, low IL-8 and CCL-2 correlated with OS. The PCA identified a cluster of patients, with high IL-2, IL-12 and IFN-γ levels at T0 having longer PFS and OS. In all cohorts, IL-2 and IL-5 increased from T0 to T2; a higher CCL-4 level compared to T2 and a higher IL-8 level compared to T0 were found at TPD. The progressive increase of the IL-10 level during treatment negatively correlated with OS. Our data suggested that baseline cytokine levels may predict patients’ outcome and that the treatment may affect their kinetic even in end-stage patients. Cytokine profiling of end-stage patients might offer a tool for medical decisions (EUDRACT: 2016-000578-39).

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Activation of immune responses in patients with relapsed-metastatic head and neck cancer (CONFRONT phase I-II trial): Multimodality immunotherapy with avelumab, short-course radiotherapy, and cyclophosphamide

Cited by 12 publications

References 42 publications

Combination Strategies to Augment Immune Check Point Inhibitors Efficacy - Implications for Translational Research

Combination Strategies to Augment Immune Check Point Inhibitors Efficacy - Implications for Translational Research

Current Understanding of the Mechanisms Underlying Immune Evasion From PD-1/PD-L1 Immune Checkpoint Blockade in Head and Neck Cancer

Cytokine Profiling of End Stage Cancer Patients Treated with Immunotherapy

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