Incidence of Immune-Related Adverse Events with Program Death Receptor-1- and Program Death Receptor-1 Ligand-Directed Therapies in Genitourinary Cancers

Maughan, Benjamin L.; Bailey, Erin; Gill, David; Agarwal, Neeraj

doi:10.3389/fonc.2017.00056

Cited by 79 publications

(60 citation statements)

References 29 publications

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“…The advent of immunotherapy has shown promising outcomes in several disease models, albeit the response rates have been suboptimal (41). In addition, immune-related adverse toxicity and development of resistance poses a major hurdle that compromises the efficacy of immunotherapeutic agents (5,42). Thus, it is important to search for alternate therapeutic strategies that can remodel the tumor immune microenvironment to generate a potent antitumor immune response.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of EphB4–Ephrin-B2 Signaling Reprograms the Tumor Immune Microenvironment in Head and Neck Cancers

et al. 2019

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Identifying targets present in the tumor microenvironment that contribute to immune evasion has become an important area of research. In this study, we identified EphB4-ephrin-B2 signaling as a regulator of both innate and adaptive components of the immune system. EphB4 belongs to receptor tyrosine kinase family that interacts with ephrin-B2 ligand at sites of cell-cell contact, resulting in bidirectional signaling. We found that EphB4-ephrin-B2 inhibition alone or in combination with radiation (RT) reduced intratumoral regulatory T cells (Tregs) and increased activation of both CD8 þ and CD4 þ Foxp3 À T cells compared with the control group in an orthotopic head and neck squamous cell carcinoma (HNSCC) model. We also compared the effect of EphB4-ephrin-B2 inhibition combined with RT with combined anti-PDL1 and RT and observed similar tumor growth suppression, particularly at early time-points. A patient-derived xenograft model showed reduction of tumor-associated M2 macrophages and favored polarization towards an antitumoral M1 phenotype following EphB4-ephrin-B2 inhibition with RT. In vitro, EphB4 signaling inhibition decreased Ki67-expressing Tregs and Treg activation compared with the control group. Overall, our study is the first to implicate the role of EphB4-ephrin-B2 in tumor immune response. Moreover, our findings suggest that EphB4-ephrin-B2 inhibition combined with RT represents a potential alternative for patients with HNSCC and could be particularly beneficial for patients who are ineligible to receive or cannot tolerate anti-PDL1 therapy.Significance: These findings present EphB4-ephrin-B2 inhibition as an alternative to anti-PDL1 therapeutics that can be used in combination with radiation to induce an effective antitumor immune response in patients with HNSCC.

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Section: Discussionmentioning

confidence: 99%

Inhibition of EphB4–Ephrin-B2 Signaling Reprograms the Tumor Immune Microenvironment in Head and Neck Cancers

et al. 2019

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“…33,34 PD-1/PD-L1 For PD-1/PD-L1 inhibitors, the reported overall incidence of any-grade irAE was up to 30% based on patients in phase III trials. 1,[35][36][37] To date, the incidence of highgrade AEs associated with PD-1/PD-L1 inhibitors appears to be somewhat less dose-dependent than for ipilimumab and to vary by disease site. 29 In a recent meta-analysis of anti-PD-1/PD-L1 agents, any-grade and severe-grade irAEs occurred in about 26.8% and 6.1% of patients, respectively.…”

Section: Ctla-4mentioning

confidence: 99%

Management of Immunotherapy-Related Toxicities, Version 1.2019, NCCN Clinical Practice Guidelines in Oncology

Thompson

Schneider

Brahmer

et al. 2019

Journal of the National Comprehensive Cancer Network

436

332

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The aim of the NCCN Guidelines for Management of Immunotherapy-Related Toxicities is to provide guidance on the management of immune-related adverse events resulting from cancer immunotherapy. The NCCN Management of Immunotherapy-Related Toxicities Panel is an interdisciplinary group of representatives from NCCN Member Institutions and ASCO, consisting of medical and hematologic oncologists with expertise in a wide array of disease sites, and experts from the fields of dermatology, gastroenterology, neuro-oncology, nephrology, emergency medicine, cardiology, oncology nursing, and patient advocacy. Several panel representatives are members of the Society for Immunotherapy of Cancer (SITC). The initial version of the NCCN Guidelines was designed in general alignment with recommendations published by ASCO and SITC. The content featured in this issue is an excerpt of the recommendations for managing toxicity related to immune checkpoint blockade and a review of existing evidence. For the full version of the NCCN Guidelines, including recommendations for managing toxicities related to chimeric antigen receptor T-cell therapy, visit NCCN.org.

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“…Furthermore, although less frequently, neurological, cardiological, pulmonary and renal toxicities are being reported. Overall, 75% of patients treated with ipilimumab experience AEs (of any grade), while in the case of PD/PDL-1 inhibitors, AEs are reported in 30% of cases [37,38]. A recent large retrospective analysis showed an incidence of fatal outcomes in 0.36% of patients treated with PD1 inhibitors and in 1.23% of patients treated with combined therapy (PD1 inhibitors plus anti CTLA-4).…”

Section: Adverse Events In Ovarian Cancer Trialsmentioning

confidence: 99%

Immune Checkpoint Inhibitors in Epithelial Ovarian Cancer: An Overview on Efficacy and Future Perspectives

et al. 2020

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Epithelial ovarian cancer (EOC) is the leading cause of death among gynecological cancers. Despite improvements in medical treatments, the prognosis for EOC remains poor, and there is an urgent need for new therapeutic strategies. Immune checkpoint inhibitors (CPIs) have dramatically improved survival of several cancers and are under evaluation in OC. Unfortunately, CPIs have shown globally unsatisfactory results. The aim of this manuscript is to critically review the results from early-phase trials with CPIs in terms of safety and activity, discuss the possible reasons for disappointing results and the new therapeutic approaches to improve patient outcomes. However, despite the success of immunotherapy in other malignancies such as in melanoma, non-small cell lung cancer (NSCLC) and urothelial cancers [25,26], the use of antibodies inhibiting the immune checkpoint programmed cell death (PD-1) or its ligand (PD-L1) obtained modest results in EOC so far, with median response rates of 10% up to 15% [18][19][20]27].Interestingly, the combination of the anti-PD1 nivolumab and the anti-lymphocyte-associated protein 4 (anti-CTLA4) ipilimumab showed promising results in platinum-resistant EOC at six-month interim analyses with an overall response rate (ORR) of 34% (doubling the results of nivolumab monotherapy). However, final results are still awaited [28].As a consequence, no immunotherapeutic agent has obtained regulatory approval for EOC thus far. PD1/PD-L1

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Incidence of Immune-Related Adverse Events with Program Death Receptor-1- and Program Death Receptor-1 Ligand-Directed Therapies in Genitourinary Cancers

Cited by 79 publications

References 29 publications

Inhibition of EphB4–Ephrin-B2 Signaling Reprograms the Tumor Immune Microenvironment in Head and Neck Cancers

Inhibition of EphB4–Ephrin-B2 Signaling Reprograms the Tumor Immune Microenvironment in Head and Neck Cancers

Management of Immunotherapy-Related Toxicities, Version 1.2019, NCCN Clinical Practice Guidelines in Oncology

Immune Checkpoint Inhibitors in Epithelial Ovarian Cancer: An Overview on Efficacy and Future Perspectives

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