194 research outputs found
Immune-checkpoint inhibitors in melanoma and kidney cancer: from sequencing to rational selection
No full textImmune-checkpoint inhibitors (ICPIs), including antibodies against cytotoxic T-lymphocyte associated antigen 4 and programmed cell death protein 1, have been shown to induce durable complete responses in a proportion of patients in the first-line and refractory setting in advanced melanoma and renal cell carcinoma. In fact, there are several lines of both targeted agents and ICPI that are now feasible treatment options. However, survival in the metastatic setting continues to be poor and there remains a need for improved therapeutic approaches. In order to enhance patient selection for the most appropriate next line of therapy, better predictive biomarkers of responsiveness will need to be developed in tandem with technologies to identify mechanisms of ICPI resistance. Adaptive, biomarker-driven trials will drive this evolution. The combination of ICPI with specific chemotherapies, targeted therapies and other immuno-oncology (IO) drugs in order to circumvent ICPI resistance and enhance efficacy is discussed. Recent data support the role for both targeted therapies and ICPI in the adjuvant setting of melanoma and targeted therapies in the adjuvant setting for renal cell carcinoma, which may influence the consideration of treatment on subsequent relapse. Approaches to select the optimal treatment sequences for these patients will need to be refined
Resolving genetic heterogeneity in cancer
No full textTo a large extent, cancer conforms to evolutionary rules defined by the rates at which clones mutate, adapt and grow. Next-generation sequencing has provided a snapshot of the genetic landscape of most cancer types, and cancer genomics approaches are driving new insights into cancer evolutionary patterns in time and space. In contrast to species evolution, cancer is a particular case owing to the vast size of tumour cell populations, chromosomal instability and its potential for phenotypic plasticity. Nevertheless, an evolutionary framework is a powerful aid to understand cancer progression and therapy failure. Indeed, such a framework could be applied to predict individual tumour behaviour and support treatment strategies
Clinical and immunologic implications of COVID-19 in patients with melanoma and renal cell carcinoma receiving immune checkpoint inhibitors
No full textThe clinical and immunologic implications of the SARS-CoV-2 pandemic for patients with cancer receiving systemic anticancer therapy have introduced a multitude of clinical challenges and academic controversies. This review summarizes the current evidence, discussion points, and recommendations regarding the use of immune checkpoint inhibitors (ICIs) in patients with cancer during the SARS-CoV-2 pandemic, with a focus on patients with melanoma and renal cell carcinoma (RCC). More specifically, we summarize the theoretical concepts and available objective data regarding the relationships between ICIs and the antiviral immune response, along with recommended clinical approaches to the management of melanoma and RCC patient cohorts receiving ICIs throughout the course of the COVID-19 pandemic. Additional insights regarding the use of ICIs in the setting of current and upcoming COVID-19 vaccines and broader implications toward future pandemics are also discussed.</p
Kidney cancer: The next decade
No full textChris Boshoff, Senior Vice President of Immuno-Oncology, Translational and Early Development at Pfizer, and colleagues Samra Turajlic and Charles Swanton from the Francis Crick Institute and University College London give us their personal point of view on new insights and future therapeutic approaches for renal cancer
Predicting development of ipilimumab-induced hypophysitis: utility of T4 and TSH index but not TSH.
No full textPURPOSE: Ipilimumab, a monoclonal antibody inhibiting CLTA-4, is an established treatment in metastatic melanoma, either alone or in combination with nivolumab, and results in immune mediated adverse events, including endocrinopathy. Hypophysitis is one of the most common endocrine abnormalities. An early recognition of hypophysitis may prevent life threatening consequences of hypopituitarism; therefore, biomarkers to predict which patients will develop hypophysitis would have clinical utility. Recent studies suggested that a decline in TSH may serve as an early marker of IH. This study was aimed at assessing the utility of thyroid function tests in predicting development of hypophysitis. METHODS: A retrospective cohort study was performed for all patients (n = 308) treated with ipilimumab either as a monotherapy or in combination with nivolumab for advanced melanoma at the Royal Marsden Hospital from 2010 to 2016. Thyroid function tests, other pituitary function tests and Pituitary MRIs were used to identify those with hypophysitis. RESULTS AND CONCLUSIONS: Ipilimumab-induced hypophysitis (IH) was diagnosed in 25 patients (8.15%). A decline in TSH was observed in hypophysitis cohort during the first three cycles but it did not reach statistical significance (P = 0.053). A significant fall in FT4 (P < 0.001), TSH index (P < 0.001) and standardised TSH index (P < 0.001) prior to cycles 3 and 4 in hypophysitis cohort was observed. TSH is not useful in predicting development of IH. FT4, TSH index and standardised TSH index may be valuable but a high index of clinical suspicion remains paramount in early detection of hypophysitis
Efficacy and toxicity of rechallenge with combination immune checkpoint blockade in metastatic melanoma: a case series
No full textBackgroundThe efficacy and potential toxicity of rechallenge with combination ipilimumab and nivolumab has not been described. Retreatment of patients with immune checkpoint inhibitors in the setting of prior significant toxicity lacks evidence-based guidance.MethodsWe present the first three, consecutive patients who received re-treatment with combination ipilimumab and nivolumab for metastatic melanoma managed at our institution.ResultsRechallenge with combination ipilimumab and nivolumab in the setting of prior grade 3 toxicity with initial combination therapy is feasible, and responses are seen. We highlight the fact that grade 3 toxicity is likely to recur, but if so, can be manageable.ConclusionsRetreatment with ipi + nivo may be considered an option in carefully selected, well-informed patients. More research is required to delineate the benefits and risks with this approach
How we treat neurological toxicity from immune checkpoint inhibitors.
No full textNeurological adverse events from immune checkpoint inhibition are increasingly recognised, especially with combination anti-cytotoxic T-lymphocyte antigen 4 (CTLA4) and anti-programmed death receptor 1 (anti-PD-1) therapies. Their presenting symptoms and signs are often subacute and highly variable, reflecting the numerous components of the nervous system. Given the risk of substantial morbidity and mortality, it is important to inform patients of symptoms that may be of concern, and to assess any suspected toxicity promptly. As with other immune-related adverse events, the cornerstone of management is administration of corticosteroids. Specialist neurology input is vital in this group of patients to guide appropriate investigations and tailor treatment strategies
Therapeutic inhibition of monocyte recruitment prevents checkpoint inhibitor-induced hepatitis
No full textBackground Checkpoint inhibitor-induced hepatitis (CPI-hepatitis) is an emerging problem with the widening use of CPIs in cancer immunotherapy. Here, we developed a mouse model to characterize the mechanism of CPI-hepatitis and to therapeutically target key pathways driving this pathology.Methods C57BL/6 wild-type (WT) mice were dosed with toll-like receptor (TLR)9 agonist (TLR9-L) for hepatic priming combined with anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) plus anti-programmed cell death 1 (PD-1) (“CPI”) or phosphate buffered saline (PBS) control for up to 7 days. Flow cytometry, histology/immunofluorescence and messenger RNA sequencing were used to characterize liver myeloid/lymphoid subsets and inflammation. Hepatocyte damage was assessed by plasma alanine transaminase (ALT) and cytokeratin-18 (CK-18) measurements. In vivo investigations of CPI-hepatitis were carried out in Rag2−/− and Ccr2rfp/rfp transgenic mice, as well as following anti-CD4, anti-CD8 or cenicriviroc (CVC; CCR2/CCR5 antagonist) treatment.Results Co-administration of combination CPIs with TLR9-L induced liver pathology closely resembling human disease, with increased infiltration and clustering of granzyme B+perforin+CD8+ T cells and CCR2+ monocytes, 7 days post treatment. This was accompanied by apoptotic hepatocytes surrounding these clusters and elevated ALT and CK-18 plasma levels. Liver RNA sequencing identified key signaling pathways (JAK-STAT, NF-ΚB) and cytokine/chemokine networks (Ifnγ, Cxcl9, Ccl2/Ccr2) as drivers of CPI-hepatitis. Using this model, we show that CD8+ T cells mediate hepatocyte damage in experimental CPI-hepatitis. However, their liver recruitment, clustering, and cytotoxic activity is dependent on the presence of CCR2+ monocytes. The absence of hepatic monocyte recruitment in Ccr2rfp/rfp mice and CCR2 inhibition by CVC treatment in WT mice was able to prevent the development and reverse established experimental CPI-hepatitis.Conclusion This newly established mouse model provides a platform for in vivo mechanistic studies of CPI-hepatitis. Using this model, we demonstrate the central role of liver infiltrating CCR2+ monocyte interaction with tissue-destructive CD8+ T cells in the pathogenesis of CPI-hepatitis and highlight CCR2 inhibition as a novel therapeutic target
Contemporary outcomes from the use of regular imaging to detect relapse in high-risk cutaneous melanoma
No full textBackground Agreement on the utility of imaging follow-up in patients with high-risk melanoma is lacking. A UK consensus statement recommends a surveillance schedule of CT or positron-emission tomography-CT and MRI brain (every 6 months for 3 years, then annually in years 4 and 5) as well as clinical examination for high-risk resected Stages II and III cutaneous melanoma. Our aim was to assess patterns of relapse and whether imaging surveillance could be of clinical benefit.Patients and methods A retrospective study of patients enrolled between July 2013 and June 2015 from three UK tertiary cancer centres followed-up according to this protocol was undertaken. We evaluated time-to-recurrence (TTR), recurrence-free survival (RFS), method of detection and characteristics of recurrence, treatment received and overall survival (OS).Results A total of 173 patients were included. Most (79%) had treated Stages IIIB and IIIC disease. With a median follow-up of 23.3 months, 82 patients (47%) had relapsed. Median TTR was 10.1 months and median RFS was 21.2 months. The majority of recurrences (66%) were asymptomatic and detected by scheduled surveillance scan. Fifty-six (68%) patients recurred with Stage IV disease, with a median OS of 25.3 months; 26 (31.7%) patients had a locoregional recurrence, median OS not reached (P=0.016). Patients who underwent surgery at recurrence for either Stage III (27%) or IV (18%) disease did not reach their median OS. The median OS for the 33 patients (40%) who received systemic therapy was 12.9 months.Conclusion Imaging appears to reliably detect subclinical disease and identify patients suitable for surgery, conferring favourable outcomes. The short median TTR provides rationale to intensify imaging schedule in the first year of surveillance. The poor OS of patients treated with systemic therapy probably reflects the relatively inferior treatment options during this time and requires further evaluation in the current era
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