Selective Expansion of Cross-Reactive Cd8+ Memory T Cells by Viral Variants

The role of memory T cells during the immune response against random antigenic variants has not been resolved. Here, we show by simultaneous staining with two tetrameric major histocompatibility complex (MHC)–peptide molecules, that the polyclonal CD8+ T cell response against a series of natural variants of the influenza A nucleoprotein epitope is completely dominated by infrequent cross-reactive T cells that expand from an original memory population. Based on both biochemical and functional criteria, these cross-reactive cytotoxic T cells productively recognize both the parental and the mutant epitope in vitro and in vivo. These results provide direct evidence that the repertoire of antigen-specific T cells used during an infection critically depends on prior antigen encounters, and indicate that polyclonal memory T cell populations can provide protection against a range of antigenic variants

Vemurafenib plus cobimetinib in unresectable stage IIIc or stage IV melanoma:Response monitoring and resistance prediction with positron emission tomography and tumor characteristics (REPOSIT): study protocol of a phase II, open-label, multicenter study

BACKGROUND: In patients with BRAFV600 mutated unresectable stage IIIc or metastatic melanoma, molecular targeted therapy with combined BRAF/MEK-inhibitor vemurafenib plus cobimetinib has shown a significantly improved progression-free survival and overall survival compared to treatment with vemurafenib alone. Nevertheless, the majority of BRAFV600 mutation-positive melanoma patients will eventually develop resistance to treatment. Molecular imaging with F-18-Fluorodeoxyglucose (F-18-FDG) PET has been used to monitor response to vemurafenib in some BRAFV600 mutated metastatic melanoma patients, showing a rapid decline of F-18-FDG uptake within 2 weeks following treatment. Furthermore, preliminary results suggest that metabolic alterations might predict the development of resistance to treatment. F-18-Fluoro-3'-deoxy-3' L-fluorothymidine (F-18-FLT), a PET-tracer visualizing proliferation, might be more suitable to predict response or resistance to therapy than F-18-FDG. METHODS: This phase II, open-label, multicenter study evaluates whether metabolic response to treatment with vemurafenib plus cobimetinib in the first 7 weeks as assessed by F-18-FDG/F-18-FLT PET can predict progression-free survival and whether early changes in F-18-FDG/F-18-FLT can be used for early detection of treatment response compared to standard response assessment with RECISTv1.1 ceCT at 7 weeks. Ninety patients with BRAFV600E/K mutated unresectable stage IIIc/IV melanoma will be included. Prior to and during treatment all patients will undergo F-18-FDG PET/CT and in 25 patients additional F-18-FLT PET/CT is performed. Histopathological tumor characterization is assessed in a subset of 40 patients to unravel mechanisms of resistance. Furthermore, in all patients, blood samples are taken for pharmacokinetic analysis of vemurafenib/cobimetinib. Outcomes are correlated with PET/CT-imaging and therapy response. DISCUSSION: The results of this study will help in linking PET measured metabolic alterations induced by targeted therapy of BRAFV600 mutated melanoma to molecular changes within the tumor. We will be able to correlate both F-18-FDG and F-18-FLT PET to outcome and decide on the best modality to predict long-term remissions to combined BRAF/MEK-inhibitors. Results coming from this study may help in identifying responders from non-responders early after the initiation of therapy and reveal early development of resistance to vemurafenib/cobimetinib. Furthermore, we believe that the results can be fundamental for further optimizing individual patient treatment

Is a History of Optimal Staging by Sentinel Lymph Node Biopsy in the Era Prior to Adjuvant Therapy Associated with Improved Outcome Once Melanoma Patients have Progressed to Advanced Disease?

Introduction: Sentinel lymph node biopsy (SLNB) is important for staging in patients with primary cutaneous melanoma. Did having previously undergone SLNB also affect outcomes in patients once they have progressed to metastatic melanoma in the era prior to adjuvant therapy?Methods: Data were retrieved from the Dutch Melanoma Treatment Registry, a prospectively collected, nationwide database of patients with unresectable stage IIIC or IV (advanced) melanoma between 2012 and 2018. Melanoma-specific survival (MSS) was compared between patients with advanced cutaneous melanoma, previously treated with a wide local excision (WLE) or WLE combined with SLNB as initial treatment of their primary tumor. Cox regression analyses were used to analyze the influence of different variables on MSS.Results: In total, 2581 patients were included, of whom 1412 were treated with a WLE of the primary tumor alone and 1169 in whom this was combined with SLNB. At a median follow-up of 44 months from diagnosis of advanced melanoma, MSS was significantly longer in patients who had previously undergone SLNB {median 23 months (95% confidence interval [CI] 19–29) vs. 18 months (95% CI 15–20) for patients treated with WLE alone; p = 0.002}. However, multivariate Cox regression did not identify SLNB as an independent favorable prognostic factor for MSS after diagnosis of advanced melanoma.Conclusion: Prior to the availability of adjuvant systemic therapy, once patients have unresectable stage IIIC or IV (advanced) melanoma, there was no difference in disease outcome for patients who were or were not previously staged with SLNB.</p

Neoadjuvant immunotherapy with nivolumab and ipilimumab induces major pathological responses in patients with head and neck squamous cell carcinoma

Surgery for locoregionally advanced head and neck squamous cell carcinoma (HNSCC) results in 30‒50% five-year overall survival. In IMCISION (NCT03003637), a non-randomized phase Ib/IIa trial, 32 HNSCC patients are treated with 2 doses (in weeks 1 and 3) of immune checkpoint blockade (ICB) using nivolumab (NIVO MONO, n = 6, phase Ib arm A) or nivolumab plus a single dose of ipilimumab (COMBO, n = 26, 6 in phase Ib arm B, and 20 in phase IIa) prior to surgery. Primary endpoints are feasibility to resect no later than week 6 (phase Ib) and primary tumor pathological response (phase IIa). Surgery is not delayed or suspended for any patient in phase Ib, meeting the primary endpoint. Grade 3‒4 immune-related adverse events are seen in 2 of 6 (33%) NIVO MONO and 10 of 26 (38%) total COMBO patients. Pathological response, defined as the %-change in primary tumor viable tumor cell percentage from baseline biopsy to on-treatment resection, is evaluable in 17/20 phase IIa patients and 29/32 total trial patients (6/6 NIVO MONO, 23/26 COMBO). We observe a major pathological response (MPR, 90‒100% response) in 35% of patients after COMBO ICB, both in phase IIa (6/17) and in the whole trial (8/23), meeting the phase IIa primary endpoint threshold of 10%. NIVO MONO’s MPR rate is 17% (1/6). None of the MPR patients develop recurrent HSNCC during 24.0 months median postsurgical follow-up. FDG-PET-based total lesion glycolysis identifies MPR patients prior to surgery. A baseline AID/APOBEC-associated mutational profile and an on-treatment decrease in hypoxia RNA signature are observed in MPR patients. Our data indicate that neoadjuvant COMBO ICB is feasible and encouragingly efficacious in HNSCC

Immunotherapy of Cancer: Towards a New Era

In the past two decades, immunotherapy of cancer has developed into an established treatment option. At first, the development of monoclonal antibodies – targeting overexpressed cell surface molecules on tumour cells – resulted in improved survival when combined with standard chemotherapy or radiotherapy. More recently, T cell immunotherapy has impacted on survival of certain cancer types. In melanoma especially, but now also in renal cell cancer and non-small cell lung cancer, immune checkpoint inhibitors, such as cytotoxic T lymphocyte–associated antigen-4 (anti-CTLA4) and blockade of programmed death receptor-1-PD- ligand 1 (PD1-PD-L1) interaction, represent a completely new treatment paradigm, lowering the threshold for an anticancer immune response and breaking self-tolerance. Adoptive T cell transfer using tumour- infiltrating lymphocytes or genetically modified T cells are under development, but have shown impressive clinical efficacy in several Phase II studies. These emerging but highly promising treatments can give rise to durable tumour control in diseases that were lethal in all patients only a few years ago

Metabolic biomarker–based BRAFV600 mutation association and prediction in melanoma

The aim of this study was to associate and predict B-rapidly accelerated fibrosarcoma valine 600 (BRAFV600) mutation status with both conventional and radiomics 18F-FDG PET/CT features, while exploring several methods of feature selection in melanoma radiomics. Methods: Seventy unresectable stage III–IV melanoma patients who underwent a baseline 18F-FDG PET/CT scan were identified. Patients were assigned to the BRAFV600 group or BRAF wild-type group according to mutational status. 18F-FDG uptake quantification was performed by semiautomatic lesion delineation. Four hundred eighty radiomics features and 4 conventional PET features (SUVmax, SUVmean, SUVpeak, and total lesion glycolysis) were extracted per lesion. Six different methods of feature selection were implemented, and 10-fold cross-validated predictive models were built for each. Model performances were evaluated with areas under the curve (AUCs) for the receiver operating characteristic curves. Results: Thirty-five BRAFV600 mutated patients (100 lesions) and 35 BRAF wild-type patients (79 lesions) were analyzed. AUCs predicting the BRAFV600 mutation varied from 0.54 to 0.62 and were susceptible to feature selection method. The best AUCs were achieved by feature selection based on literature, a penalized binary logistic regression model, and random forest model. No significant difference was found between the BRAFV600 and BRAF wild-type group in conventional PET features or predictive value. Conclusion: BRAFV600 mutation status is not associated with, nor can it be predicted with, conventional PET features, whereas radiomics features were of low predictive value (AUC 5 0.62). We showed feature selection methods to influence predictive model performance, describing and evaluating 6 unique methods. Detecting BRAFV600 status in melanoma based on 18F-FDG PET/CT alone does not yet provide clinically relevant knowledge