It is not always chlorhexidine: Identification of benzoxonium chloride and lauramine oxide as culprit allergens in a popular antiseptic in Switzerland.

BACKGROUND: A popular antiseptic spray in Switzerland (Merfen spray), containing chlorhexidine digluconate, benzoxonium chloride and lauramine oxide, is frequently used to treat skin wounds. However, it is also increasingly reported as a major cause of adverse skin reactions, including allergic contact dermatitis (ACD). OBJECTIVES: To investigate the contact allergens responsible for ACD from this antiseptic. PATIENTS/METHODS: Patch tests were performed on seven patients with a clinical history compatible with contact dermatitis from this antiseptic mixture. RESULTS: All patients presented with acute eczematous reactions following contact with either Merfen spray alone, or with multiple products including this spray. Patients showed positive reactions to this product in both patch tests and repeated open application tests (ROATs). Four patients showed dose-dependent reactions to both benzoxonium chloride and lauramine oxide. One patient showed a dose-dependent reaction to the former and a non-dose-dependent reaction to the latter. Finally, two subjects showed responses only to lauramine oxide. One patient reacted to chlorhexidine digluconate 0.5% aq. in addition to both other allergens. CONCLUSIONS: Two commercially unavailable allergens, that is, benzoxonium chloride and/or lauramine oxide were identified as major causes of ACD from Merfen antiseptic spray, whereas chlorhexidine digluconate was a contributing culprit in only one patient.

Low-Dose Nivolumab with or without Ipilimumab as Adjuvant Therapy Following the Resection of Melanoma Metastases: A Sequential Dual Cohort Phase II Clinical Trial.

BACKGROUND: Optimal dosing and duration of adjuvant treatment with PD-1 and CTLA-4 immune checkpoint inhibitors have not been established. Prior to their regulatory approval we investigated a low-dose regimen of nivolumab with or without ipilimumab in a sequential dual-cohort phase II clinical trial. METHODS: Following the complete resection of melanoma metastases, patients were treated with a single fixed dose of ipilimumab (50 mg) plus 4 bi-weekly fixed doses of nivolumab (10 mg) (cohort-1), or nivolumab for 1 year (10 mg fixed dose, Q2w x9, followed by Q8w x4) (cohort-2). Twelve-months relapse-free survival (RFS) served as the primary endpoint. RESULTS: After a median follow-up of 235 weeks for cohort-1 (34 patients), and 190 weeks for cohort-2 (21 patients), the 12-months RFS-rate was, respectively, 55.9% (95% CI, 39-72), and 85.7% (95% CI, 70-100). Treatment-related adverse events occurred in 27 (79%), and 18 (86%) patients, with 3 (9%), and 1 (5%) grade 3 adverse events in cohort-1 and -2, respectively. Immunohistochemical quantification of intra- and peritumoral CD3+ T cells and CD20+ B cells, but not PD-1/PD-L1 staining, correlated significantly with RFS. CONCLUSIONS: One year of adjuvant low-dose nivolumab could be an effective and economically advantageous alternative for standard dosing, at the condition of further confirmation in a larger patient cohort. A shorter low-dose nivolumab plus ipilimumab regimen seems inferior and less tolerable.

A Comprehensive Analysis of Baseline Clinical Characteristics and Biomarkers Associated with Outcome in Advanced Melanoma Patients Treated with Pembrolizumab.

BACKGROUND: Pembrolizumab improves the survival of patients with advanced melanoma. A comprehensive analysis of baseline variables that predict the benefit of pembrolizumab monotherapy has not been conducted. METHODS: Survival data of patients with advanced melanoma who were treated with pembrolizumab in a single university hospital were collected. A multivariate Cox regression analysis was performed to correlate baseline clinical, laboratory, and radiologic characteristics and NanoString IO360 gene expression profiling (GEP) with survival. RESULTS: 183 patients were included (stage IV 85.2%, WHO performance status ≥1 31.1%; pembrolizumab first-line 25.7%), of whom 112 underwent baseline 18F-FDG-PET/CT imaging, 58 had circulating tumor DNA (ctDNA) assessments, and GEP was available in 27 patients. Active brain metastases, a higher number of metastatic sites, lower albumin and absolute lymphocyte count (ALC), higher C-reactive protein (CRP) and neutrophil-to-lymphocyte ratio, higher total metabolic tumor volume (TMTV), and higher ctDNA levels were associated with worse survival. Elevated lactate dehydrogenase (LDH) ≥ 2ULN (upper limit of normal), CRP ≥ 10ULN, or ALC < 750/mm3 delineate a subpopulation where treatment with pembrolizumab is futile. A TMTV ≥ 80 mL encompassed 17/21 patients with LDH ≥ 2ULN, CRP ≥ 10ULN, or ALC < 750/mm3. No significant associations were observed between baseline GEP scores and survival. CONCLUSION: Multiple baseline variables correlate with survival on pembrolizumab. TMTV is a more comprehensive baseline biomarker than CRP, LDH, or ALC in predicting the futility of pembrolizumab.

Whole-Body MRI for the Detection of Recurrence in Melanoma Patients at High Risk of Relapse.

Introduction: No standard protocol for surveillance for melanoma patients is established. Whole-body magnetic resonance imaging (whole-body MRI) is a safe and sensitive technique that avoids exposure to X-rays and contrast agents. This prospective study explores the use of whole-body MRI for the early detection of recurrences. Material and Methods: Patients with American Joint Committee on Cancer Staging Manual (seventh edition; AJCC-7) stages IIIb/c or -IV melanoma who were disease-free following resection of macrometastases (cohort A), or obtained a durable complete response (CR) or partial response (PR) following systemic therapy (cohort B), were included. All patients underwent whole-body MRI, including T1, Short Tau Inversion Recovery, and diffusion-weighted imaging, every 4 months the first 3 years of follow-up and every 6 months in the following 2 years. A total body skin examination was performed every 6 months. Results: From November 2014 to November 2019, 111 patients were included (four screen failures, cohort A: 68 patients; cohort B: 39 patients). The median follow-up was 32 months. Twenty-six patients were diagnosed with suspected lesions. Of these, 15 patients were diagnosed with a recurrence on MRI. Eleven suspected lesions were considered to be of non-neoplastic origin. In addition, nine patients detected a solitary subcutaneous metastasis during self-examination, and two patients presented in between MRIs with recurrences. The overall sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were, respectively, 58%, 98%, 58%, 98%, and 98%. Sensitivity and specificity for the detection of distant metastases was respectively 88% and 98%. No patient experienced a clinically meaningful (>grade 1) adverse event. Conclusions: Whole-body MRI for the surveillance of melanoma patients is a safe and sensitive technique sparing patients' cumulative exposure to X-rays and contrast media.

Pembrolizumab for the treatment of uveal melanoma: A case series.

Uveal melanoma is a rare disease. Up to 50% of the patients will develop metastases for which the treatment options are limited. No randomized controlled data for the treatment of uveal melanoma patients are available. In this study we describe the clinical course of nine uveal melanoma patients included in the pembrolizumab expanded access program (EAP) in Belgium. Nine uveal melanoma patients were treated in the EAP with 2mg/kg pembrolizumab every 3 weeks. Patients received pembrolizumab as first or second-line treatment. Baseline characteristics and tumor responses were prospectively collected. During a median follow-up of 40 weeks, the estimated median PFS was 18 weeks (95% CI 0.7-35) and median OS was 46 weeks (95% CI 33-59%). Four patients had stable disease (SD) for more than 20 weeks (PFS of 21, 22, and 27 weeks respectively) and 1 patient presented with SD for 119 weeks. No objective responses according to irRC were observed. One grade 3 hepatitis occurred which was reversible with the administration of high doses oral corticosteroids. Even though treatment with pembrolizumab is well tolerated, clinical benefit is disappointing. Nevertheless long-term diseases control can be achieved in selected cases.

Application of Circulating Cell-Free Tumor DNA Profiles for Therapeutic Monitoring and Outcome Prediction in Genetically Heterogeneous Metastatic Melanoma.

PURPOSE: Circulating cell-free tumor DNA (ctDNA) reflects the heterogeneous spectrum of tumor-specific mutations, especially in systemic disease. We validated plasma-based assays that allow the dynamic quantitative detection of ctDNA as a prognostic biomarker for tumor load and prediction of therapy response in melanoma. MATERIALS AND METHODS: We analyzed plasma-derived ctDNA from a large training cohort (n = 96) of patients with advanced-stage melanoma, with assays for the BRAF V600E and NRAS Q61 driver mutations as well as TERT C250T and TERT C228T promoter mutations. An independent patient cohort (n = 35) was used to validate the utility of ctDNA monitoring under mitogen-activated protein kinase-targeted or immune checkpoint therapies. RESULTS: Elevated plasma ctDNA level at baseline was an independent prognostic factor of disease progression when compared with serum S100 and lactate dehydrogenase levels in multivariable analyses (hazard ratio [HR], 7.43; 95% CI, 1.01 to 55.19; P = .05). The change in ctDNA levels during therapy correlated with treatment response, where increasing ctDNA was predictive for shorter progression-free survival (eg, for BRAF V600E ctDNA, HR, 3.70; 95% CI, 1.86 to 7.34; P < .001). Increasing ctDNA levels predicted disease progression significantly earlier than did routine radiologic scans (P < .05), with a mean lead time of 3.5 months. NRAS-mutant ctDNA was detected in a significant proportion of patients with BRAF-mutant tumors under therapy, but unexpectedly also at baseline. In vitro sensitivity studies suggested that this represents higher-than-expected intratumoral heterogeneity. The detection of NRAS Q61 ctDNA in baseline samples of patients with BRAF V600E mutation who were treated with mitogen-activated protein kinase inhibitors significantly correlated with shorter progression-free survival (HR, 3.18; 95% CI, 1.31 to 7.68; P = .03) and shorter overall survival (HR, 4.08; 95% CI, 1.57 to 10.58; P = .01). CONCLUSION: Our results show the potential role of ctDNA measurement as a sensitive monitoring and prediction tool for the early assessment of disease progression and therapeutic response in patients with metastatic melanoma.

A randomized controlled phase II clinical trial on mRNA electroporated autologous monocyte-derived dendritic cells (TriMixDC-MEL) as adjuvant treatment for stage III/IV melanoma patients who are disease-free following the resection of macrometastases.

BACKGROUND: Autologous monocyte-derived mRNA co-electroporated dendritic cells with mRNA encoding CD40 ligand (CD40L), CD70 and a constitutively activated TLR4 (caTLR4) (referred to as TriMixDC-MEL) have anti-tumor activity in advanced melanoma patients. We investigated the safety and activity of adjuvant TriMixDC-MEL in stage III/IV melanoma patients. MATERIALS AND METHODS: Forty-one patients were randomly assigned to treatment with TriMixDC-MEL (n = 21) and standard follow-up (n = 20). "Cross-over" was allowed at the time of non-salvageable recurrence. The primary endpoint was the percentage of patients alive and disease-free at 1-year. For a subset of patients, (formalin-fixed paraffin-embedded), tumor tissue samples were available for mRNA expression profiling and PD-L1 immunohistochemical staining. RESULTS: Baseline characteristics were well balanced. One-year after randomization, 71% of patients in the study arm were alive and free of disease compared to 35% in the control arm. After a median follow-up of 53 months (range 3-67), 23 patients experienced a non-salvageable melanoma recurrence (TriMixDC-Mel arm n = 9 and control arm n = 14).The median time to non-salvageable recurrence was superior in the TriMixDC-MEL arm (median 8 months (range 1-6) vs. not reached; log-rank p 0.044). TriMixDC-MEL-related adverse events (AE) consisted of transient local skin reactions, flu-like symptoms and post-infusion chills. No grade ≥ 3 AE's occurred. The mRNA expression profiling revealed four genes (STAT2, TPSAB1, CD9 and CSF2) as potential predictive biomarkers. CONCLUSION: TriMixDC-MEL id/iv as adjuvant therapy is tolerable and may improve the 1-year disease-free survival rate. Combination of optimized autologous monocyte-derived DC-formulations warrants further investigation in combination with currently approved adjuvant therapy options.

Undetectable circulating tumor DNA (ctDNA) levels correlate with favorable outcome in metastatic melanoma patients treated with anti-PD1 therapy.

BACKGROUND: Treatment with anti-PD1 monoclonal antibodies improves the survival of metastatic melanoma patients but only a subgroup of patients benefits from durable disease control. Predictive biomarkers for durable benefit could improve the clinical management of patients. METHODS: Plasma samples were collected from patients receiving anti-PD1 therapy for ctDNA quantitative assessment of BRAFV600 and NRASQ61/G12/G13 mutations. RESULTS: After a median follow-up of 84 weeks 457 samples from 85 patients were analyzed. Patients with undetectable ctDNA at baseline had a better PFS (Hazard ratio (HR) = 0.47, median 26 weeks versus 9 weeks, p = 0.01) and OS (HR = 0.37, median not reached versus 21.3 weeks, p = 0.005) than patients with detectable ctDNA. Additionally, the HR for death was lower after the ctDNA level became undetectable during follow-up (adjusted HR: 0.16 (95% CI 0.07-0.36), p-value < 0.001). ctDNA levels > 500 copies/ml at baseline or week 3 were associated with poor clinical outcome. Patients progressive exclusively in the central nervous system (CNS) had undetectable ctDNA at baseline and at subsequent assessments. In multivariate analysis adjusted for LDH, CRP, ECOG and number of metastatic sites, the ctDNA remained significant for PFS and OS. A positive correlation was observed between ctDNA levels and total metabolic tumor volume (TMTV), number of metastatic sites and total tumor burden. CONCLUSIONS: Assessment of ctDNA baseline and during therapy was predictive for tumor response and clinical outcome in metastatic melanoma patients and reflected the tumor burden. ctDNA evaluation provided reliable complementary information during anti-PD1 antibody therapy.

Phase I clinical trial of decitabine (5-aza-2'-deoxycytidine) administered by hepatic arterial infusion in patients with unresectable liver-predominant metastases.

DNA demethylating agents may increase the immunogenicity of malignant tumours and increase the efficacy of subsequent treatment with immune check point inhibitors. We investigated the safety of administrating the demethylating agent decitabine by hepatic arterial infusionin patients with unresectable liver meta stases from solid tumours in a dose escalation phase I clinical trial. A total of nine eligible patients were enrolled and initiated study treatment at three different dose levels (two patients at 10, four at 15 and six at a dose level of 20mg decitabine/m2/day) (per protocol there was no intent to escalate the dose above the median tolerated intravenous dose level). Decitabine was administered as a 1-hour hepatic arterial infusion on five consecutive days every 4 weeks. Intrapatient dose escalation was applied in five patients. Grades 1 and 2 haematological toxicity was the most frequent treatment-related adverse event. None of the patients experienced treatment-limiting adverse events. Expression analysis of 30 cancer test is antigens (CTA) in pretreatment and post-treatment biopsies from patients indicated an increased expression of 21 CTAs after treatment. There were no objective tumour responses on study treatment or during post study exposure to immune checkpoint therapy in four patients with uveal melanoma liver metastases. We conclude that the investigate d hepatic arterial administration regimen for decitabine can be safely applied, and a dose level of 20 mg/m2/day on five consecutive days every 4 weeks can be considered for further investigation in combinatorial immunotherapy regimens. TRIAL REGISTRATION NUMBER: NCT02316028.

Phase 2 Trial of Nivolumab Combined With Stereotactic Body Radiation Therapy in Patients With Metastatic or Locally Advanced Inoperable Melanoma.

PURPOSE: Nivolumab improves survival in patients with metastatic melanoma. Unfortunately, most patients do not respond to this treatment. Preclinical data indicate that radiation therapy could work synergistically with nivolumab and improve response rates. METHODS AND MATERIALS: We conducted a phase 2 trial in 20 patients with inoperable or metastatic melanoma with ≥2 measurable lesions (Response Evaluation Criteria in Solid Tumors v1.1). Stereotactic body radiation therapy (SBRT) of 3 × 8 Gy to the largest lesion was delivered before the second nivolumab cycle. The primary endpoint was overall response rate (ORR) in the nonirradiated lesions (Response Evaluation Criteria in Solid Tumors v1.1). Secondary endpoints included toxicity. An exploratory endpoint was mutant BRAF and NRAS circulating tumor DNA (ctDNA) on serial blood samples. RESULTS: An ORR of 45% was noted with 3 complete and 6 partial responses. Three patients experienced stable disease and 7 had progressive disease as best response. All patients with a complete response in the nonirradiated lesions exhibited a local complete response in the irradiated lesion. Grade 1 to 2 treatment-related adverse events (AEs) occurred in 17 patients; 3 patients experienced grade 3 AEs (lymphopenia, gastroenteritis, and bullous pemphigoid). No grade 4 to 5 AEs occurred. ctDNA was detected in 8 patients, and changes corresponded to clinical response and suggested that a subset of patients with a low programmed death ligand-1 score only started responding after SBRT. CONCLUSIONS: We conclude that the combination treatment was well tolerated and led to an ORR of 45% in patients with metastatic or inoperable melanoma, similar to historical response rates of nivolumab monotherapy. Although underpowered, our data therefore do not indicate a substantial abscopal response. Nonetheless, serial ctDNA analyses suggest that a subset of patients responded only after the addition of SBRT.

Anaphylaxis-like reaction to anti-BRAF inhibitor dabrafenib confirmed by drug provocation test.

The combination of BRAF and MEK inhibitors is a standard therapeutic option for patients with metastatic melanoma with BRAF-mutated tumors. This type of targeted therapy improved patient survival, having a manageable toxicity profile. Nevertheless, potentially life-threatening severe toxicity as anaphylaxis-like reactions was observed in two reported cases. No confirmatory testing was performed for these two patients. We report a case of anaphylactic reaction to the BRAF inhibitor dabrafenib administered as a first-line treatment. The clinical picture is different compared with the reported cases, with the main life-threatening symptom being severe hypotension. An important feature of our case report is the diagnostic assessment by drug provocation test, which is considered the 'gold standard' investigation for the diagnosis of drug hypersensitivity. Additionally, serum tryptase levels were assessed, and the basophil activation test has been performed as an in-vitro diagnostic test. Elements in favor of both IgE-mediated and non-IgE-mediated reaction were observed, which is suggestive of a complex pathomechanism. This can be evocative for the heterogenous clinical manifestation of the immediate hypersensitivity reactions to BRAF inhibitors. The mechanisms responsible for the reactions should be investigated in future molecular and cellular studies.

Successful treatment with intralesional talimogene laherparepvec in two patients with immune checkpoint inhibitor-refractory, advanced-stage melanoma.

Monoclonal antibodies that block the programmed death-1 (anti-PD-1) or cytotoxic T-lymphocyte antigen-4 (CTLA-4) immune checkpoint receptors (pembrolizumab, nivolumab, ipilimumab, or the combination of nivolumab with ipilimumab) are approved treatment option for patients with advanced melanoma. Over half of all patients are refractory to these immunotherapies and are in need of alternative or complementary treatment options. Talimogene laherparepvec (T-VEC) is a first-in-class intralesionally delivered oncolytic immunotherapy, which has proven efficacy in the treatment of advanced melanoma. A proportion of patients treated with T-VEC will benefit from an abscopal response of noninjected metastases indicative of a systemic antitumor immune response elicited by the intratumoral injections. At present it remains unknown whether the systemic antitumor responses elicited by T-VEC are nonredundant with immune-checkpoint blockade. Recent data on potential synergy between T-VEC and both PD-1 and CTLA-4 blockade suggest that the mechanism of action may be complementary. We report on the successful treatment with intralesional T-VEC of two female patients with locoregionally advanced BRAF V600 wild-type melanoma who previously progressed on anti-PD-1 and anti-CTLA-4 inhibitors.

Illustrative cases for monitoring by quantitative analysis of BRAF/NRAS ctDNA mutations in liquid biopsies of metastatic melanoma patients who gained clinical benefits from anti-PD1 antibody therapy.

Anti-programmed death 1 (PD-1) monoclonal antibodies improve the survival of metastatic melanoma patients. Predictive or monitoring biomarkers for response to this therapy could improve the clinical management of these patients. To date, no established biomarkers are available for monitoring the response to immunotherapy. Tumor- specific mutations in circulating tumor DNA (ctDNA) such as BRAF and NRAS mutations for melanoma patients have been proposed for monitoring of immunotherapy response. We present seven illustrative cases for the use of ctDNA BRAF and NRAS mutations' monitoring in plasma. The cases described exemplify four distinct clinical benefit patterns: rapid and durable complete response (CR), early progression, followed by CR, CR followed by early progression after interrupting treatment and long-term disease stabilization. These representative cases suggest that comprehensive BRAF/NRAS ctDNA monitoring during anti-PD1 therapy is informative and can be of added value for the monitoring of melanoma patients gaining clinical benefit on anti-PD1 treatment. An important advantage of our approach is that using the cartridge system on the Idylla platform for mutation analysis, the results become available the same day 2 h after plasma collection. Therefore, in the future, the ctDNA level can be an element in the clinical management of the patients.

Combination of dabrafenib plus trametinib for BRAF and MEK inhibitor pretreated patients with advanced BRAFV600-mutant melanoma: an open-label, single arm, dual-centre, phase 2 clinical trial.

BACKGROUND: Patients with BRAFV600-mutant melanoma benefit from treatment with the combination of BRAF and MEK inhibitors, but resistance and disease progression develops in most patients. Preclinical studies and case studies have indicated that acquired resistance to BRAF inhibition can be reversible. We aimed to assess the anti-tumour activity of rechallenge with BRAF plus MEK inhibition in a prospective clinical trial. METHODS: In this open-label, single arm, dual-centre, phase 2 academic study in Belgium, patients aged 18 years or older with BRAFV600-mutant melanoma who had previously progressed on BRAF inhibitors (with or without MEK inhibitors) and were off-treatment for at least 12 weeks, were treated with dabrafenib 150 mg orally twice per day plus trametinib 2 mg orally once per day. The primary endpoint was the proportion of patients with investigator-assessed overall response at any time (defined as complete response or partial response according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 confirmed on two occasions, at least 28 days after the first response was recorded). Analyses were done in the intention-to-treat population. The study is ongoing but no longer recruiting patients. This trial is registered with ClinicalTrials.gov, number NCT02296996. FINDINGS: Between April 5, 2014, and Feb 2, 2016, 25 patients were enrolled and initiated treatment in our study. A partial response was documented in eight (32%) of 25 patients (95% CI 15-54; six patients had progressed on previous treatment with dabrafenib plus trametinib and two patients had progressed on previous BRAF inhibitor monotherapy). Stable disease was noted in ten patients (40%; 95% CI 21-61). Rechallenge with dabrafenib plus trametinib was well tolerated. There were no unexpected or grade 4 or 5 treatment-related adverse events. Grade 3 adverse events occurred in two patients (8%; panniculitis [n=1] and pyrexia [n=1]). Serious adverse events which occurred on study were one patient with an Addison crisis triggered by grade 2 pyrexia symptoms that resolved after discontinuation of dabrafenib and trametinib. No patients died as a result of study treatment. INTERPRETATION: Rechallenge with dabrafenib plus trametinib showed anti-tumour activity in patients who had previously progressed on BRAF inhibitors and as such, rechallenge represents a potential new treatment option for these patients. FUNDING: Vlaamse Liga Tegen Kanker, Novartis.

Molecular and epigenetic features of melanomas and tumor immune microenvironment linked to durable remission to ipilimumab-based immunotherapy in metastatic patients.

BACKGROUND: Ipilimumab (Ipi) improves the survival of advanced melanoma patients with an incremental long-term benefit in 10-15 % of patients. A tumor signature that correlates with this survival benefit could help optimizing individualized treatment strategies. METHODS: Freshly frozen melanoma metastases were collected from patients treated with either Ipi alone (n: 7) or Ipi combined with a dendritic cell vaccine (TriMixDC-MEL) (n: 11). Samples were profiled by immunohistochemistry (IHC), whole transcriptome (RNA-seq) and methyl-DNA sequencing (MBD-seq). RESULTS: Patients were divided in two groups according to clinical evolution: durable benefit (DB; 5 patients) and no clinical benefit (NB; 13 patients). 20 metastases were profiled by IHC and 12 were profiled by RNA- and MBD-seq. 325 genes were identified as differentially expressed between DB and NB. Many of these genes reflected a humoral and cellular immune response. MBD-seq revealed differences between DB and NB patients in the methylation of genes linked to nervous system development and neuron differentiation. DB tumors were more infiltrated by CD8(+) and PD-L1(+) cells than NB tumors. B cells (CD20(+)) and macrophages (CD163(+)) co-localized with T cells. Focal loss of HLA class I and TAP-1 expression was observed in several NB samples. CONCLUSION: Combined analyses of melanoma metastases with IHC, gene expression and methylation profiling can potentially identify durable responders to Ipi-based immunotherapy.