Comprehensive multiplexed immune profiling of the ductal carcinoma in situ immune microenvironment regarding subsequent ipsilateral invasive breast cancer risk

Background: Ductal carcinoma in situ (DCIS) is treated to prevent subsequent ipsilateral invasive breast cancer (iIBC). However, many DCIS lesions will never become invasive. To prevent overtreatment, we need to distinguish harmless from potentially hazardous DCIS. We investigated whether the immune microenvironment (IME) in DCIS correlates with transition to iIBC.Methods: Patients were derived from a Dutch population-based cohort of 10,090 women with pure DCIS with a median follow-up time of 12 years. Density, composition and proximity to the closest DCIS cell of CD20+ B-cells, CD3+CD8+ T-cells, CD3+CD8- T-cells, CD3+FOXP3+ regulatory T-cells, CD68+ cells, and CD8+Ki67+ T-cells was assessed with multiplex immunofluorescence (mIF) with digital whole-slide analysis and compared between primary DCIS lesions of 77 women with subsequent iIBC (cases) and 64 without (controls).Results: Higher stromal density of analysed immune cell subsets was significantly associated with higher grade, ER negativity, HER-2 positivity, Ki67 ≥ 14%, periductal fibrosis and comedonecrosis (P Conclusion: IME features analysed by mIF in 141 patients from a well-annotated cohort of pure DCIS with long-term follow-up are no predictors of subsequent iIBC, but do correlate with other factors (grade, ER, HER2 status, Ki-67) known to be associated with invasive recurrences.</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.Immune checkpoint blockade has become standard care for patients with recurrent metastatic head and neck squamous cell carcinoma (HNSCC). Here the authors present the results of a non-randomized phase Ib/IIa trial, reporting safety and efficacy of neoadjuvant nivolumab monotherapy and nivolumab plus ipilimumab prior to standard-of-care surgery in patients with HNSCC. .Otorhinolaryngolog

Immune cells in mesothelioma microenvironment simplistic marker of response to nivolumab plus ipilimumab?

Introduction: Malignant pleural mesothelioma (MPM) is a malignant disease of the pleura which recently can be treated with immune checkpoint inhibitors (ICI). To optimize this treatment, a better understanding of the tumor micro environment is needed. We investigated subgroups of immune cells in subsequent tumor biopsies of patients treated with ICI. Methods: Biopsies from MPM patients included in two clinical ICI trials (nivolumab alone and an ipilimumab/nivolumab combination) were examined. At baseline and after 6 weeks of treatment, pleural biopsies were taken to examine the tumor microenvironment (CD20+, CD4+, CD8+, FoxP3+ and PD-1+ ). Cell density was defined as the number of marker positive cells per mm(2). Radiological responses were evaluated as partial response, stable disease or progressive disease according to modified RECIST criteria. Results: Thirty-four and 36 patients were included in the nivolumab and ipiliumumab/nivolumab trial respectively. In the nivolumab trial, no significant differences in cell densities were seen in baseline biopsies of patients with partial response versus progressive disease. In contrast, in the ipilimumab/nivolumab trial, a higher cell density of CD4+, CD8+, FoxP3+ and PD-1+ cells at baseline was significantly correlated with partial responses. On-treatment biopsies of both trials did not show significant changes when compared to baseline biopsies. Conclusion: Biopsies from patients responding to nivolumab plus ipilimumab treatment show a significant higher cell density of CD4+, CD8+, FoxP3+ and PD-1+ cells, without a change after 6 weeks of treatment. This observation is a first step in exploring the tumor microenvironment as predictor of response in ICI treatment in MPM