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We study the resistive evolution of a localized self-organizing magnetohydrodynamic equilibrium. In this configuration the magnetic forces are balanced by a pressure force caused by a toroidal depression in the pressure. Equilibrium is attained when this low-pressure region prevents further expansion into the higher-pressure external plasma. We find that, for the parameters investigated, the resistive evolution of the structures follows a universal pattern when rescaled to resistive time. The finite resistivity causes both a decrease in the magnetic field strength and a finite slip of the plasma fluid against the static equilibrium. This slip is caused by a Pfirsch–Schlüter-type diffusion, similar to what is seen in tokamak equilibria. The net effect is that the configuration remains in magnetostatic equilibrium whilst it slowly grows in size. The rotational transform of the structure becomes nearly constant throughout the entire structure, and decreases according to a power law. In simulations this equilibrium is observed when highly tangled field lines relax in a high-pressure (relative to the magnetic field strength) environment, a situation that occurs when the twisted field of a coronal loop is ejected into the interplanetary solar wind. In this paper we relate this localized magnetohydrodynamic equilibrium to magnetic clouds in the solar wind.

The newly published top mass prediction of 85.1 GeV conflicts with indirect limits on the top mass, based on precision measurements interpreted by calculations using dimensional regularization. The top quark contribution to part of the electroweak W and Z vacuum polarization tensor is recomputed using the symmetrical theory of generalised functions. The squared top mass coefficient is larger by a factor 1.44. The indirect limits on the top mass based on this computation should therefore be divided by 1.2. Further recomputation and data analysis is needed.

The efficacy of programmed cell death protein 1 (PD-1) blockade in metastatic triple-negative breast cancer (TNBC) is low1–5, highlighting a need for strategies that render the tumor microenvironment more sensitive to PD-1 blockade. Preclinical research has suggested immunomodulatory properties for chemotherapy and irradiation6–13. In the first stage of this adaptive, non-comparative phase 2 trial, 67 patients with metastatic TNBC were randomized to nivolumab (1) without induction or with 2-week low-dose induction, or with (2) irradiation (3 × 8 Gy), (3) cyclophosphamide, (4) cisplatin or (5) doxorubicin, all followed by nivolumab. In the overall cohort, the objective response rate (ORR; iRECIST14) was 20%. The majority of responses were observed in the cisplatin (ORR 23%) and doxorubicin (ORR 35%) cohorts. After doxorubicin and cisplatin induction, we detected an upregulation of immune-related genes involved in PD-1–PD-L1 (programmed death ligand 1) and T cell cytotoxicity pathways. This was further supported by enrichment among upregulated genes related to inflammation, JAK–STAT and TNF-α signaling after doxorubicin. Together, the clinical and translational data of this study indicate that short-term doxorubicin and cisplatin may induce a more favorable tumor microenvironment and increase the likelihood of response to PD-1 blockade in TNBC. These data warrant confirmation in TNBC and exploration of induction treatments prior to PD-1 blockade in other cancer types.A pick-the-winner clinical trial design in patients with metastatic triple-negative breast cancer shows that immune induction with doxorubicin or cisplatin may improve clinical responses to PD-1 blockade and induce a more favorable tumor microenvironment.

Neoadjuvant ipilimumab plus nivolumab showed high pathologic response rates (pRRs) in patients with macroscopic stage III melanoma in the phase 1b OpACIN ( NCT02437279 ) and phase 2 OpACIN-neo ( NCT02977052 ) studies 1 , 2 . While the results are promising, data on the durability of these pathologic responses and baseline biomarkers for response and survival were lacking. After a median follow-up of 4 years, none of the patients with a pathologic response ( n  = 7/9 patients) in the OpACIN study had relapsed. In OpACIN-neo ( n  = 86), the 2-year estimated relapse-free survival was 84% for all patients, 97% for patients achieving a pathologic response and 36% for nonresponders ( P  < 0.001). High tumor mutational burden (TMB) and high interferon-gamma-related gene expression signature score (IFN-γ score) were associated with pathologic response and low risk of relapse; pRR was 100% in patients with high IFN-γ score/high TMB; patients with high IFN-γ score/low TMB or low IFN-γ score/high TMB had pRRs of 91% and 88%; while patients with low IFN-γ score/low TMB had a pRR of only 39%. These data demonstrate long-term benefit in patients with a pathologic response and show the predictive potential of TMB and IFN-γ score. Our findings provide a strong rationale for a randomized phase 3 study comparing neoadjuvant ipilimumab plus nivolumab versus standard adjuvant therapy with antibodies against the programmed cell death protein-1 (anti-PD-1) in macroscopic stage III melanoma. Long-term outcomes and biomarker analyses of two neoadjuvant immunotherapy clinical trials in melanoma patients support the clinical benefit of this treatment approach and uncover prognostic correlates of response.

Treatment of metastatic melanoma with autologous tumor infiltrating lymphocytes (TILs) is currently applied in several centers. Robust and remarkably consistent overall response rates, of around 50% of treated patients, have been observed across hospitals, including a substantial fraction of durable, complete responses.PurposeExecute a phase I/II feasibility study with TIL therapy in metastatic melanoma at the Netherlands Cancer Institute, with the goal to assess feasibility and potential value of a randomized phase III trial.ExperimentalTen patients were treated with TIL therapy. Infusion products and peripheral blood samples were phenotypically characterized and neoantigen reactivity was assessed. Here, we present long-term clinical outcome and translational data on neoantigen reactivity of the T cell products.ResultsFive out of 10 patients, who were all anti-PD-1 naïve at time of treatment, showed an objective clinical response, including two patients with a complete response that are both ongoing for more than 7 years. Immune monitoring demonstrated that neoantigen-specific T cells were detectable in TIL infusion products from three out of three patients analyzed. For six out of the nine neoantigen-specific T cell responses detected in these TIL products, T cell response magnitude increased significantly in the peripheral blood compartment after therapy, and neoantigen-specific T cells were detectable for up to 3 years after TIL infusion.ConclusionThe clinical results from this study confirm the robustness of TIL therapy in metastatic melanoma and the potential role of neoantigen-specific T cell reactivity. In addition, the data from this study supported the rationale to initiate an ongoing multicenter phase III TIL trial.

Inhibitors of the PD-1–PD-L1 axis have been approved as therapy for many human cancers. In spite of the evidence for their widespread clinical activity, little is known about the immunological alterations that occur in human cancer tissue after PD-1 blockade. We developed and employed a patient-derived tumor fragment platform to dissect the early immunological response of human tumor tissue to ex vivo PD-1 blockade. We observed that the capacity of immune cells to be reactivated ex vivo was predictive of clinical response, and perturbation analyses identified tumor-resident T cells as a key component of this immunological response. In addition, through combined analysis of baseline properties and immune response capacity, we identified a new subgroup of infiltrated tumors that lacks the capacity to respond to PD-1 blockade. Finally, the baseline presence of tertiary lymphoid structures and their components correlated with the capacity of cancers to undergo intratumoral immune cell reactivation. An ex vivo platform of patient-derived tumor fragments enables the assessment of intratumoral immune reactivation after PD-1 blockade that is predictive of clinical outcomes in patients with cancer.

Adjuvant ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) both improve relapse-free survival of stage III melanoma patients 1 , 2 . In stage IV disease, the combination of ipilimumab + nivolumab is superior to ipilimumab alone and also appears to be more effective than nivolumab monotherapy 3 . Preclinical work suggests that neoadjuvant application of checkpoint inhibitors may be superior to adjuvant therapy 4 . To address this question and to test feasibility, 20 patients with palpable stage III melanoma were 1:1 randomized to receive ipilimumab 3 mg kg −1 and nivolumab 1 mg kg −1 , as either four courses after surgery (adjuvant arm) or two courses before surgery and two courses postsurgery (neoadjuvant arm). Neoadjuvant therapy was feasible, with all patients undergoing surgery at the preplanned time point. However in both arms, 9/10 patients experienced one or more grade 3/4 adverse events. Pathological responses were achieved in 7/9 (78%) patients treated in the neoadjuvant arm. None of these patients have relapsed so far (median follow-up, 25.6 months). We found that neoadjuvant ipilimumab + nivolumab expand more tumor-resident T cell clones than adjuvant application. While neoadjuvant therapy appears promising, with the current regimen it induced high toxicity rates; therefore, it needs further investigation to preserve efficacy but reduce toxicity. Neoadjuvant combination immunotherapy in patients with advanced melanoma shows favorable activity over adjuvant treatment and warrants future evaluation with modified dosing schedules to reduce treatment-related adverse events.

Background Patients with irresectable stage III or metastatic melanoma presenting with poor prognostic factors are usually treated with a combination of immune checkpoint inhibitors (ICIs), consisting of ipilimumab and nivolumab. This combination therapy is associated with severe immune related adverse events (irAEs) in about 60% of patients. In current clinical practice, patients are usually treated with ICIs for up to two years or until disease progression or the occurrence of unacceptable AEs. The incidence of irAEs gradually increases with duration of treatment. While durable tumour responses have been observed after early discontinuation of treatment, no consensus has been reached on optimal treatment duration. The objective of the Safe Stop IPI-NIVO trial is to evaluate whether early discontinuation of ICIs is safe in patients with irresectable stage III or metastatic melanoma who are treated with combination therapy. Methods The Safe Stop IPI-NIVO trial is a nationwide, multicentre, prospective, single-arm, interventional study in the Netherlands. A total of 80 patients with irresectable stage III or metastatic melanoma who are treated with combination therapy of ipilimumab-nivolumab and have a complete or partial response (CR/PR) according to RECIST v1.1 will be included to early discontinue maintenance therapy with anti-PD-1. The primary endpoint is the rate of ongoing response at 12 months after start of ICI. Secondary endpoints include ongoing response at 24 months, disease control at different time points, melanoma specific and overall survival, the incidence of irAEs and health-related quality of life. Discussion From a medical, healthcare and economic perspective, overtreatment should be prevented and shorter treatment duration of ICIs is preferred. If early discontinuation of ICIs is safe for patients who are treated with the combination of ipilimumab-nivolumab, the treatment duration of nivolumab could be shortened in patients with a favourable tumour response. Trial registration ClinicalTrials.gov ID NCT05652673, registration date: 08–12-2022.

Immune checkpoint inhibition (ICI) with chemotherapy is now the standard of care for stage II–III triple-negative breast cancer; however, it is largely unknown for which patients ICI without chemotherapy could be an option and what the benefit of combination ICI could be. The adaptive BELLINI trial explored whether short combination ICI induces immune activation (primary end point, twofold increase in CD8 + T cells or IFNG ), providing a rationale for neoadjuvant ICI without chemotherapy. Here, in window-of-opportunity cohorts A (4 weeks of anti-PD-1) and B (4 weeks of anti-PD-1 + anti-CTLA4), we observed immune activation in 53% (8 of 15) and 60% (9 of 15) of patients, respectively. High levels of tumor-infiltrating lymphocytes correlated with response. Single-cell RNA sequencing revealed that higher pretreatment tumor-reactive CD8 + T cells, follicular helper T cells and shorter distances between tumor and CD8 + T cells correlated with response. Higher levels of regulatory T cells after treatment were associated with nonresponse. Based on these data, we opened cohort C for patients with high levels of tumor-infiltrating lymphocytes (≥50%) who received 6 weeks of neoadjuvant anti-PD-1 + anti-CTLA4 followed by surgery (primary end point, pathological complete response). Overall, 53% (8 of 15) of patients had a major pathological response (<10% viable tumor) at resection, with 33% (5 of 15) having a pathological complete response. All cohorts met Simon’s two-stage threshold for expansion to stage II. We observed grade ≥3 adverse events for 17% of patients and a high rate (57%) of immune-mediated endocrinopathies. In conclusion, neoadjuvant immunotherapy without chemotherapy demonstrates potential efficacy and warrants further investigation in patients with early triple-negative breast cancer. ClinicalTrials.gov registration: NCT03815890 . In the phase 2 adaptive BELLINI trial, patients with early-stage triple-negative breast cancer received neoadjuvant nivolumab with or without ipilimumab, showing immune activation, clearance of circulating tumor DNA and promising clinical response rates, especially in patients preselected based on high levels of tumor-infiltrating lymphocytes.