Jon Amund Kyte

• Ullern, Andreas; Garborg, Kjetil Kjeldstad; Chauhan, Sudhir Kumar; Holm, Kristian; Bang, Corinna & Dunn, Claire [Show all 9 contributors for this article] (2026). Safety and efficacy of fecal microbiota transplantation in solid cancers resistant to immune checkpoint inhibitors: results of the MITRIC trial. Journal for ImmunoTherapy of Cancer (JITC). 14(7), p. 015122–015122. doi: 10.1136/jitc-2026-015122. Full text in Research Archive Show summary

  Background Fecal microbiota transplantation (FMT) has shown promise in overcoming resistance to immune checkpoint inhibitors (ICIs) in early-phase cancer trials. We investigated the safety, feasibility and efficacy of FMT from ICI responders to patients with advanced cancers progressing on ICIs. Methods This was a single-arm phase IIa basket trial (MITRIC; NCT05286294 ) including patients with ICI-refractory cancer. Long-term ICI responders were used as FMT donors. Patients received FMTs in combination with ICIs; two FMT administrations (by colonoscopy) were scheduled before the first radiological evaluation after 6 weeks, and up to three later FMTs were allowed (by enema). Co-primary endpoints were the evaluation of FMT-related adverse events and objective response rate. Feasibility, clinical benefit rate, progression-free survival (PFS), overall survival (OS), implant engraftment, immune response and biomarkers were among the secondary objectives. Results The study enrolled 12 patients with melanoma (n=9), head and neck squamous cell carcinoma (HNSCC; n=1), renal cell carcinoma (n=1) or microsatellite instability-high pancreatic cancer (n=1). FMT was well tolerated, whereas immune-related toxicity occurred in 6/12 patients. All patients received the first FMT; 10/12 patients also underwent the second FMT. No objective responses were observed, while 5/12 patients recorded stable disease. Clinical benefit per-protocol (stable disease >6 months) was achieved in a patient with melanoma, who had regression of some lesions and remains alive after 33 months without further systemic treatment. Mixed responses with regression of some lesions were observed in another melanoma patient, and in a patient with HNSCC. The median PFS was 1.5 months, and median OS was 10.1 months. Sequencing of fecal samples indicated engraftment after the first FMT in most patients. Mass cytometry analysis of peripheral blood cells suggested that an activated and differentiated T-cell signature was associated with improved PFS and OS, while a naïve T-cell phenotype and a myeloid-dominant environment were unfavorable. CD14 + monocytes and serum interleukin-8 increased at group level over time. Conclusion FMT in combination with ICIs was safe and feasible in patients with advanced cancers, but with limited clinical activity. Further studies are required to clarify the potential benefit of FMT, identify the appropriate patient population and define criteria for donor selection. Trial registration number NCT05286294 .

• Eide, Hanne Astrid; Grut, Harald; Jebsen, Peter Wilhelm; Kyte, Jon A & Bratland, Åse (2026). Hyperfractionated reirradiation and PD-1 blockade in recurrent squamous cell head and neck carcinomas with poor prognosis, results from the REPORT-trial. Radiotherapy and Oncology. ISSN 0167-8140. 219. doi: 10.1016/j.radonc.2026.111514. Full text in Research Archive
• Svalheim, K. G.; Andresen, Nikolai Kragøe; Bjerre, C.; Gilje, Bjørnar; Jakobsen, E. H. & Falk, Ragnhild Sørum [Show all 9 contributors for this article] (2026). Patient-reported outcomes from the randomized ALICE trial evaluating the addition of atezolizumab to anthracycline-based chemotherapy in metastatic triple-negative breast cancer. Breast. ISSN 0960-9776. 86. doi: 10.1016/j.breast.2026.104704. Full text in Research Archive Show summary

  Background The ALICE trial demonstrated that adding atezolizumab to anthracycline-based immunomodulatory chemotherapy improved progression-free survival (PFS) in patients with metastatic triple-negative breast cancer (mTNBC), including those with PD-L1–negative tumors. Here, we report the patient-reported outcome measures (PROMs). Methods Patients were randomized to receive chemotherapy plus atezolizumab (atezo-chemo) or chemotherapy plus placebo (placebo-chemo). PROMs were collected at baseline and weeks 9, 17, 25, and 49 using the EORTC QLQ-C15-PAL, Chalder Fatigue Questionnaire (CFQ), and Numeric Rating Scale (NRS) for pain. Results PROMs were available from 64 of 68 patients. At week 9, mean changes from baseline favored the atezo-chemo arm across all QLQ-C15-PAL domains, CFQ scores, and NRS pain intensity. Time-to-deterioration analyses also favored atezo-chemo, with statistically significant hazard ratios for global quality of life (QoL; HR 0.24), emotional functioning (HR 0.30), and pain (HR 0.20). Pain—a pre-specified cardinal symptom—improved in the atezo-chemo group at all time points. At 12 months, PROMs indicated sustained tolerability. Better baseline PROM scores were associated with improved PFS and overall survival, especially among patients treated with atezolizumab. Patients with >median QoL score at baseline recorded improved PFS when treated with atezolizumab (HR 0.25), while patients with ≤median QoL score did not (HR 1.02). Conclusions Adding atezolizumab to the study-chemotherapy in mTNBC improves both PFS and patient-reported quality of life, emotional well-being and symptom control. These findings support continued development of this combination regimen and suggest that baseline quality of life may serve as a useful predictor of immunotherapy benefit.

• Ullern, Andreas; Holm, Kristian; Andresen, Nikolai Kragøe; Røssevold, Andreas Hagen; Bang, Corinna & Naume, Bjørn [Show all 8 contributors for this article] (2025). Gut microbiota diversity is prognostic in metastatic hormone receptor‐positive breast cancer patients receiving chemotherapy and immunotherapy. Molecular Oncology. ISSN 1574-7891. doi: 10.1002/1878-0261.70117. Full text in Research Archive Show summary

  Immune checkpoint blockade (ICB) is standard treatment in several cancer types, despite not being proven efficacious in metastatic hormone receptor‐positive breast cancer (HR+ mBC). The gut microbiota is associated with patient outcome and toxicity from cancer therapy, although limited data are available for breast cancer. In the randomized phase 2b trial ICON, immunomodulating chemotherapy was investigated in combination with dual ICB in HR+ mBC. To determine whether gut microbiota could inform prognosis, we performed 16S (V3‐V4) rRNA sequencing on fecal samples collected at baseline and after 8 weeks of study treatment. We showed that high alpha diversity before treatment was associated with prolonged progression‐free survival (PFS; primary trial endpoint) and overall survival. Alpha diversity was lower in patients with prior chemotherapy in the metastatic setting. However, alpha diversity remained significantly associated with PFS after correcting for prior chemotherapy and other factors in bivariate analyses. High‐grade immune‐related toxicity was also associated with high alpha diversity. These findings suggest that high alpha diversity should be further investigated as a positive prognostic factor in HR+ mBC and approaches to increase alpha diversity could potentially improve clinical outcome.

• Singh, Rohit & Kyte, Jon A (2025). STEAP1: a promising target in prostate cancer therapy. Trends in Cancer. ISSN 2405-8033. 11(8), p. 722–725. doi: 10.1016/j.trecan.2025.05.007. Full text in Research Archive
• Røssevold, Andreas Hagen; Tekpli, Xavier; Lingjærde, Ole Christian; Russnes, Hege Elisabeth Giercksky; Vallon-Christersson, Johan & Borgen, Elin [Show all 12 contributors for this article] (2025). High tumor expression of CTLA4 identifies lymph node-negative basal-like breast cancer patients with excellent prognosis. Communications Medicine. 5(1), p. 1–13. doi: 10.1038/s43856-025-00865-z. Full text in Research Archive Show summary

  Background Tumor immune cell infiltration is a favorable prognostic factor in triple-negative breast cancer. Most triple-negative tumors belong to the aggressive basal-like subtype. We hypothesized that immune gene expression may identify low-risk patients for whom adjuvant chemotherapy can be de-escalated. Methods The expression of 753 immune-related genes was analyzed in tumor biopsies from 45 patients with basal-like disease and no lymph node metastases (Oslo1 cohort) and evaluated for prognostic value. Findings were validated in two independent cohorts. Oslo1 biopsies were also analyzed for tumor-infiltrating lymphocytes (TIL) and tertiary lymphoid structures (TLS). Results Here we show that a high expression of CTLA4 (above 63rd percentile) is associated with an excellent prognosis in the Oslo1 cohort. None of the patients in the CTLA4high group suffered disease recurrence (median follow-up 7.4 years) or breast cancer-related death (median follow-up 17.7 years). Analysis of the SCAN-B (n = 233; 97% without distant recurrence in CTLA4high group) and METABRIC cohorts (n = 155; 93% disease-specific survival in CTLA4high group) validates this finding, which also applies to patients who did not receive chemotherapy. CTLA4 expression correlates with TIL score and TLS levels (Oslo1 cohort), but no TILlow/CTLA4high patients died from breast cancer, suggesting that the CTLA4 readout identifies low-risk patients not captured by TIL assessment. Conclusions A high primary tumor expression of CTLA4 identifies patients with an excellent prognosis, for whom standard chemotherapy may be de-escalated or omitted.

• Pati, Niladri Bhusan; Jin, Yixin; Kumar, Suman; Kyte, Jon A & Ciosk, Rafal (2025). Thermal potentiation improves IFN-γ production but not cytotoxicity in human CAR-T cells. BMC Research Notes. 18(1). doi: 10.1186/s13104-025-07249-5. Full text in Research Archive Show summary

  Objective Body temperature plays an important role in cancer, with febrile temperature generally associated with improved cancer resistance. In murine models, this resistance has been linked to the cytotoxic T cells, whose differentiation into cancer-killing effector cells is poor at lower but robust at elevated temperatures. If conserved, temperature-mediated potentiation of patient-derived T cells could be implemented to improve the existing cancer treatments, including the chimeric antigen receptor T-cell therapy (CAR T-cell therapy). Here, we tested this possibility using human STEAP1 CAR-T cells developed to target prostate cancer. Results In mice, transient exposure to febrile temperature (39–40 ºC) increases the production of IFN-γ and the cancer-killing ability of CD8 + T cells. Using a similar temperature treatment, we observed elevated levels of IFN-γ also in the human CAR-T cells. However, these cells displayed no improvement in their ability to kill cancer cells. Although we cannot discount the possibility that alternative protocols might lead to other outcomes, our findings suggest that incorporating thermal potentiation into existing protocols of CAR-T cell therapy may be more complicated than anticipated.

• Jin, Yixin; Dunn, Claire; Persiconi, Irene; Sike, Adam; Skorstad, Gjertrud & Beck, Carole Anne [Show all 7 contributors for this article] (2024). Comparative Evaluation of STEAP1 Targeting Chimeric Antigen Receptors with Different Costimulatory Domains and Spacers. International Journal of Molecular Sciences. ISSN 1661-6596. 25(1). doi: 10.3390/ijms25010586. Full text in Research Archive
• Lereim, Ragnhild Reehorst; Dunn, Claire; Aamdal, Elin; Chauhan, Sudhir Kumar; Straume, Oddbjørn & Guren, Tormod Kyrre [Show all 7 contributors for this article] (2024). Plasma protein dynamics during ipilimumab treatment in metastatic melanoma: associations with tumor response, adverse events and survival. Oncoimmunology. ISSN 2162-4011. 14(1). doi: 10.1080/2162402X.2024.2440967. Full text in Research Archive Show summary

  The immune checkpoint inhibitor ipilimumab provides long term survival in some metastatic melanoma patients, but the majority has no benefit, and may experience serious side effects. Here, we investigated the dynamics of plasma cytokine concentrations and their potential utility for predicting treatment response, adverse events and overall survival (OS) in patients with metastatic melanoma undergoing ipilimumab monotherapy. A cohort of 148 patients was examined, with plasma samples collected prior to treatment initiation and at the end of the first and second treatment cycles. Concentrations of 48 plasma proteins were measured using a multiplex immunoassay. The results revealed a general increase in cytokine levels following the first ipilimumab dose, consistent with immune activation. Patients not responding to treatment exhibited significantly elevated baseline levels of G-CSF, IL-2RA, MIP-1a, and SCF, compared to tumor responders (p < 0.05). Furthermore, high levels of IL-2RA, IFNγ, PDGF-bb and MIG were linked to inferior OS, while high concentrations of MIF and RANTES were associated with improved OS (p < 0.05). A multivariate model containing CRP, LDH, ECOG, IL-2RA and PDGF-bb identified a subgroup of patients with poor OS. Patients who experienced severe immune-related adverse events within three months of treatment initiation had higher baseline concentrations of several cytokines, indicating a potential association between preexisting inflammation and adverse events. These findings indicate that the first dose of ipilimumab induces a systemic response with increased levels of circulating cytokines and suggest candidate biomarkers for clinical response, immune-mediated toxicity and survival. Further studies in independent patient cohorts are required to confirm the findings.

• Ullern, Andreas; Holm, Kristian; Røssevold, Andreas Hagen; Andresen, Nikolai Kragøe; Bang, Corinna & Lingjærde, Ole Christian [Show all 9 contributors for this article] (2024). Gut microbiota diversity is prognostic and associated with benefit from chemo-immunotherapy in metastatic triple-negative breast cancer. Molecular Oncology. ISSN 1574-7891. doi: 10.1002/1878-0261.13760. Full text in Research Archive
• Andresen, Nikolai Kragøe; Røssevold, Andreas Hagen; Borgen, Elin; Schirmer, Cecilie; Gilje, Bjørnar & Garred, Øystein [Show all 14 contributors for this article] (2024). Circulating tumor cells in metastatic breast cancer patients treated with immune checkpoint inhibitors – a biomarker analysis of the ALICE and ICON trials. Molecular Oncology. ISSN 1574-7891. doi: 10.1002/1878-0261.13675. Full text in Research Archive Show summary

  Immune checkpoint inhibitors (ICIs) have been introduced in breast cancer (BC) treatment and better biomarkers are needed to predict benefit. Circulating tumor cells (CTCs) are prognostic in BC, but knowledge is limited on CTCs in the context of ICI therapy. In this study, serial sampling of CTCs (CellSearch system) was evaluated in 82 patients with metastatic BC enrolled in two randomized trials investigating ICI plus chemotherapy. Programmed death-ligand 1 (PD-L1) expression on CTCs was also measured. Patients with ≥ 2 CTCs per 7.5 mL at baseline had gene expression profiles in tumor suggestive of increased T-cell activity, including increased tumor inflammation signature (TIS) in both triple-negative (P = 0.010) and hormone receptor-positive (P = 0.024) disease. Patients with luminal A BC had higher CTC levels. The association between CTC status and outcome was most apparent 4 weeks into therapy. PD-L1 expression in CTCs was observed in 6/17 CTC-positive patients and was associated with inferior survival. In conclusion, our study indicates that CTC numbers may inform on tumor immune composition, as well as prognosis. These findings suggest a potential of using CTCs as an accessible biomarker source in BC patients treated with immunotherapy.

• Willemsen, M.; Bulgarelli, J.; Chauhan, Sudhir Kumar; Lereim, Ragnhild Reehorst; Angeli, D. & Grisendi, G. [Show all 12 contributors for this article] (2024). Changes in AXL and/or MITF melanoma subpopulations in patients receiving immunotherapy. Immuno-Oncology and Technology (IOTECH). 24. doi: 10.1016/j.iotech.2024.101009. Full text in Research Archive
• Andresen, Nikolai Kragøe; Røssevold, Andreas Hagen; Quaghebeur, Claire; Gilje, Bjørnar; Boge, Beate & Gombos, Andrea [Show all 17 contributors for this article] (2024). Ipilimumab and nivolumab combined with anthracycline-based chemotherapy in metastatic hormone receptor-positive breast cancer: A randomized phase 2b trial. Journal for ImmunoTherapy of Cancer (JITC). 12:e007990(1), p. 1–12. doi: 10.1136/jitc-2023-007990. Full text in Research Archive Show summary

  Background Immune checkpoint inhibitors have shown minimal clinical activity in hormone receptor-positive metastatic breast cancer (HR+ mBC). Doxorubicin and low- dose cyclophosphamide are reported to induce immune responses and counter regulatory T cells (Tregs). Here, we report the efficacy and safety of combined programmed cell death protein-1/cytotoxic T-lymphocyte- associated protein 4 blockade concomitant with or after immunomodulatory chemotherapy for HR + mBC. Methods Patients with HR+ mBC starting first-/second- line chemotherapy (chemo) were randomized 2:3 to chemotherapy (pegylated liposomal doxorubicin 20 mg/ m 2 every second week plus cyclophosphamide 50 mg by mouth/day in every other 2-week cycle) with or without concomitant ipilimumab (ipi; 1 mg/kg every sixth week) and nivolumab (nivo; 240 mg every second week). Patients in the chemo-only arm were offered cross-over to ipi/ nivo without chemotherapy. Co-primary endpoints were safety in all patients starting therapy and progression-free survival (PFS) in the per-protocol (PP) population, defined as all patients evaluated for response and receiving at least two treatment cycles. Secondary endpoints included objective response rate, clinical benefit rate, Treg changes during therapy and assessment of programmed death- ligand 1 (PD-L1), mutational burden and immune gene signatures as biomarkers. Results Eighty-two patients were randomized and received immune-chemo (N=49) or chemo-only (N=33), 16 patients continued to the ipi/nivo-only cross- over arm. Median follow-up was 41.4 months. Serious adverse events occurred in 63% in the immune-chemo arm, 39% in the chemo-only arm and 31% in the cross- over-arm. In the PP population (N=78) median PFS in the immune- chemo arm was 5.1 months, compared with 3.6 months in the chemo-only arm, with HR 0.94 (95% CI 0.59 to 1.51). Clinical benefit rates were 55% (26/47) and 48% (15/31) in the immune-chemo and chemo- only arms, respectively. In the cross-over-arm (ipi/nivo-only), objective responses were observed in 19% of patients (3/16) and clinical benefit in 25% (4/16). Treg levels in blood decreased after study chemotherapy. High-grade immune-related adverse events were associated with prolonged PFS. PD-L1 status and mutational burden were not associated with ipi/nivo benefit, whereas a numerical PFS advantage was observed for patients with a high Treg gene signature in tumor. Conclusion The addition of ipi/nivo to chemotherapy increased toxicity without improving efficacy. Ipi/nivo administered sequentially to chemotherapy was tolerable and induced clinical responses.

• Chauhan, Sudhir Kumar; Dunn, Claire; Andresen, Nikolai Kragøe; Røssevold, Andreas Hagen; Skorstad, Gjertrud & Sike, Adam [Show all 11 contributors for this article] (2024). Peripheral immune cells in metastatic breast cancer patients display a systemic immunosuppressed signature consistent with chronic inflammation. NPJ breast cancer. 10(1). doi: 10.1038/s41523-024-00638-2. Full text in Research Archive Show summary

  Immunotherapies blocking the PD-1/PD-L1 checkpoint show some efficacy in metastatic breast cancer (mBC) but are often hindered by immunosuppressive mechanisms. Understanding these mechanisms is crucial for personalized treatments, with peripheral blood monitoring representing a practical alternative to repeated biopsies. In the present study, we performed a comprehensive mass cytometry analysis of peripheral blood immune cells in 104 patients with HER2 negative mBC and 20 healthy donors (HD). We found that mBC patients had significantly elevated monocyte levels and reduced levels of CD4+ T cells and plasmacytoid dendritic cells, when compared to HD. Furthermore, mBC patients had more effector T cells and regulatory T cells, increased expression of immune checkpoints and other activation/exhaustion markers, and a shift to a Th2/Th17 phenotype. Furthermore, T-cell phenotypes identified by mass cytometry correlated with functionality as assessed by IFN-γ production. Additional analysis indicated that previous chemotherapy and CDK4/6 inhibition impacted the numbers and phenotype of immune cells. From 63 of the patients, fresh tumor samples were analyzed by flow cytometry. Paired PBMC-tumor analysis showed moderate correlations between peripheral CD4+ T and NK cells with their counterparts in tumors. Further, a CD4+ T cell cluster in PBMCs, that co-expressed multiple checkpoint receptors, was negatively associated with CD4+ T cell tumor infiltration. In conclusion, the identified systemic immune signatures indicate an immune-suppressed environment in mBC patients who had progressed/relapsed on standard treatments and is consistent with ongoing chronic inflammation. These activated immuno-suppressive mechanisms may be investigated as therapeutic targets, and for use as biomarkers of response or treatment resistance.

• Gombos, A.; Goncalves, A.; Curigliano, G.; Bartsch, R.; Kyte, Jon A & Ignatiadis, M. [Show all 7 contributors for this article] (2023). How I treat endocrine-dependent metastatic breast cancer. ESMO Open. 8(2). doi: 10.1016/j.esmoop.2023.100882. Full text in Research Archive Show summary

  Estrogen receptor-positive (ER+)/HER2-negative (HER2−), the so-called luminal-type breast cancer, is the most frequent subset, accounting for around 70% of all breast cancer cases. Endocrine therapy (ET) combined with cyclin-dependent kinases (CDK) 4/6 inhibitors is the standard first option in the management of advanced luminal breast cancer independently of disease extension. Classically, patients undergo multiple lines of ET ± targeted treatments until endocrine resistance occurs and palliative chemotherapy is proposed. Understanding endocrine resistance mechanisms and development of novel ET options is one of the main challenges in current clinical research. Another area of utmost interest is the improvement of post-endocrine therapeutic approaches. Among others, the development of antibody–drug conjugates (ADCs) is very promising, and some of these drugs will probably soon become a part of the therapeutic arsenal against this incurable disease. This review paper provides an overview of currently available treatment options in ER+/HER2− metastatic breast cancer and extensively discusses new approaches in late clinical development.

• Beck, Carole Anne; Casey, Nicholas Paul; Persiconi, Irene; Moharrami, Neda Nejati; Sike, Adam & Jin, Yixin [Show all 7 contributors for this article] (2023). Development of a TGFβ—IL-2/15 Switch Receptor for Use in Adoptive Cell Therapy. Biomedicines. 11(2). doi: 10.3390/biomedicines11020459. Full text in Research Archive
• Kyte, Jon A (2022). Strategies for Improving the Efficacy of CAR T Cells in Solid Cancers. Cancers. 14(3). doi: 10.3390/cancers14030571. Full text in Research Archive
• Jin, Yixin; Lorvik, Kristina Berg; Jin, Yang; Beck, Carole; Sike, Adam & Persiconi, Irene [Show all 10 contributors for this article] (2022). Development of STEAP1 targeting chimeric antigen receptor for adoptive cell therapy against cancer. Molecular Therapy Oncolytics. 26, p. 189–206. doi: 10.1016/j.omto.2022.06.007. Full text in Research Archive
• Røssevold, Andreas Hagen; Andresen, Nikolai Kragøe; Bjerre, Christina Annette; Gilje, Bjørnar; Jakobsen, Erik Hugger & Raj, Sunil Xavier [Show all 17 contributors for this article] (2022). Atezolizumab plus anthracycline-based chemotherapy in metastatic triple-negative breast cancer: the randomized, double-blind phase 2b ALICE trial. Nature Medicine. ISSN 1078-8956. p. 1–28. doi: 10.1038/s41591-022-02126-1. Full text in Research Archive Show summary

  Immune checkpoint inhibitors have shown efficacy against metastatic triple-negative breast cancer (mTNBC) but only for PD-L1positive disease. The randomized, placebo-controlled ALICE trial (NCT03164993, 24 May 2017) evaluated the addition of atezolizumab (anti-PD-L1) to immune-stimulating chemotherapy in mTNBC. Patients received pegylated liposomal doxorubicin (PLD) and low-dose cyclophosphamide in combination with atezolizumab (atezo-chemo; n = 40) or placebo (placebo-chemo; n = 28). Primary endpoints were descriptive assessment of progression-free survival in the per-protocol population (>3 atezolizumab and >2 PLD doses; n = 59) and safety in the full analysis set (FAS; all patients starting therapy; n = 68). Adverse events leading to drug discontinuation occurred in 18% of patients in the atezo-chemo arm (7/40) and in 7% of patients in the placebo-chemo arm (2/28). Improvement in progression-free survival was indicated in the atezo-chemo arm in the per-protocol population (median 4.3 months versus 3.5 months; hazard ratio (HR) = 0.57; 95% confidence interval (CI) 0.33–0.99; log-rank P = 0.047) and in the FAS (HR = 0.56; 95% CI 0.33–0.95; P = 0.033). A numerical advantage was observed for both the PD-L1positive (n = 27; HR = 0.65; 95% CI 0.27–1.54) and PD-L1negative subgroups (n = 31; HR = 0.57, 95% CI 0.27–1.21). The progression-free proportion after 15 months was 14.7% (5/34; 95% CI 6.4–30.1%) in the atezo-chemo arm versus 0% in the placebo-chemo arm. The addition of atezolizumab to PLD/cyclophosphamide was tolerable with an indication of clinical benefit, and the findings warrant further investigation of PD1/PD-L1 blockers in combination with immunomodulatory chemotherapy.

• Aamdal, Elin; Skovlund, Eva; Jacobsen, Kari Dolven; Straume, Oddbjørn; Kersten, Christian & Herlofsen, Oluf [Show all 17 contributors for this article] (2022). Health-related quality of life in patients with advanced melanoma treated with ipilimumab: prognostic implications and changes during treatment. ESMO Open. 7(5), p. 1–10. doi: 10.1016/j.esmoop.2022.100588. Full text in Research Archive Show summary

  Background: We have previously reported that the safety and efficacy of ipilimumab in real-world patients with metastatic melanoma were comparable to clinical trials. Few studies have explored health-related quality of life (HRQL) in real-world populations receiving checkpoint inhibitors. This study reports HRQL in real-world patients receiving ipilimumab and assesses the prognostic value of patient-reported outcome measures. Patients and methods: Ipi4 (NCT02068196) was a prospective, multicentre, interventional phase IV trial. Real-world patients (N = 151) with metastatic melanoma were treated with ipilimumab 3 mg/kg intravenously as labelled. HRQL was assessed by the European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire at baseline and after 10-12 weeks. Results: The European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire was completed by 93% (141/151 patients) at baseline, and by 82% at 10-12 weeks. Poor performance status and elevated C-reactive protein (CRP) were associated with worse baseline HRQL. Clinically relevant and statistically significant deteriorations in HRQL from baseline to weeks 10-12 were reported (P <0.05). Baseline physical functioning [hazard ratio (HR) 1.96, P = 0.016], role functioning (HR 2.15, P <0.001), fatigue (HR 1.60, P = 0.030), and appetite loss (HR 1.76, P = 0.012) were associated with poorer overall survival independent of performance status, lactate dehydrogenase (LDH), and CRP. We further developed a prognostic model, combining HRQL outcomes with performance status, LDH, and CRP. This model identified three groups with large and statistically significant differences in survival. Conclusions: Systemic inflammation is associated with impaired HRQL. During treatment with ipilimumab, HRQL deteriorated significantly. Combining HRQL outcomes with objective risk factors provided additional prognostic information that may aid clinical decision making.

• Dorraji, Seyed Esmaeil; Borgen, Elin; Segura-Pena, Dario; Rawat, Puneet; Smorodina, Eva & Dunn, Claire [Show all 10 contributors for this article] (2022). Development of a High-Affinity Antibody against the Tumor-Specific and Hyperactive 611-p95HER2 Isoform. Cancers. 14:4859(19), p. 1–24. doi: 10.3390/cancers14194859. Full text in Research Archive Show summary

  Simple Summary In the present study, we addressed the unmet need for a molecular antibody (mAb) with high affinity and specificity against a truncated hyperactive isoform of human epidermal growth factor receptor 2 (HER2), called 611-carboxy terminal fragment (CTF)-p95HER2. Patients with p95HER2+ breast cancer are at risk of developing metastatic breast cancer with a poor prognosis and resistance to therapies targeting full-length HER2. We have generated a mAb named Oslo-2, which react specifically with 611-CTF-p95HER2 and has a high affinity. We also characterized the antigenic determinant (epitope) on the p95HER2 protein and the antigen-binding site (paratope) on the Oslo-2 mAb. The antibody can be used to develop antibody- or cell-based therapies targeting p95HER2, as well as a diagnostic assay to identify p95HER2+ disease. Abstract The expression of human epidermal growth factor receptor 2 (HER2) is a key classification factor in breast cancer. Many breast cancers express isoforms of HER2 with truncated carboxy-terminal fragments (CTF), collectively known as p95HER2. A common p95HER2 isoform, 611-CTF, is a biomarker for aggressive disease and confers resistance to therapy. Contrary to full-length HER2, 611-p95HER2 has negligible normal tissue expression. There is currently no approved diagnostic assay to identify this subgroup and no therapy targeting this mechanism of tumor escape. The purpose of this study was to develop a monoclonal antibody (mAb) against 611-CTF-p95HER2. Hybridomas were generated from rats immunized with cells expressing 611-CTF. A hybridoma producing a highly specific Ab was identified and cloned further as a mAb. This mAb, called Oslo-2, gave strong staining for 611-CTF and no binding to full-length HER2, as assessed in cell lines and tissues by flow cytometry, immunohistochemistry and immunofluorescence. No cross-reactivity against HER2 negative controls was detected. Surface plasmon resonance analysis demonstrated a high binding affinity (equilibrium dissociation constant 2 nM). The target epitope was identified at the N-terminal end, using experimental alanine scanning. Further, the mAb paratope was identified and characterized with hydrogen-deuterium-exchange, and a molecular model for the (Oslo-2 mAb:611-CTF-p95HER2) complex was generated by an experimental-information-driven docking approach. We conclude that the Oslo-2 mAb has a high affinity and is highly specific for 611-CTF-p95HER2. The Ab may be used to develop potent and safe therapies, overcoming p95HER2-mediated tumor escape, as well as for developing diagnostic assays. Keywords: HER2; p95HER2; antibody; tumor-specific; breast cancer; cancer stem cells; HDX-MS; epitope and paratope mapping; docking

• Aamdal, Elin; Jacobsen, Kari Dolven; Straume, Oddbjørn; Kersten, Christian; Herlofsen, Oluf & Karlsen, Jarle [Show all 19 contributors for this article] (2021). Ipilimumab in a real-world population: A prospective Phase IV trial with long-term follow-up. International Journal of Cancer. ISSN 0020-7136. 150(1), p. 100–111. doi: 10.1002/ijc.33768. Full text in Research Archive Show summary

  Ipilimumab was the first treatment that improved survival in advanced melanoma. Efficacy and toxicity in a real-world setting may differ from clinical trials, due to more liberal eligibility criteria and less intensive monitoring. Moreover, high costs and lack of biomarkers have raised cost-benefit concerns about ipilimumab in national healthcare systems and limited its use. Here, we report the prospective, interventional study, Ipi4 (NCT02068196), which aimed to investigate the toxicity and efficacy of ipilimumab in a real-world population with advanced melanoma. This national, multicentre, phase IV trial included 151 patients. Patients received ipilimumab 3 mg/kg intravenously and were followed for at least 5 years or until death. Treatment interruption or cessation occurred in 38%, most frequently due to disease progression (19%). Treatment-associated grade 3 to 4 toxicity was observed in 28% of patients, and immune-related toxicity in 56%. The overall response rate was 9%. Median overall survival was 12.1 months (95% CI: 8.3-15.9); and progression-free survival 2.7 months (95% CI: 2.6-2.8). After 5 years, 20% of patients were alive. In a landmark analysis from 6 months, improved survival was associated with objective response (HR 0.16, P = .001) and stable disease (HR 0.49, P = .005) compared to progressive disease. Poor performance status, elevated lactate dehydrogenase and C-reactive protein were identified as biomarkers. This prospective trial represents the longest reported follow-up of a real-world melanoma population treated with ipilimumab. Results indicate safety and efficacy comparable to phase III

• Brunsvig, Paal Fr.; Guren, Tormod Kyrre; Nyakas, Marta Sølvi; Reisse, Claudius; Rasch, Wenche & Kyte, Jon A [Show all 10 contributors for this article] (2020). Long-term outcomes of a phase I study with UV1, a second generation telomerase based vaccine, in patients with advanced non-small cell lung cancer. Frontiers in Immunology. 11:572172, p. 1–12. doi: 10.3389/fimmu.2020.572172. Full text in Research Archive
• Casey, Nicholas Paul; Kyte, Jon A & Fujiwara, Hiroshi (2020). Use of RNA Interference with TCR Transfer to Enhance Safety and Efficiency. Methods in molecular biology. ISSN 1064-3745. 2115, p. 327–349. doi: 10.1007/978-1-0716-0290-4_18. Full text in Research Archive
• Kyte, Jon A; Røssevold, Andreas Hagen; Falk, Ragnhild Sørum & Naume, Bjørn (2020). ALICE: A randomized placebo-controlled phase II study evaluating atezolizumab combined with immunogenic chemotherapy in patients with metastatic triple-negative breast cancer. Journal of Translational Medicine. 18:252, p. 1–7. doi: 10.1186/s12967-020-02424-7. Full text in Research Archive Show summary

  Background Immunotherapy with checkpoint inhibitors (CI) represents an important novel development in cancer treatment. Metastatic triple-negative breast cancer (mTNBC) is incurable, with a median survival of only ~ 13 months. We have initiated the randomized placebo-controlled phase IIb study ALICE, evaluating PD-L1 blockade combined with immunogenic chemotherapy in mTNBC patients (n = 75). Intriguingly, the host immune response is strongly predictive for the effect of chemotherapy in mTNBC. In the ALICE trial, we release the brake on the immune response by use of atezolizumab, an inhibitory antibody against PD-L1. We utilize anthracyclines, shown to trigger the immune system, and low-dose cyclophosphamide, which has been reported to counter immunosuppressive cells. Methods ALICE is a randomized, double-blind, placebo-controlled exploratory phase II study evaluating the safety and efficacy of atezolizumab when combined with immunogenic chemotherapy in subjects with mTNBC. The trial will enroll 75 evaluable subjects, randomized 2:3 into two arms (A:B). The patients receive identical chemotherapy, i.e. pegylated liposomal doxorubicin (PLD 20 mg/m2 intravenously every 2nd week) + cyclophosphamide (50 mg per day, first 2 weeks in each 4 week cycle). Patients in arm A receive placebo, while patients in arm B receive atezolizumab. The primary objectives are assessment of toxicity and progression-free survival. The secondary objectives include overall survival, tumor response rate, clinical benefit rate, patient reported outcomes, biomarkers and assessment of tumor-immune evolution during therapy. Discussion The question of how CI should be combined with chemotherapy, is a key challenge facing the field. There is a strong preclinical rationale for exploring if anthracyclines, which are considered to induce immunogenic cell death, synergize with PD-L1 blockade, and if low-dose cyclophosphamide counters tumor tolerance. However, the data from patients is as yet very limited, and the clinical evaluation of these hypotheses is among the key objectives in the ALICE trial. The study includes extensive biobanking and translational sub-projects, also addressing other clinically important questions. These analyses may uncover mechanisms of drug efficacy or tumor resistance, and identify biomarkers allowing personalized therapy. If the trial suggests acceptable safety of the ALICE therapy and provide a signal of clinical efficacy, further studies are warranted. Trial registration NCT03164993, May 24th 2017; https://clinicaltrials.gov/ct2/show/record/NCT03164993

• Kyte, Jon A; Andresen, Nikolai Kragøe; Russnes, Hege Elisabeth Giercksky; Fretland, Signe Øien; Falk, Ragnhild Sørum & Lingjærde, Ole Christian [Show all 7 contributors for this article] (2020). ICON: A randomized phase IIb study evaluating immunogenic chemotherapy combined with ipilimumab and nivolumab in patients with metastatic hormone receptor positive breast cancer. Journal of Translational Medicine. 18(1). doi: 10.1186/s12967-020-02421-w. Full text in Research Archive Show summary

  Background Immunotherapy with checkpoint inhibitors (CPI) targeting PD-1 or CTLA-4 has emerged as an important treatment modality for several cancer forms. In hormone receptor positive breast cancer (HR + BC), this therapeutic approach is largely unexplored. We have started a clinical trial, ICON (CA209-9FN), evaluating CPI combined with selected chemotherapy in patients with metastatic HR + BC. The tumor lymphocyte infiltration is predictive for the effect of chemotherapy in BC. In ICON, we use anthracycline, which are considered as “immunogenic” chemotherapy, and low-dose cyclophosphamide, which has been reported to counter immunosuppressive cells. Methods ICON is a randomized exploratory phase IIb study evaluating the safety and efficacy of combining nivolumab (nivo; anti-PD-1) and ipilimumab (ipi; anti-CTLA-4) with chemotherapy in subjects with metastatic HR + BC. Primary objectives are aassessment of toxicity and progression-free survival. The trial will enrol 75 evaluable subjects, randomized 2:3 into two arms (A:B). Patients in Arm A receive only chemotherapy, i.e. pegylated liposomal doxorubicin (PLD 20 mg/m2 intravenously every 2nd week) + cyclophosphamide (cyclo; 50 mg per day, first 2 weeks in each 4 week cycle). Patients in Arm B receive PLD + cyclo + ipilimumab (1 mg intravenously every 6th week) + nivolumab (240 mg intravenously every 2nd week). Patients in arm A will be offered ipi + nivo after disease progression. Discussion ICON is among the first clinical trials combining chemotherapy with PD-1 and CTLA-4 blockade, and the first in BC. There is a strong preclinical rationale for exploring if anthracyclines, which are considered to induce immunogenic cell death, synergize with CPI, and for combining PD-1 and CTLA-4 blockade, as these checkpoints are important in different phases of the immune response. If the ICON trial suggests acceptable safety and provide a signal of clinical efficacy, further studies are warranted. The cross-over patients from Arm A receiving ipilimumab/nivolumab without concomitant chemotherapy represent the first BC cohort receiving this therapy. The ICON trial includes a series of translational sub-projects addressing clinically important knowledge gaps. These studies may uncover biomarkers or mechanisms of efficacy and resistance, thereby informing the development of novel combinatory regimes and of personalised biomarker-based therapy. Trial registration NCT03409198, Jan 24th 2018; https://clinicaltrials.gov/ct2/show/record/NCT03409198

• Kyte, Jon A; Fåne, Anne; Pulè, Martin & Gaudernack, Gustav (2019). Transient redirection of T cells for adoptive cell therapy with telomerase-specific T helper cell receptors isolated from long term survivors after cancer vaccination. Oncoimmunology. ISSN 2162-4011. 8(4). doi: 10.1080/2162402X.2019.1565236. Full text in Research Archive
• Tekpli, Xavier; Lien, Tonje Gulbrandsen; Røssevold, Andreas Hagen; Nebdal, Daniel J.H.; Borgen, Elin & Ohnstad, Hege Oma [Show all 19 contributors for this article] (2019). An independent poor-prognosis subtype of breast cancer defined by a distinct tumor immune microenvironment. Nature Communications. 10:5499, p. 1–14. doi: 10.1038/s41467-019-13329-5. Full text in Research Archive Show summary

  How mixtures of immune cells associate with cancer cell phenotype and affect pathogenesis is still unclear. In 15 breast cancer gene expression datasets, we invariably identify three clusters of patients with gradual levels of immune infiltration. The intermediate immune infiltration cluster (Cluster B) is associated with a worse prognosis independently of known clinicopathological features. Furthermore, immune clusters are associated with response to neoadjuvant chemotherapy. In silico dissection of the immune contexture of the clusters identified Cluster A as immune cold, Cluster C as immune hot while Cluster B has a pro-tumorigenic immune infiltration. Through phenotypical analysis, we find epithelial mesenchymal transition and proliferation associated with the immune clusters and mutually exclusive in breast cancers. Here, we describe immune clusters which improve the prognostic accuracy of immune contexture in breast cancer. Our discovery of a novel independent prognostic factor in breast cancer highlights a correlation between tumor phenotype and immune contexture.

• Eide, Hanne Astrid; Knudtsen, Ingerid Skjei; Sandhu, Vandana; Løndalen, Ayca; Halvorsen, Ann Rita & Abravan, Azadeh [Show all 12 contributors for this article] (2018). Serum cytokine profiles and metabolic tumor burden in patients with non-small cell lung cancer undergoing palliative thoracic radiation therapy. Advances in Radiation Oncology. ISSN 2452-1094. 3(2), p. 130–138. doi: 10.1016/j.adro.2017.12.007. Full text in Research Archive Show summary

  Purpose: Radiation therapy effectively kills cancer cells and elicits local effects in the irradiated tissue. The aim of this study was to investigate the kinetics of cytokines in the serum of patients with lung cancer undergoing radiation therapy and to identify associations with metabolic tumor burden as determined by 2-deoxy-2-fluoro-D-glucose (18F-FDG) positron emission tomography (PET). Methods and materials: Forty-five patients with advanced non-small cell lung cancer were included in a phase 2 clinical trial and randomized between fractionated thoracic radiation therapy alone or concurrent with an epidermal growth factor receptor inhibitor. Blood was sampled at 4 different time points: prior to treatment, midtherapy, at the end of therapy, and 6 to 8 weeks after the start of treatment. The serum concentrations of 48 cytokines and 9 matrix metalloproteinases were measured with multiplex immunoassays. A subset of patients was examined by 18F-FDG PET/computed tomography before, during, and after radiation therapy. The maximum standardized uptake values (SUVmax) of the primary lung tumor, whole-body metabolic tumor volume, and total lesion glycolysis were calculated, and correlations between the PET parameters and cytokines were investigated. Results: The SUVmax decreased from baseline through midtherapy to posttherapy 18F-FDG PET/computed tomography (P = .018). The serum levels of C-C motif chemokine ligand (CCL) 23, CCL24, C-X3-C motif chemokine ligand 1, and interleukin-8 (C-X-C motif ligand [CXCL]8) were significantly correlated to SUVmax, metabolic tumor volume, and total lesion glycolysis before, during, and after radiation therapy. CXCL2 (P = .030) and CXCL6 (P = .010) decreased after the start of therapy and changed significantly across the sample time points. Serum concentrations of CCL15 (P = .031), CXCL2 (P = .028), and interleukin-6 (P = .007) were positively correlated to the irradiated volume during the second week of treatment. Conclusions: Cytokine serum levels vary and correlate with metabolic tumor burden in patients with advanced non-small cell lung cancer undergoing palliative thoracic radiation therapy.

• Oei, Vincent Yi Sheng; Siernicka, Marta; Graczyk-Jarzynka, Agnieszka; Hoel, Hanna Julie; Yang, Weiwen & Orellana, Daniel Alfredo Palacios [Show all 17 contributors for this article] (2018). Intrinsic functional potential of NK-Cell subsets constrains retargeting driven by chimeric antigen receptors. Cancer immunology research. ISSN 2326-6066. 6(4), p. 467–480. doi: 10.1158/2326-6066.CIR-17-0207. Full text in Research Archive Show summary

  Natural killer (NK) cells hold potential as a source of allogeneic cytotoxic effector cells for chimeric antigen receptor (CAR)-mediated therapies. Here, we explored the feasibility of transfecting CAR-encoding mRNA into primary NK cells and investigated how the intrinsic potential of discrete NK-cell subsets affects retargeting efficiency. After screening five second- and third-generation anti-CD19 CAR constructs with different signaling domains and spacer regions, a third-generation CAR with the CH2-domain removed was selected based on its expression and functional profiles. Kinetics experiments revealed that CAR expression was optimal after 3 days of IL15 stimulation prior to transfection, consistently achieving over 80% expression. CAR-engineered NK cells acquired increased degranulation toward CD19+ targets, and maintained their intrinsic degranulation response toward CD19− K562 cells. The response of redirected NK-cell subsets against CD19+ targets was dependent on their intrinsic thresholds for activation determined through both differentiation and education by killer cell immunoglobulin-like receptors (KIR) and/or CD94/NKG2A binding to self HLA class I and HLA-E, respectively. Redirected primary NK cells were insensitive to inhibition through NKG2A/HLA-E interactions but remained sensitive to inhibition through KIR depending on the amount of HLA class I expressed on target cells. Adaptive NK cells, expressing NKG2C, CD57, and self-HLA–specific KIR(s), displayed superior ability to kill CD19+, HLA low, or mismatched tumor cells. These findings support the feasibility of primary allogeneic NK cells for CAR engineering and highlight a need to consider NK-cell diversity when optimizing efficacy of cancer immunotherapies based on CAR-expressing NK cells.

• Jabeen, Shakila; Zucknick, Manuela; Nome, Marianne Eikhom; dannenfelser, ruth; Fleischer, Thomas & Kumar, Surendra [Show all 15 contributors for this article] (2018). Serum cytokine levels in breast cancer patients during neoadjuvant treatment with bevacizumab. Oncoimmunology. ISSN 2162-4011. 7(11), p. e1457598-1–e1457598-15. doi: 10.1080/2162402X.2018.1457598. Full text in Research Archive Show summary

  A high concentration of circulating vascular endothelial growth factor (VEGF) in cancer patients is associated with an aggressive tumor phenotype. Here, serum levels of 27 cytokines and blood cell counts were assessed in breast cancer patients receiving neoadjuvant chemotherapy with or without bevacizumab (Bev) in a randomized cohort of 132 patients with non-metastatic HER2-negative tumors. Cytokine levels were determined prior to treatment and at various time-points. The cytotoxic chemotherapy regimen of fluorouracil, epirubicin, and cyclophosphamide (FEC) had a profound impact on both circulating white blood cells and circulating cytokine levels. At the end of FEC treatment, the global decrease in cytokine levels correlated with the drop in white blood cell counts and was significantly greater in the patients of the Bev arm for cytokines, such as VEGF-A, IL-12, IP-10 and IL-10. Among patients who received Bev, those with pathological complete response (pCR) exhibited significantly lower levels of VEGF-A, IFN-γ, TNF-α and IL-4 than patients without pCR. This effect was not observed in the chemotherapy-only arm. Certain circulating cytokine profiles were found to correlate with different immune cell types at the tumor site. For the Bev arm patients, the serum cytokine levels correlated with higher levels of cytotoxic T cells at the end of the therapy regimen, which was indicative of treatment response. The higher response rate for Bev-treated patients and stronger correlations between serum cytokine levels and infiltrating CD8T cells merits further investigation. KEYWORDS: Bevacizumab, VEGF-A, neoadjuvant, cytokines, immunity

• Jabeen, Shakila; Espinoza, Jaime; Torland, Lilly Anne; Zucknick, Manuela; Kumar, Surendra & Haakensen, Vilde Drageset [Show all 15 contributors for this article] (2018). Noninvasive profiling of serum cytokines in breast cancer patients and clinicopathological characteristics. Oncoimmunology. ISSN 2162-4011. :e1537691. doi: 10.1080/2162402X.2018.1537691. Full text in Research Archive Show summary

  Cancers elicit an immune response by modifying the microenvironment. The immune system plays a pivotal role in cancer recognition and eradication. While the potential clinical value of infiltrating lymphocytes at the tumor site has been assessed in breast cancer, circulating cytokines – the molecules coordinating and fine-tuning immune response – are still poorly characterized. Using two breast cancer cohorts (MicMa, n = 131, DCTB, n = 28) and the multiplex Luminex platform, we measured the levels of 27 cytokines in the serum of breast cancer patients prior to treatment. We investigated the cytokine levels in relation to clinicopathological characteristics and in perspective of the tumor infiltrating immune cells predicted from the bulk mRNA expression data. Unsupervised clustering analysis of the serum cytokine levels in the MicMa cohort identified a cluster of pro-inflammatory, pro-angiogenic, and Th2-related cytokines which was associated with poor prognosis. Notably high levels of platelet derived growth factor BB (PDGF) reflected a more aggressive tumor phenotype and larger tumor size. A significant positive correlation between serum levels of interferon gamma-induced protein 10 (IP10) and its mRNA expression at the tumor site suggested that tumor-IP10-production may outflow to the bloodstream. High IP10 serum levels were associated with a worse prognosis. Finally, we found serum levels of both PDGF and IP10 associated with enrichment scores of specific tumor infiltrating immune cells. Our study suggests that monitoring cytokine circulating levels in breast cancer could be used to characterize breast cancers and the immune composition of their microenvironment through readily available biological material. KEYWORDS: Breast cancer, cytokines, pathological markers, immune response, prognosis

• Ohnstad, Hege Oma; Borgen, Elin; Falk, Ragnhild Sørum; Lien, Tonje Gulbrandsen; Aaserud, Marit & Sveli, My Anh Tu [Show all 14 contributors for this article] (2017). Prognostic value of PAM50 and risk of recurrence score in patients with early-stage breast cancer with long-term follow-up. Breast Cancer Research. ISSN 1465-5411. 19(120). doi: 10.1186/s13058-017-0911-9. Full text in Research Archive Show summary

  Background The aim of this study was to investigate the prognostic value of the PAM50 intrinsic subtypes and risk of recurrence (ROR) score in patients with early breast cancer and long-term follow-up. A special focus was placed on hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) pN0 patients not treated with chemotherapy. Methods Patients with early breast cancer (n = 653) enrolled in the observational Oslo1 study (1995–1998) were followed for distant recurrence and breast cancer death. Clinicopathological parameters were collected from hospital records. The primary tumors were analyzed using the Prosigna® PAM50 assay to determine the prognostic value of the intrinsic subtypes and ROR score in comparison with pathological characteristics. The primary endpoints were distant disease-free survival (DDFS) and breast cancer-specific survival (BCSS). Results Of 653 tumors, 52.2% were classified as luminal A, 26.5% as luminal B, 10.6% as HER2-enriched, and 10.7% as basal-like. Among the HR+/HER2− patients (n = 476), 37.8% were categorized as low risk by ROR score, 22.7% as intermediate risk, and 39.5% as high risk. Median follow-up durations for BCSS and DDFS were 16.6 and 7.1 years, respectively. Multivariate analysis showed that intrinsic subtypes (all patients) and ROR risk classification (HR+/HER2− patients) yielded strong prognostic information. Among the HR+/HER2− pN0 patients with no adjuvant treatment (n = 231), 53.7% of patients had a low ROR, and their prognosis at 15 years was excellent (15-year BCSS 96.3%). Patients with intermediate risk had reduced survival compared with those with low risk (p = 0.005). In contrast, no difference in survival between the low- and intermediate-risk groups was seen for HR+/HER2− pN0 patients who received tamoxifen only. Ki-67 protein, grade, and ROR score were analyzed in the unselected, untreated pT1pN0 HR+/HER2− population (n = 171). In multivariate analysis, ROR score outperformed both Ki-67 and grade. Furthermore, 55% of patients who according to the PREDICT tool ( http://www.predict.nhs.uk/ ) would be considered chemotherapy candidates were ROR low risk (33%) or luminal A ROR intermediate risk (22%). Conclusions The PAM50 intrinsic subtype classification and ROR score improve classification of patients with breast cancer into prognostic groups, allowing for a more precise identification of future recurrence risk and providing an improved basis for adjuvant treatment decisions. Node-negative patients with low ROR scores had an excellent outcome at 15 years even in the absence of adjuvant therapy.

• Kyte, Jon A; Gaudernack, Gustav; Fåne, Anne; Lislerud, Kari; Inderberg, Else Marit & Brunsvig, Paal Fr. [Show all 10 contributors for this article] (2016). T-helper cell receptors from long-term survivors after telomerase cancer vaccination for use in adoptive cell therapy. Oncoimmunology. ISSN 2162-4011. 5:e1249090(12). doi: 10.1080/2162402X.2016.1249090. Full text in Research Archive
• Cairns, Linda; Aspeslagh, Sandrine; Anichini, Andrea; Kyte, Jon A; Blank, Christian & Ascierto, Paolo [Show all 9 contributors for this article] (2016). Cancer immunotherapy: From the lab to clinical applications - Potential impact on cancer centres' organisation. ecancermedicalscience. 10. doi: 10.3332/ecancer.2016.691. Full text in Research Archive
• Kyte, Jon A; Aamdal, Steinar; Dueland, Svein; Sæbøe-Larssen, Stein; Inderberg, Else Marit & Madsbu, Ulf Erik [Show all 9 contributors for this article] (2016). Immune response and long-term clinical outcome in advanced melanoma patients vaccinated with tumor-mRNA-transfected dendritic cells. Oncoimmunology. ISSN 2162-4011. 5(11). doi: 10.1080/2162402X.2016.1232237. Full text in Research Archive
• Eide, Hanne Astrid; Halvorsen, Ann Rita; Sandhu, Vandana; Fåne, Anne; Berg, Janna & Haakensen, Vilde Drageset [Show all 11 contributors for this article] (2016). Non-small cell lung cancer is characterised by a distinct inflammatory signature in serum compared with chronic obstructive pulmonary disease. Clinical & translational immunology. 5. doi: 10.1038/cti.2016.65. Full text in Research Archive Show summary

  Development of lung cancer is closely related to smoking in a majority of patients. Most smokers, however, do not develop lung cancer in spite of a high mutational load accumulating in the lung tissue. Here we investigate whether a cancer-specific footprint can be revealed by investigating circulating inflammatory markers in patients with non-small cell lung cancer (NSCLC) compared with patients with chronic obstructive pulmonary disease (COPD), both cohorts characterised by similar smoking history. Serum concentrations of 57 cytokines and matrix metalloproteinases (MMPs) from 43 patients with advanced NSCLC were evaluated by multiplex immunoassays and compared with serum samples from 35 patients with COPD. Unsupervised hierarchical clustering and non-parametric analyses were performed. False discovery rate was used to adjust for multiple testing. Clustering of cytokine and MMP concentrations in the serum revealed a distinct separation of the NSCLC patients from the COPD group. Individual concentrations of thymus and activation-regulated cytokine (C-C motif chemokine ligand 17), Gro-b (C-X-C motif chemokine ligand 2 (CXCL2)), CXCL13, interleukin (IL)-1ra, IL-6, IL-8 (CXCL8), IL-16, IL-17A, macrophage migration inhibitory factor (MIF), granulocyte colony-stimulating factor, platelet-derived growth factor subunit B, MMP-2, MMP-8 and MMP-12 were significantly different in serum from NSCLC and COPD patients. Moreover, the interferon-γ/IL-10 ratio was lower in cancer patients compared with COPD patients, consistent with a cytokine milieu favouring tumour tolerance. Our results suggest that NSCLC is characterised by a distinct inflammatory signature in serum. The different cytokine profiles in NSCLC and COPD patients may represent tumour-promoting and tumour-suppressing immune responses developing in response to mucosal inflammation and mutations induced by smoking.

• Hansen, Gaute Lund; Gaudernack, Gustav; Brunsvig, Paal Fr.; Småstuen, Milada Cvancarova & Kyte, Jon A (2015). Immunological factors influencing clinical outcome in lung cancer patients after telomerase peptide vaccination. Cancer Immunology and Immunotherapy. ISSN 0340-7004. 64(12), p. 1609–1621. doi: 10.1007/s00262-015-1766-5. Full text in Research Archive
• Almåsbak, Hilde Kjersti; Walseng, Even; Kristian, Alexandr; Myhre, Marit Renee; Suso, Else Marit Inderberg & Munthe, Ludvig Andre [Show all 11 contributors for this article] (2015). Inclusion of an IgG1-Fc spacer abrogates efficacy of CD19 CAR T cells in a xenograft mouse model. Gene Therapy. ISSN 0969-7128. 22(5), p. 391–403. doi: 10.1038/gt.2015.4. Full text in Research Archive
• Campo, Ana B. del; Kyte, Jon A; Carretero, Javier; Zinchencko, Svitlana; Méndez, Rosa & González-Aseguinolaza, Gloria [Show all 11 contributors for this article] (2014). Immune escape of cancer cells with beta2-microglobulin loss over the course of metastatic melanoma. International Journal of Cancer. ISSN 0020-7136. 134(1), p. 102–113. doi: 10.1002/ijc.28338. Full text in Research Archive
• Kyte, Jon A; Gaudernack, Gustav; Dueland, Svein; Trachsel, Sissel; Julsrud, Lars & Aamdal, Steinar (2011). Telomerase Peptide Vaccination Combined with Temozolomide: A Clinical Trial in Stage IV Melanoma Patients. Clinical Cancer Research. ISSN 1078-0432. 17(13), p. 4568–4580. doi: 10.1158/1078-0432.CCR-11-0184. Full text in Research Archive
• Brunsvig, Paal Fr.; Kyte, Jon A; Kersten, Christian; Sundstrøm, Stein Harald; Møller, Mona & Nyakas, Marta Sølvi [Show all 9 contributors for this article] (2011). Telomerase Peptide Vaccination in NSCLC: A Phase II Trial in Stage III Patients Vaccinated after Chemoradiotherapy and an 8-Year Update on a Phase I/II Trial. Clinical Cancer Research. ISSN 1078-0432. 17(21), p. 6847–6857. doi: 10.1158/1078-0432.CCR-11-1385. Full text in Research Archive
• Kyte, Jon A; Trachsel, S; Risberg, Bjørn; Straten, Per Thor; Smebye, Kari Lislerud & Gaudernack, Gustav (2009). Unconventional cytokine profiles and development of T cell memory in long-term survivors after cancer vaccination. Cancer Immunology and Immunotherapy. ISSN 0340-7004. 58(10), p. 1609–1626. doi: 10.1007/s00262-009-0670-2. Full text in Research Archive
• Kyte, Jon A (2009). Cancer vaccination with telomerase peptide GV1001. Expert Opinion on Investigational Drugs. ISSN 1354-3784. 18(5), p. 687–694. doi: 10.1517/13543780902897631. Full text in Research Archive
• Kyte, Jon A; Kvalheim, Gunnar; Smebye, Kari Lislerud; Straten, PT; Dueland, S & Aamdal, Steinar [Show all 7 contributors for this article] (2007). T cell responses in melanoma patients after vaccination with tumor-mRNA transfected dendritic cells. Cancer Immunology and Immunotherapy. ISSN 0340-7004. 56. doi: 10.1007/s00262-006-0222-y. Full text in Research Archive
• Kyte, Jon A & Gaudernack, Gustav (2006). Immuno-gene therapy of cancer with tumour-mRNA transfected dendritic cells. Cancer Immunology and Immunotherapy. ISSN 0340-7004. 55, p. 1432–1442. Full text in Research Archive
• Kyte, Jon Amund; Mu, L J; Aamdal, S; Kvalheim, G; Dueland, S & Hauser, M [Show all 11 contributors for this article] (2006). Phase I/II trial of melanoma therapy with dendritic cells transfected with autologous tumor-mRNA. Cancer Gene Therapy. ISSN 0929-1903. 13, p. 905–918. Full text in Research Archive
• Mu, L J; Kyte, Jon A; Kvalheim, Gunnar; Aamdal, Steinar; Dueland, Svein & Hauser, Markus [Show all 10 contributors for this article] (2005). Immunotherapy with allotumour mRNA-transfected dendritic cells in androgen-resistant prostate cancer patients. British Journal of Cancer. ISSN 0007-0920. 93(7), p. 749–756. Full text in Research Archive
• Kyte, Jon A; Kvalheim, Gunnar; Aamdal, Steinar; Sæbøe-Larssen, Stein & Gaudernack, Gustav (2005). Preclinical full-scale evaluation of dendritic cells transfected with autologous tumor-mRNA for melanoma vaccination. Cancer Gene Therapy. ISSN 0929-1903. 12. Full text in Research Archive

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• Jin, Yixin; Dunn, Claire; Persiconi, Irene; Sike, Adam; Skorstad, Gjertrud & Beck, Carole Anne [Show all 7 contributors for this article] (2024). Correction to: Comparative Evaluation of STEAP1 Targeting Chimeric Antigen Receptors with Different Costimulatory Domains and Spacers (International Journal of Molecular Sciences, (2024), 25, 1, (586), 10.3390/ijms25010586). International Journal of Molecular Sciences. ISSN 1661-6596. 25(18). doi: 10.3390/ijms251810024. Full text in Research Archive
• Westgaard, Arne; Kyte, Jon A & Gjersvik, Petter (2023). Genforandringer som egner seg for målrettet kreftbehandling. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. doi: 10.4045/TIDSSKR.23.0076. Full text in Research Archive
• Tasken, Kjetil; Russnes, Hege Elisabeth Giercksky; Aas, Eline; Bjørge, Line; Blix, Egil Støre & Ahlquist, Terje C. [Show all 116 contributors for this article] (2022). A national precision cancer medicine implementation initiative for Norway. Nature Medicine. ISSN 1078-8956. 28(5), p. 885–887. doi: 10.1038/s41591-022-01777-4. Full text in Research Archive
• Pedersen, Lars Håkon & Kyte, Jon A (2022). Oppløftende prøvemetode mot brystkreft : – Ville ikke stått her uten den. [Internet]. NRK. Full text in Research Archive
• Weltzien, Solveig Brekke; Kyte, Jon A & Røssevold, Andreas Hagen (2022). Et stort gjennombrudd i norsk brystkreftforskning. [Internet]. Brystkreftforeningen. Full text in Research Archive
• Helland, Åslaug; Russnes, Hege Elisabeth Giercksky; Fagereng, Gro Live; Al-Shibli, Khalid Ibrahim; Andersson, Yvonne & Berg, Thomas [Show all 53 contributors for this article] (2022). Correction to: Improving public cancer care by implementing precision medicine in Norway: IMPRESS-Norway (Journal of Translational Medicine, (2022), 20, 1, (225), 10.1186/s12967-022-03432-5). Journal of Translational Medicine. 20(1). doi: 10.1186/s12967-022-03518-0. Full text in Research Archive
• Grødeland, Gunnveig; Kyte, Jon A; Walaa, Abuelmagd & Lindmoe, Karine Yttredal (2022). Kreftvaksiner – hva er det, egentlig? [Radio]. Oncocast - MSD Norge. Full text in Research Archive
• Helland, Åslaug; Russnes, Hege Elisabeth Giercksky; Fagereng, Gro Live; Al-Shibli, Khalid Ibrahim; Andersson, Yvonne & Berg, Thomas [Show all 53 contributors for this article] (2022). Improving public cancer care by implementing precision medicine in Norway: IMPRESS-Norway. Journal of Translational Medicine. 20(1), p. 1–11. doi: 10.1186/s12967-022-03432-5. Full text in Research Archive Show summary

  Background Matching treatment based on tumour molecular characteristics has revolutionized the treatment of some cancers and has given hope to many patients. Although personalized cancer care is an old concept, renewed attention has arisen due to recent advancements in cancer diagnostics including access to high-throughput sequencing of tumour tissue. Targeted therapies interfering with cancer specific pathways have been developed and approved for subgroups of patients. These drugs might just as well be efficient in other diagnostic subgroups, not investigated in pharma-led clinical studies, but their potential use on new indications is never explored due to limited number of patients. Methods In this national, investigator-initiated, prospective, open-label, non-randomized combined basket- and umbrella-trial, patients are enrolled in multiple parallel cohorts. Each cohort is defined by the patient’s tumour type, molecular profile of the tumour, and study drug. Treatment outcome in each cohort is monitored by using a Simon two-stage-like ‘admissible’ monitoring plan to identify evidence of clinical activity. All drugs available in IMPRESS-Norway have regulatory approval and are funded by pharmaceutical companies. Molecular diagnostics are funded by the public health care system.

• Anderssen, Hans; Kyte, Jon A & Røssevold, Andreas (2022). Norsk studie med ny og lovende behandling for pasienter med trippelnegativ brystkreft. [Internet]. Health Talk. Full text in Research Archive
• Kyte, Jon A (2013). Kreftgåten er utgått på dato. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 133(18), p. 1907–1907. doi: 10.4045/tidsskr.13.1037. Full text in Research Archive
• Hestnes, Nina; Bruunsvig, Paal & Kyte, Jon A (2012). Lungekreftvaksine gir håp. [Journal]. Forskning.no. Full text in Research Archive
• Aamdal, Steinar; Kyte, Jon Amund; Dueland, Svein; Mu, LJ; Gullestad, HP & Ryder, Truls [Show all 10 contributors for this article] (2005). Phase VII trial of vaccine therapy with tumor-RNA transfected dendritic cells in patients with advanced malignant melanoma. Journal of Clinical Oncology. ISSN 0732-183X. 23, p. 175S–175S. Full text in Research Archive
• Kyte, Jon A; Gaudernack, Gustav; Smeland, Erlend B & Funderud, Steinar (2007). Immuno-gene therapy of cancer with tumor-mRNA transfected dendritic cells. Universitetet i Oslo. ISSN 9788280724182. Full text in Research Archive

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