Adjuvant dendritic cell therapy in stage IIIB/C melanoma: the MIND-DC randomized phase III trial.

Autologous natural dendritic cells (nDCs) treatment can induce tumor-specific immune responses and clinical responses in cancer patients. In this phase III clinical trial (NCT02993315), 148 patients with resected stage IIIB/C melanoma were randomized to adjuvant treatment with nDCs (n = 99) or placebo (n = 49). Active treatment consisted of intranodally injected autologous CD1c+ conventional and plasmacytoid DCs loaded with tumor antigens.

Immunological responses to adjuvant vaccination with combined CD1c myeloid and plasmacytoid dendritic cells in stage III melanoma patients.

We evaluated the immunological responses of lymph-node involved (stage III) melanoma patients to adjuvant dendritic cell vaccination with subsets of naturally occurring dendritic cells (nDCs). Fifteen patients with completely resected stage III melanoma were randomized to receive adjuvant dendritic cell vaccination with CD1c myeloid dendritic cells (cDC2s), plasmacytoid dendritic cells (pDCs) or the combination. Immunological response was the primary endpoint and secondary endpoints included safety and survival.

Homologous recombination repair deficient prostate cancer represents an immunologically distinct subtype.

Homologous recombination repair deficiency (HRD) is observed in 10% of patients with castrate-resistant prostate cancer (PCa). Preliminary data suggest that HRD-PCa might be more responsive to immune checkpoint inhibitors (ICIs). In this study, we compare the tumor immune landscape and peripheral T cell receptor (TCR) repertoire of patients with and without HRD-PCa to gain further insight into the immunogenicity of HRD-PCa.

Intratumoral T cell depletion following neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer is associated with poor clinical outcome.

Background: Whereas neoadjuvant cisplatin-based chemotherapy (NAC) followed by a radical cystectomy remains the standard treatment for patients with muscle-invasive bladder cancer (MIBC), increasing evidence suggests that checkpoint inhibitors, either alone or in combination with chemotherapy, are effective in the (neo)adjuvant setting. The major aim of this study was to improve our understanding of the immune-modulating effects of NAC in MIBC.

Methods: Tumor tissue of 81 patients was used, including 60 patients treated with NAC and 21 patients undergoing upfront cystectomy.

Spatial and Temporal Heterogeneity of Tumor-Infiltrating Lymphocytes in Advanced Urothelial Cancer.

Checkpoint inhibitors targeting PD-(L)1 induce objective responses in 20% of patients with metastatic urothelial cancer (UC). CD8 T cell infiltration has been proposed as a putative biomarker for response to checkpoint inhibitors. Nevertheless, data on spatial and temporal heterogeneity of tumor-infiltrating lymphocytes in advanced UC are lacking.

Whole Blood Transcriptome Profiling Identifies DNA Replication and Cell Cycle Regulation as Early Marker of Response to Anti-PD-1 in Patients with Urothelial Cancer.

Although immune checkpoint inhibitors improve median overall survival in patients with metastatic urothelial cancer (mUC), only a minority of patients benefit from it. Early blood-based response biomarkers may provide a reliable way to assess response weeks before imaging is available, enabling an early switch to other therapies. We conducted an exploratory study aimed at the identification of early markers of response to anti-PD-1 in patients with mUC.

Plasma BRAF Mutation Detection for the Diagnostic and Monitoring Trajectory of Patients with LDH-High Stage IV Melanoma.

For patients with newly diagnosed metastatic melanoma, rapid BRAF mutation (mBRAF) assessment is vital to promptly initiate systemic therapy. Additionally, blood-based biomarkers are desired to monitor and predict treatment response. Circulating tumor DNA (ctDNA) has shown great promise for minimally invasive mBRAF assessment and treatment monitoring, but validation studies are needed.

Homologous Recombination Repair Deficiency and Implications for Tumor Immunogenicity.

Homologous recombination repair deficiency (HRD) can be observed in virtually all cancer types. Although HRD sensitizes tumors to DNA-damaging chemotherapy and poly(ADP-ribose) polymerase (PARP) inhibitors, all patients ultimately develop resistance to these therapies. Therefore, it is necessary to identify therapeutic regimens with a more durable efficacy.

Response and survival of metastatic melanoma patients treated with immune checkpoint inhibition for recurrent disease on adjuvant dendritic cell vaccination.

Vaccination with autologous dendritic cells (DC) loaded ex vivo with melanoma-associated antigens is currently being tested as an adjuvant treatment modality for resected locoregional metastatic (stage III) melanoma. Based on its mechanism of action, DC vaccination might potentiate the clinical efficacy of concurrent or sequential immune checkpoint inhibition (ICI). The purpose of this study was to determine the efficacy of ICI administered following recurrent disease during, or after, adjuvant DC vaccination.

Autologous monocyte-derived DC vaccination combined with cisplatin in stage III and IV melanoma patients: a prospective, randomized phase 2 trial.

Background: Autologous dendritic cell (DC) vaccines can induce tumor-specific T cells, but their effect can be counteracted by immunosuppressive mechanisms. Cisplatin has shown immunomodulatory effects in vivo which may enhance efficacy of DC vaccination.

Methods: This is a prospective, randomized, open-label phase 2 study (NCT02285413) including stage III and IV melanoma patients receiving 3 biweekly vaccinations of gp100 and tyrosinase mRNA-loaded monocyte-derived DCs with or without cisplatin.

Switching to Immune Checkpoint Inhibitors upon Response to Targeted Therapy; The Road to Long-Term Survival in Advanced Melanoma Patients with Highly Elevated Serum LDH?

The prognosis of patients with advanced melanoma has improved dramatically. However, the clinical outcomes of patients with highly elevated serum lactate dehydrogenase (LDH) remain very poor. The aim of this study was to explore whether patients with normalized LDH after targeted therapy could benefit from subsequent treatment with immune checkpoint inhibitors (ICI).

[Pseudoprogression in immune therapy].

Immune therapy is increasingly used as an effective treatment for various types of cancer. The response of tumours to immune therapy is different from conventional chemotherapy. In about 10% of patients, pseudoprogression may occur.

[Immunotherapy for cancer: from medical breakthrough to application in daily practice].

Immunotherapy induces a response against cancer by activating the immune system. Examples are therapies with checkpoint inhibitors, oncolytic viruses and chimeric antigen receptor T-cells (CAR T-cells). These therapies have, due to their rapid development, found their way to daily practice.

Association Between Pembrolizumab-related Adverse Events and Treatment Outcome in Advanced Melanoma: Results From the Dutch Expanded Access Program.

Toxicity of immune checkpoint inhibitors such as ipilimumab and nivolumab is likely associated with clinical efficacy. In this study, we aim to evaluate this association for pembrolizumab. To this end, data of 147 patients included in the Dutch cohort of the Pembrolizumab Expanded Access Program were collected.

Early Recurrence in Completely Resected IIIB and IIIC Melanoma Warrants Restaging Prior to Adjuvant Therapy.

Purpose: To evaluate the results of restaging completely resected stage IIIB/C melanoma prior to start of adjuvant therapy.

Patients And Methods: One hundred twenty patients with stage IIIB or IIIC (AJCC 2009) melanoma who underwent complete surgical resection were screened for inclusion in our trial investigating adjuvant dendritic cell therapy (NCT02993315). All patients underwent imaging to exclude local relapse or metastasis before entering the trial.

53BP1 as a potential predictor of response in PARP inhibitor-treated homologous recombination-deficient ovarian cancer.

Objective: Poly(ADP-ribose) polymerase (PARP) inhibitors have shown substantial activity in homologous recombination- (HR-) deficient ovarian cancer and are undergoing testing in other HR-deficient tumors. For reasons that are incompletely understood, not all patients with HR-deficient cancers respond to these agents. Preclinical studies have demonstrated that changes in alternative DNA repair pathways affect PARP inhibitor (PARPi) sensitivity in ovarian cancer models.

The Impact of Dose and Simultaneous Use of Acid-Reducing Agents on the Effectiveness of Vemurafenib in Metastatic BRAF V600 Mutated Melanoma: a Retrospective Cohort Study.

Background: The impact of dose and simultaneous use of acid-reducing agents (ARAs) on the effectiveness of vemurafenib is unknown.

Objectives: To determine the association between progression of metastatic BRAF V600 mutated melanoma and (1) dose reductions of vemurafenib and (2) simultaneous use of vemurafenib and ARAs.

Patient And Methods: A retrospective cohort study of 112 first-line vemurafenib users for melanoma was conducted (March 2012-March 2016), using electronic patient records and pharmacy dispensing records of a Dutch academic hospital.

Nivolumab-associated Nephrotic Syndrome in a Patient With Renal Cell Carcinoma: A Case Report.

Introduction: Immune checkpoint inhibitors have taken an important place in the treatment of different types of malignancies. These drugs are known to have specific immune-mediated adverse events. We describe a case of severe nephrotic syndrome secondary to treatment with nivolumab in a patient with renal cell carcinoma.

Ipilimumab administered to metastatic melanoma patients who progressed after dendritic cell vaccination.

Background: Ipilimumab has proven to be effective in metastatic melanoma patients. The purpose of this study was to determine the efficacy of ipilimumab in advanced melanoma patients who showed progressive disease upon experimental dendritic cell (DC) vaccination.

Methods: Retrospective analysis of 48 stage IV melanoma patients treated with ipilimumab after progression upon DC vaccination earlier in their treatment.

Immune-related Adverse Events of Dendritic Cell Vaccination Correlate With Immunologic and Clinical Outcome in Stage III and IV Melanoma Patients.

The purpose of this study was to determine the toxicity profile of dendritic cell (DC) vaccination in stage III and IV melanoma patients, and to evaluate whether there is a correlation between side effects and immunologic and clinical outcome. This is a retrospective analysis of 82 stage III and 137 stage IV melanoma patients, vaccinated with monocyte-derived or naturally circulating autologous DCs loaded with tumor-associated antigens gp100 and tyrosinase. Median follow-up time was 54.

Effective Clinical Responses in Metastatic Melanoma Patients after Vaccination with Primary Myeloid Dendritic Cells.

Purpose: Thus far, dendritic cell (DC)-based immunotherapy of cancer was primarily based on in vitro-generated monocyte-derived DCs, which require extensive in vitro manipulation. Here, we report on a clinical study exploiting primary CD1c(+) myeloid DCs, naturally circulating in the blood.

Experimental Design: Fourteen stage IV melanoma patients, without previous systemic treatment for metastatic disease, received autologous CD1c(+) myeloid DCs, activated by only brief (16 hours) ex vivo culture and loaded with tumor-associated antigens of tyrosinase and gp100.

Case series: indoor-photosensitivity caused by fluorescent lamps in patients treated with vemurafenib for metastatic melanoma.

Background: Vemurafenib, a selective inhibitor of genetically activated BRAF, is registered for unresectable stage III and stage IV melanomas harboring a BRAF mutation. Photosensitivity related to exposure to sunlight is a common side-effect. We here present three cases of indoor-photosensitivity due to fluorescent lamps, whilst undergoing treatment with vemurafenib.

Management of fatigue in patients with cancer -- a practical overview.

Cancer-related fatigue (CRF) is a serious clinical problem and is one of the most common symptoms experienced by cancer patients. CRF has deleterious effects on many aspects of patient quality of life including their physical, psychological and social well-being. It can also limit their ability to function, socialise and participate in previously enjoyable activities.

Dynamics of IGF-1R expression during endocrine breast cancer treatment.

Purpose: The aim was to assess changes in insulin-like growth factor 1 receptor (IGF-1R) expression with immunoSPECT/CT and to study the dynamics of IGF-1R expression of human breast tumors during endocrine treatment.

Procedures: Mice with MCF-7 xenografts were treated with estradiol or tamoxifen, and IGF-1R expression was measured by immunohistochemistry and immunoSPECT/CT using (111)In-R1507 (anti-IGF-1R antibody). Moreover, IGF-1R expression was analyzed immunohistochemically on 22 human breast tumors, treated preoperatively with endocrine therapy.

PIK3CA mutations, phosphatase and tensin homolog, human epidermal growth factor receptor 2, and insulin-like growth factor 1 receptor and adjuvant tamoxifen resistance in postmenopausal breast cancer patients.

Introduction: Inhibitors of the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway can overcome endocrine resistance in estrogen receptor (ER) α-positive breast cancer, but companion diagnostics indicating PI3K/AKT/mTOR activation and consequently endocrine resistance are lacking. PIK3CA mutations frequently occur in ERα-positive breast cancer and result in PI3K/AKT/mTOR activation in vitro. Nevertheless, the prognostic and treatment-predictive value of these mutations in ERα-positive breast cancer is contradictive.