Metronomic cyclophosphamide attenuates mTOR-mediated expansion of regulatory T cells, but does not impact clinical outcome in patients with metastatic renal cell cancer treated with everolimus.

Introduction: Metastatic renal cell cancer (mRCC) patients have a median overall survival (mOS) of approximately 28 months. Until recently, mammalian target of rapamycin (mTOR) inhibition with everolimus was the standard second-line treatment regimen for mRCC patients, improving median progression-free survival (mPFS). Treatment with everolimus supports the expansion of immunosuppressive regulatory T cells (Tregs), which exert a negative effect on antitumor immune responses.

A large pooled analysis refines gene expression-based molecular subclasses in cutaneous melanoma.

This study aimed to establish the number of expression-based molecular subclasses in cutaneous melanoma, identify their dominant biological pathways and evaluate their clinical relevance. To this end, consensus clustering was performed separately on two independent datasets (n = 405 and n = 473) composed of publicly available cutaneous melanoma expression profiles from previous studies. Four expression-based molecular subclasses were identified and labelled 'Oxidative phosphorylation', 'Oestrogen response/p53-pathway', 'Immune' and 'Cell cycle', based on their dominantly expressed biological pathways determined by gene set enrichment analysis.

The effect of everolimus and low-dose cyclophosphamide on immune cell subsets in patients with metastatic renal cell carcinoma: results from a phase I clinical trial.

For the treatment of metastatic renal cell cancer several strategies are used among which the mTOR inhibitor everolimus. As mTOR plays an important role in the immune system, e.g.

Small-scale GMP production of plasmid DNA using a simplified and fully disposable production method.

In the past years, the demand for small batches of clinical grade plasmid DNA has been growing. For that purpose, we designed and qualified a scaled-down Good Manufacturing Practices (GMP) production method, able to produce small batches (1-4 mg) of plasmid. The developed method does not require any complex production equipment and utilizes only disposable production materials, which makes it easy to implement and simplifies line-clearance.

Dysfunctional CD8 T Cells Form a Proliferative, Dynamically Regulated Compartment within Human Melanoma.

Tumor immune cell compositions play a major role in response to immunotherapy, but the heterogeneity and dynamics of immune infiltrates in human cancer lesions remain poorly characterized. Here, we identify conserved intratumoral CD4 and CD8 T cell behaviors in scRNA-seq data from 25 melanoma patients. We discover a large population of CD8 T cells showing continuous progression from an early effector "transitional" into a dysfunctional T cell state.

NKG2A, a New Kid on the Immune Checkpoint Block.

One of the major breakthroughs of cancer immunotherapy has come from blocking immune checkpoint molecules on tumor-reactive T cells. Now, two studies examine targeting of a novel immune checkpoint, NKG2A, that can be expressed on both NK cells and on CD8 T cells, either combined with a tumor-targeting antibody or with a tumor-specific vaccine.

Comparison of Immediate vs Deferred Cytoreductive Nephrectomy in Patients With Synchronous Metastatic Renal Cell Carcinoma Receiving Sunitinib: The SURTIME Randomized Clinical Trial.

Importance: In clinical practice, patients with primary metastatic renal cell carcinoma (mRCC) have been offered cytoreductive nephrectomy (CN) followed by targeted therapy, but the optimal sequence of surgery and systemic therapy is unknown.

Objective: To examine whether a period of sunitinib therapy before CN improves outcome compared with immediate CN followed by sunitinib.

Design, Setting, And Participants: This randomized clinical trial began as a phase 3 trial on July 14, 2010, and continued until March 24, 2016, with a median follow-up of 3.

Low and variable tumor reactivity of the intratumoral TCR repertoire in human cancers.

Infiltration of human cancers by T cells is generally interpreted as a sign of immune recognition, and there is a growing effort to reactivate dysfunctional T cells at such tumor sites. However, these efforts only have value if the intratumoral T cell receptor (TCR) repertoire of such cells is intrinsically tumor reactive, and this has not been established in an unbiased manner for most human cancers. To address this issue, we analyzed the intrinsic tumor reactivity of the intratumoral TCR repertoire of CD8 T cells in ovarian and colorectal cancer-two tumor types for which T cell infiltrates form a positive prognostic marker.

Adoptive cellular therapies: the current landscape.

For many cancer types, the immune system plays an essential role in their development and growth. Based on these rather novel insights, immunotherapeutic strategies have been developed. In the past decade, immune checkpoint blockade has demonstrated a major breakthrough in cancer treatment and has currently been approved for the treatment of multiple tumor types.

Autoantibody Development under Treatment with Immune-Checkpoint Inhibitors.

Immune-checkpoint inhibitors (ICIs) activate the immune system to assault cancer cells in a manner that is not antigen specific. We hypothesized that tolerance may also be broken to autoantigens, resulting in autoantibody formation, which could be associated with immune-related adverse events (irAEs) and antitumor efficacy. Twenty-three common clinical autoantibodies in pre- and posttreatment sera from 133 ipilimumab-treated melanoma patients were determined, and their development linked to the occurrence of irAEs, best overall response, and survival.

Peripheral Blood TCR Repertoire Profiling May Facilitate Patient Stratification for Immunotherapy against Melanoma.

Many metastatic melanoma patients experience durable responses to anti-PD1 and/or anti-CTLA4; however, a significant proportion (over 50%) do not benefit from the therapies. In this study, we sought to assess pretreatment liquid biopsies for biomarkers that may correlate with response to checkpoint blockade. We measured the combinatorial diversity evenness of the T-cell receptor (TCR) repertoire (the DE, with low values corresponding to more clonality and lack of TCR diversity) in pretreatment peripheral blood mononuclear cells from melanoma patients treated with anti-CTLA4 ( = 42) or anti-PD1 ( = 38) using a multi-N-plex PCR assay on genomic DNA (gDNA).

Phase 1 study of everolimus and low-dose oral cyclophosphamide in patients with metastatic renal cell carcinoma.

mTOR inhibitors are frequently used in the treatment of metastatic renal cell cancer (mRCC). mTOR regulates cell growth, proliferation, angiogenesis, and survival, and additionally plays an important role in immune regulation. Since mTOR inhibitors were shown to benefit immunosuppressive regulatory T-cell (Treg) expansion, this might suppress antitumor immune responses.

Treatment With Tumor-infiltrating Lymphocytes in Advanced Melanoma: Evaluation of Early Clinical Implementation of an Advanced Therapy Medicinal Product.

Tumor-infiltrating lymphocytes (TIL)-therapy in advanced melanoma is an advanced therapy medicinal product (ATMP) which, despite promising results, has not been implemented widely. In a European setting, TIL-therapy has been in use since 2011 and is currently being evaluated in a randomized controlled trial. As clinical implementation of ATMPs is challenging, this study aims to evaluate early application of TIL-therapy, through the application of a constructive technology assessment (CTA).

Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma.

Adjuvant ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) both improve relapse-free survival of stage III melanoma patients. In stage IV disease, the combination of ipilimumab + nivolumab is superior to ipilimumab alone and also appears to be more effective than nivolumab monotherapy. Preclinical work suggests that neoadjuvant application of checkpoint inhibitors may be superior to adjuvant therapy.

Starting the fight in the tumor: expert recommendations for the development of human intratumoral immunotherapy (HIT-IT).

A European Society for Medical Oncology (ESMO)-sponsored expert meeting was held in Paris on 8 March 2018 which comprised 11 experts from academia, 11 experts from the pharmaceutical industry and 2 clinicians who were representatives of ESMO. The focus of the meeting was exclusively on the intratumoral injection/delivery of immunostimulatory agents with the aim of harmonizing the standard terms and methodologies used in the reporting of human intratumoral immunotherapy (HIT-IT) clinical trials to ensure quality assurance and avoid a blurring of the data reported from different studies. The goal was to provide a reference document, endorsed by the panel members that could provide guidance to clinical investigators, pharmaceutical companies, ethics committees, independent review boards, patient advocates and the regulatory authorities and promote an increase in the number and quality of HIT-IT clinical trials in the future.

Adoptive transfer of tumor-infiltrating lymphocytes in melanoma: a viable treatment option.

The treatment of metastatic melanoma patients with autologous tumor-infiltrating lymphocytes (TIL) shows robust, reproducible, clinical responses in clinical trials executed in several specialized centers over the world. Even in the era of targeted therapy and immune checkpoint inhibition, TIL therapy can be an additional and clinically relevant treatment line. This review provides an overview of the clinical experiences with TIL therapy thus far, including lymphodepleting regimens, the use of interleukin-2 (IL-2) and the associated toxicity.

Gender-related challenges facing oncologists: the results of the ESMO Women for Oncology Committee survey.

Background: Although women account for a growing proportion of the oncology workforce, there is evidence they are under-represented in leadership roles. To gain further insights into this issue and extend understanding of gender challenges, the European Society for Medical Oncology Women for Oncology (W4O) Committee undertook a survey of female and male oncologists in 2016.

Design: The 2016 W4O questionnaire included questions on (1) Demographics and professional environment, (2) Gender impact on career development, (3) Challenges for career progression and inappropriate behaviour experienced in the workplace, (4) Barriers for gender parity and (5) The gender gap.

Report on the status of women occupying leadership roles in oncology.

Background: While the global workforce is approaching gender parity, women occupy a small number of management level positions across most professions, including healthcare. Although the inclusion of women into the membership of many oncology societies has increased, the under-representation of women in leadership roles within international and national oncology societies remains relatively consistent. Moreover, the exact status of women participating as board members or presidents of oncology societies or as speakers at oncology congresses was undocumented to date.

Early cost-effectiveness of tumor infiltrating lymphocytes (TIL) for second line treatment in advanced melanoma: a model-based economic evaluation.

Background: An emerging immunotherapy is infusion of tumor infiltrating Lymphocytes (TIL), with objective response rates of around 50% versus 19% for ipilimumab. As an Advanced Therapeutic Medicinal Products (ATMP), TIL is highly personalized and complex therapy. It requests substantial upfront investments from the hospital in: expensive lab-equipment, staff expertise and training, as well as extremely tight hospital logistics.

Generation of Tumor-Reactive T Cells by Co-culture of Peripheral Blood Lymphocytes and Tumor Organoids.

Cancer immunotherapies have shown substantial clinical activity for a subset of patients with epithelial cancers. Still, technological platforms to study cancer T-cell interactions for individual patients and understand determinants of responsiveness are presently lacking. Here, we establish and validate a platform to induce and analyze tumor-specific T cell responses to epithelial cancers in a personalized manner.

[Recent treatment results for metastatic melanoma: data from the Dutch Melanoma Treatment Registry].

Objective: To evaluate treatment strategies and survival of patients with unresectable stage IIIc or IV melanoma since the 2012 introduction of new drugs in the Netherlands.

Design: Prospective cohort study.

Method: We analysed data from the Dutch Melanoma Treatment Registry (DMTR) regarding patients diagnosed with unresectable stage IIIc or IV melanoma in the period of 1 July 2012 to 31 December 2015.