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. Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) or gene-modified T cells expressing novel T cell receptors (TCR) or chimeric antigen receptors (CAR) is another strategy to modify the immune system to recognize tumor cells and thus carry out an anti-tumor effector function. These treatments have shown promising results in various tumor types, and multiple clinical trials are being conducted worldwide to further optimize this treatment modality. Most successful results were obtained in hematological malignancies with the use of CD19-directed CAR T cell therapy and already led to the commercial approval by the FDA. This review provides an overview of the developments in ACT, the associated toxicity, and the future potential of ACT in cancer treatment.</p

The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network

Background: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. Methods and Findings: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. Conclusion: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects

Diagnostic performance of early increase in S100B or LDH as outcome predictor for non-responsiveness to anti-PD-1 monotherapy in advanced melanoma

As a subset of advanced melanoma patients derive long-term benefit from anti-PD-1 therapy, early identification of non-responsiveness would enable an early switch to next line therapies. This study assessed if an early increase in S100B or lactate dehydrogenase (LDH) could be predictive for non-responsiveness to anti-PD-1. We retrospectively analysed advanced melanoma patients treated with anti-PD-1 monotherapy. Serum S100B and LDH levels were measured at baseline and before every infusion. Non-response was defined as progression or death at 6 months. Marker cut-offs were defined based on > 95% specificity and feasibility in clinical practice. For validation an independent cohort was analysed. In total, 313 patients were included (166 patients in training cohort, 147 patients in validation cohort). Increase of > 50% in LDH or > 100% in S100B above upper limit of normal at week 6 compared to baseline was determined as criterion to positively test for non-responsiveness. In the validation cohort, obtained specificity of the combination test was > 95% with a positive predictive value of 82%; obtained sensitivity was lower (21%), with a negative predictive value of 55%. Early increase in S100B or LDH is a strong parameter for non-responsiveness to anti-PD-1 in advanced melanoma. Prospective confirmation is needed before clinical implementation.</p

Sex-Based Differences in Treatment with Immune Checkpoint Inhibition and Targeted Therapy for Advanced Melanoma:A Nationwide Cohort Study

SIMPLE SUMMARY: Melanoma is a malignant form of skin cancer. The overall survival of patients with advanced stages of disease were initially low. Fortunately, in recent years systemic treatment with immunotherapy has prolonged survival. We set out to answer the question whether men and women with advanced melanoma differ in prognostic factors, tumor-response to immunotherapy, and treatment-related adverse events. All patients in the Netherlands were registered between July 2013 and July 2018. We showed that although clinical and tumor characteristics differ, the safety profile of immunotherapy is comparable. Furthermore, overall, a 10% survival advantage for women was seen. Following immunotherapy there was no survival difference. ABSTRACT: Recent meta-analyses show conflicting data on sex-dependent benefit following systemic treatment for advanced melanoma patients. We examined the nationwide Dutch Melanoma Treatment Registry (July 2013–July 2018), assessing sex-dependent differences in advanced melanoma patients (stage IIIC/IV) with respect to clinical characteristics, mutational profiles, treatments initiated, grade 3–4 adverse events (AEs), treatment responses, and mortality. We included 3985 patients, 2363 men (59%) and showed that although men and women with advanced melanoma differ in clinical and tumor characteristics, the safety profile of immune checkpoint inhibition (ICI) is comparable. The data suggest a 10% survival advantage for women, mainly seen in patients ≥60 years of age and patients with BRAF V600 mutant melanoma. Following ICI there was no survival difference

Neoadjuvant cytoreductive treatment with BRAF/MEK inhibition of prior unresectable regionally advanced melanoma to allow complete surgical resection, REDUCTOR: a prospective, single-arm, open-label phase II trial

Objective: To evaluate the potency of short-term neoadjuvant cytoreductive therapy with dabrafenib plus trametinib (BRAF and MEK inhibitor) to allow for radical surgical resection in patients with unresectable locally advanced melanoma. Summary Background Data: Approximately 5% of stage III melanoma patients presents with unresectable locally advanced disease, making standard of care with resection followed by adjuvant systemic therapy impossible. Although neoadjuvant targeted therapy has shown promising results in resectable stage III melanoma, its potency to enable surgical resection in patients with primarily unresectable locally advanced stage III melanoma is still unclear. Methods: In this prospective, single-arm, phase II trial, patients with unresectable BRAF-mutated locally advanced stage IIIC or oligometastatic stage IV melanoma were included. After 8 weeks of treatment with dabrafenib and trametinib, evaluation by positron emission tomography/computed tomography and physical examination were used to assess sufficient downsizing of the tumor to enable resection. The primary objective was the percentage of patients who achieved a radical (R0) resection. Results: Between August 2014 and March 2019, 21 patients (20/21 stage IIIC American Joint Committee on Cancer staging manual 7th edition) were included. Planned inclusion of 25 patients was not reached due to slow accrual and changing treatment landscape. Despite this, the predefined endpoint was successfully met. In 18/21 (86%) patients a resection was performed, of which 17 were R0 resections. At a median follow-up of 50 months (interquartile range 37.7-57.1 months), median recurrence-free survival was 9.9 months (95% confidence interval 7.52-not reached) in patients undergoing surgery. Conclusions: This prospective, single-arm, open-label phase II trial, shows neoadjuvant dabrafenib plus trametinib as a potent cytoreductive treatment, allowing radical resection of metastases in 17/21 (81%) patients with prior unresectable locally advanced melanoma.Analysis and support of clinical decision makin

Sex-based differences in treatment with immune checkpoint inhibition and targeted therapy for advanced melanoma: a nationwide cohort study

Simple Summary Melanoma is a malignant form of skin cancer. The overall survival of patients with advanced stages of disease were initially low. Fortunately, in recent years systemic treatment with immunotherapy has prolonged survival. We set out to answer the question whether men and women with advanced melanoma differ in prognostic factors, tumor-response to immunotherapy, and treatment-related adverse events. All patients in the Netherlands were registered between July 2013 and July 2018. We showed that although clinical and tumor characteristics differ, the safety profile of immunotherapy is comparable. Furthermore, overall, a 10% survival advantage for women was seen. Following immunotherapy there was no survival difference. Recent meta-analyses show conflicting data on sex-dependent benefit following systemic treatment for advanced melanoma patients. We examined the nationwide Dutch Melanoma Treatment Registry (July 2013-July 2018), assessing sex-dependent differences in advanced melanoma patients (stage IIIC/IV) with respect to clinical characteristics, mutational profiles, treatments initiated, grade 3-4 adverse events (AEs), treatment responses, and mortality. We included 3985 patients, 2363 men (59%) and showed that although men and women with advanced melanoma differ in clinical and tumor characteristics, the safety profile of immune checkpoint inhibition (ICI) is comparable. The data suggest a 10% survival advantage for women, mainly seen in patients >= 60 years of age and patients with BRAF V600 mutant melanoma. Following ICI there was no survival difference.Clinical epidemiolog

Systematic evaluation of immune regulation and modulation

Cancer immunotherapies are showing promising clinical results in a variety of malignancies. Monitoring the immune as well as the tumor response following these therapies has led to significant advancements in the field. Moreover, the identification and assessment of both predictive and prognostic biomarkers has become a key component to advancing these therapies. Thus, it is critical to develop systematic approaches to monitor the immune response and to interpret the data obtained from these assays. In order to address these issues and make recommendations to the field, the Society for Immunotherapy of Cancer reconvened the Immune Biomarkers Task Force. As a part of this Task Force, Working Group 3 (WG3) consisting of multidisciplinary experts from industry, academia, and government focused on the systematic assessment of immune regulation and modulation. In this review, the tumor microenvironment, microbiome, bone marrow, and adoptively transferred T cells will be used as examples to discuss the type and timing of sample collection. In addition, potential types of measurements, assays, and analyses will be discussed for each sample. Specifically, these recommendations will focus on the unique collection and assay requirements for the analysis of various samples as well as the high-throughput assays to evaluate potential biomarkers

Kruidenrijke weidevogelmengsels: goede opbrengsten en genoeg voedsel voor weidevogels

In kruidenrijke graslandmengsels voor weidevogels is ook daadwerkelijk meer voedsel te vinden voor de weidevogel. Ook haalden de kruidenrijke mengsels een hogere opbrengst dan regulier Engels Raaigras. Dat blijk uit het project Koeien en Kruiden