Publications by authors named "John Haanen"

Recent studies have revealed the potential of tumor-infiltrating lymphocytes (TILs) to treat solid tumors effectively and safely. However, the translation of TIL therapy for patients is still hampered by non-standardized and laborious manufacturing procedures that are expensive and produce highly variable cellular products. To address these limitations, the CliniMACS Prodigy Tumor Reactive T cell (TRT) Process has been developed.

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Background: In BRAF-mutated high-risk melanoma, targeted therapy (BRAF/MEK inhibitors) and checkpoint inhibitor (CPI) immunotherapy have durable benefits as first-line (1L) adjuvant therapy. Based on differing action mechanisms of BRAF/MEK inhibitors and CPI immunotherapies, there is interest in evaluating the activity of 2L adjuvant targeted therapy in decreasing the risk of subsequent recurrence after repeat resection following relapse on/after 1L adjuvant CPI.

Patients And Methods: This was a retrospective review of BRAF V600-mutated resected stage III/IV melanoma patients in the United States, Australia, and The Netherlands who received 1L adjuvant CPI immunotherapy, relapsed locoregionally/distantly, were again resected to no evidence of disease, and received dabrafenib/trametinib (dab/tram) as 2L adjuvant therapy.

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Objectives: The primary aim of this study was to assess differences in melanoma recurrence between patients conceiving spontaneously versus those undergoing assisted reproductive technology (ART) and to determine use of ART in post-melanoma patients. A secondary aim was to describe the use of immunotherapy as a novel treatment regimen for metastatic melanoma in a cohort of fertile patients.

Design: This study is a 30-year analysis including data from a single-center questionnaire and a retrospective cohort study.

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Article Synopsis
  • - Mucosal melanoma (MucM) is a rare and aggressive form of cancer that responds poorly to immune checkpoint inhibition (ICI), especially when compared to cutaneous melanoma (CM).
  • - Analysis of 101 MucM tumors revealed lower levels of the immune marker IFN-γ and indicated that head and neck MucM had more immune cells and higher IFN-γ levels than MucM from other body sites.
  • - The study found that immune features differed across tumor locations, with immune-infiltrated tumors showing potential resistance mechanisms to ICI, highlighting the need for personalized treatment approaches for MucM.
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Background: Previous results from this trial showed longer overall survival after treatment with nivolumab plus ipilimumab or with nivolumab monotherapy than with ipilimumab monotherapy in patients with advanced melanoma. Given that patients with advanced melanoma are living longer than 7.5 years, longer-term data were needed to address new clinically relevant questions.

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Mismatch repair deficiency (dMMR) is found in approximately 15% of non-metastatic colon cancers (CCs) and is characterized by a defective DNA mismatch repair system, resulting in hypermutated and highly immunogenic tumors. Although patients with dMMR CC have limited benefit from chemotherapy, these tumors have been shown to respond exceptionally well to neoadjuvant anti-PD-1 plus anti-CTLA-4, with high rates of pathologic responses. Here, based on data from melanoma studies, we postulated a high efficacy and favorable toxicity profile of anti-PD-1 plus anti-LAG-3.

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Introduction: Research has confirmed the safety and comparable seroconversion rates following SARS-CoV-2 vaccination in patients with solid cancers. However, the impact of cancer treatment on vaccine-induced T cell responses remains poorly understood.

Methods: In this study, we expand on previous findings within the VOICE trial by evaluating the functional and phenotypic composition of mRNA-1273-induced T cell responses in patients with solid tumors undergoing immunotherapy, chemotherapy, or both, compared to individuals without cancer.

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Adoptive transfer of tumor infiltrating lymphocytes (TIL therapy) has proven highly effective for treating solid cancers, including non-small cell lung cancer (NSCLC). However, not all patients benefit from this therapy for yet unknown reasons. Defining markers that correlate with high tumor-reactivity of the autologous TIL products is thus key for achieving better tailored immunotherapies.

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Importance: Long-term survival data from clinical trials show that survival curves of patients with advanced melanoma treated with immune checkpoint inhibitors (ICIs) gradually reach a plateau, suggesting that patients have a chance of achieving long-term survival.

Objective: To investigate long-term survival in patients with advanced melanoma treated with ICIs outside clinical trials.

Design, Setting, And Participants: Cohort study using prospectively collected data from the nationwide Dutch Melanoma Treatment Registry, including patients in the Netherlands with advanced melanoma treated with first-line ICIs from 2012 to 2019.

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: The difference in incidence and severity of anti-PD-1 therapy-related adverse events (irAEs) between adjuvant and advanced treated melanoma patients remains unclear, as no head-to-head studies have compared these groups. : This multi-center cohort study analyzed melanoma patients treated with anti-PD-1 in adjuvant or advanced settings between 2015 and 2021. Comorbidities and ECOG performance status were assessed before treatment, and grade III-IV irAEs were monitored during treatment.

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Introduction: Treatment with the immune checkpoint inhibitor anti-programmed cell death protein-1 (PD-1) often causes immune-related adverse events (irAEs). Since irAEs resemble autoimmune diseases, autoantibodies might play a role and could potentially be used to identify patients at risk. Therefore, we investigated the association between autoantibody-positivity and toxicity as well as clinical response in patients with melanoma treated with anti-PD-1.

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Previous studies demonstrated limited efficacy of immune checkpoint inhibitors in unresectable acral melanoma (AM); it remains unclear how this translates to the adjuvant setting. This study investigates clinical outcomes of acral compared to cutaneous melanoma (CM) patients treated with adjuvant anti-PD-1 after complete resection. All stages III-IV AM and CM patients receiving adjuvant anti-PD-1 after complete resection between 2018 and 2022 were included from the prospective nationwide Dutch Melanoma Treatment Registry.

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Background: Recent studies indicate an association between immunosuppression for immune-related adverse events (irAEs) and impaired survival in patients who received immune checkpoint inhibitors. Whether this is related to corticosteroids or second-line immunosuppressants is unknown. In the largest cohort thus far, we assessed the association of immunosuppressant type and dose with survival in melanoma patients with irAEs.

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Introduction: Severe immune-related adverse events (irAEs) due to immune checkpoint inhibitors (ICIs) can lead to admission to the intensive care unit (ICU). In this retrospective study, we determined the incidence, treatment patterns and survival outcomes of this patient population at a comprehensive cancer center.

Methods: All patients admitted to the ICU due to irAEs from ICI treatment between January 2015 and July 2022 were included.

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Background: Mismatch repair-deficient (dMMR) tumors can be found in 10 to 15% of patients with nonmetastatic colon cancer. In these patients, the efficacy of chemotherapy is limited. The use of neoadjuvant immunotherapy has shown promising results, but data from studies of this approach are limited.

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Article Synopsis
  • In a study comparing neoadjuvant (before surgery) and adjuvant (after surgery) immunotherapy for stage III melanoma, neoadjuvant treatment showed greater effectiveness.
  • The trial involved random assignment of 423 patients to receive either two cycles of neoadjuvant ipilimumab plus nivolumab followed by surgery, or surgery followed by 12 cycles of adjuvant nivolumab.
  • Results indicated a significantly higher 12-month event-free survival rate in the neoadjuvant group (83.7%) compared to the adjuvant group (57.2%), with neoadjuvant therapy leading to better patient outcomes and more major pathological responses despite a higher incidence of severe adverse events.
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Lifileucel or TIL has recently been FDA approved for metastatic melanoma patients as first cell therapy for a solid tumor. We discuss roll-out of TIL as new SOC and other upcoming new cell therapies.

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Purpose: This prospective study evaluates the biodistribution of 18 F-FLT PET in patients with advanced melanoma before and after treatment with BRAF/MEK inhibitors.

Patients And Methods: Eighteen BRAF-positive unresectable stage IIIc or IV melanoma patients referred for 18 F-FLT PET/CT before (BL) and during (D14) BRAF/MEK inhibition were included. 18 F-FLT accumulation in the liver, bone marrow, blood, and muscle was quantified.

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We evaluated the prognostic value of hypoalbuminemia in context of various biomarkers at baseline, including clinical, genomic, transcriptomic, and blood-based markers, in patients with metastatic melanoma treated with anti-PD-1 monotherapy or anti-PD-1/anti-CTLA-4 combination therapy (n = 178). An independent validation cohort (n = 79) was used to validate the performance of hypoalbuminemia compared to serum LDH (lactate dehydrogenase) levels. Pre-treatment hypoalbuminemia emerged as the strongest predictor of poor outcome for both OS (HR = 4.

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Purpose: The development of resistance limits the clinical benefit of BRAF and MEK inhibitors (BRAFi/MEKi) in BRAFV600-mutated melanoma. It has been shown that short-term treatment (14 days) with vorinostat was able to initiate apoptosis of resistant tumor cells. We aimed to assess the antitumor activity of sequential treatment with vorinostat following BRAFi/MEKi in patients with BRAFV600-mutated melanoma who progressed after initial response to BRAFi/MEKi.

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T cell receptor (TCR) gene therapy is a potent form of cellular immunotherapy in which patient T cells are genetically engineered to express TCRs with defined tumor reactivity. However, the isolation of therapeutic TCRs is complicated by both the general scarcity of tumor-specific T cells among patient T cell repertoires and the patient-specific nature of T cell epitopes expressed on tumors. Here we describe a high-throughput, personalized TCR discovery pipeline that enables the assembly of complex synthetic TCR libraries in a one-pot reaction, followed by pooled expression in reporter T cells and functional genetic screening against patient-derived tumor or antigen-presenting cells.

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KEYNOTE-942 is a randomized phase II adjuvant study in patients with resected stage III melanoma investigating a personalized neoantigen mRNA vaccine in combination with anti-PD-1. The study gave a clear signal of superiority for the vaccine plus anti-PD-1 in relapse-free and distant-metastasis-free survival but is not yet conclusive, and important questions remain.

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Article Synopsis
  • This study focused on assessing the safety and potential immune response of a naked DNA vaccine targeting the MART-1 antigen in patients with advanced melanoma through a phase I clinical trial.
  • Nine patients were treated, and while there were no treatment-related deaths, common side effects included skin reactions and pain; one patient achieved stable disease for 353 days.
  • The DNA vaccine was generally safe to use, highlighting the need for further research to enhance its effectiveness and understand the immune responses better.
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Therapeutic approaches for clear cell renal cell carcinoma (ccRCC) remain limited; however, chimeric antigen receptor (CAR) T-cell therapies may offer novel treatment options. CTX130, an allogeneic CD70-targeting CAR T-cell product, was developed for the treatment of advanced or refractory ccRCC. We report that CTX130 showed favorable preclinical proliferation and cytotoxicity profiles and completely regressed RCC xenograft tumors.

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Introduction: In a multicenter, open-label randomized phase 3 clinical trial conducted in the Netherlands and Denmark, treatment with ex vivo-expanded tumor-infiltrating lymphocytes (TIL-NKI/CCIT) from autologous melanoma tumor compared with ipilimumab improved progression-free survival in patients with unresectable stage IIIC-IV melanoma after failure of first-line or second-line treatment. Based on this trial, we conducted a cost-utility analysis.

Methods: A Markov decision model was constructed to estimate expected costs (expressed in 2021€) and outcomes (quality-adjusted life years (QALYs)) of TIL-NKI/CCIT versus ipilimumab in the Netherlands.

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