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Programma

Het 9e Multidisciplinair Immuno-Oncologie Symposium wordt dit jaar georganiseerd in de Prodentfabriek, Amersfoort op donderdag 1 februari 2024.

donderdag 01 feb

12:00

Ontvangst met lunch

Voorzitters: Jeroen Hiltermann & Karijn Suijkerbuijk

13:00

welkom door voorzitters

13:10

Stress en effect van neoadjuvante immuuntherapie

Prof. dr. Lonneke van der Poll, epidemioloog, hoofdonderzoeker, Antoni van Leeuwenhoek

13:40

PREMIUM Project: Inzet van kunstmatige intelligentie voor het voorspellen van respons op immuuntherapie bij patiënten met uitgezaaid melanoom

Mark Schuiveling, AIOS, UMC Utrecht

Biografie Mark Schuiveling
Ik ben een internist in opleiding en ben uiteindelijk van plan de opleiding tot medisch oncoloog te volbrengen. Momenteel ben ik een promovendus bij Karijn Suijkerbuijk waar ik op basis van histopathologiemateriaal behandelrespons probeer te voorspellen. Hiervoor maak ik gebruik van kunstmatige intelligentie modellen wat mij nu en later als dokter de mogelijkheid geeft om te begrijpen waar de kansen van het toepassen van AI in de gezondheidszorg liggen.

Samenvatting presentatie
PREMIUM: Predicting Response of metastatic Melanoma to Immunotherapy Using Machine learning

To predict response to immune checkpoint inhibitors (ICI) for advanced melanoma patients by applying machine learning techniques to readily available clinical, radiological and pathological data of the primary and metastatic melanoma at the start of treatment. Outline of the project and first results.

 

13-Schuiveling-Mark

14:10

Pauze

Voorzitters: Sofie Wilgenhof & Mick van Eijs

14:50

Neoadjuvante immuuntherapie bij het colorectaal carcinoom

Dr. Myriam Chalabi, internist-oncoloog, Antoni van Leeuwenhoek

15:15

Immuuntherapie bij blaascarcinoom

Michiel van der Heijden Antoni van Leeuwenhoek

15:40

What is new in early NSCLC (neoadjuvante immuuntherapie data)

Prof. dr. Egbert Smit, longarts, LUMC

Biografie
Egbert F. Smit graduated from the University of Groningen The Netherlands in 1988. He earned his PhD in 1991 on a thesis entitled “Aspects of Chemotherapy for Lung Cancer”. After obtaining his specialist degree in Pulmonary Medicine he has held various positions in academic medicine and general hospitals. He is currently at the Leiden University Medical Center, Leiden The Netherlands. Within the departments he conducts both (pre-) clinical and translational research regarding all aspects of lung cancer, i.e from carcinogenesis to treatment of metastatic lung cancer. Prof. Smit is author of more than 500 peer reviewed papers and 30 chapters in books and a regular reviewer of all major oncology journals.

 

18-Smit-Egbert

16:05

Pauze

Geselecteerde abstracts

Voorzitters: Karijn Suijkerbuijk & Hugo Horlings

16:35

O1 Activated cytotoxic tissue-resident CD8+ T cells in lamina propria and epithelium are a hallmark of immune checkpoint inhibitor colitis

Mick Van Eijs, UMC Utrecht

Background
Colitis is a prevalent immune-related adverse event (irAE) associated with immune checkpoint inhibitor (ICI) therapy. Detailed phenotyping of irAE-associated T cells can help identify tailored irAE treatment strategies that spare antitumor immunity. Here, we studied T cell function and localization in anti-PD-(L)1 and anti-PD-1/anti-CTLA-4 (combi-ICI) colitis.

Methods
Left-sided colon biopsies were obtained from ICI-colitis patients and healthy controls (HCs). To maintain spatial origin, intraepithelial and lamina propria lymphocyte fractions were separated before plate-based scRNA-sequencing (SORT-seq).

Results
Analyzing data from 8 subjects (3 anti-PD-[L]1, 2 combi-ICI, 3 HCs) aged 60-78 years, we identified 4 CD8+ T cell clusters (central memory [CM], effector and tissue-resident memory [Trm] cells), 3 CD4+ T cell clusters (Tregs, follicular helper and naïve/CM T cells) and γδ T cells (Fig. 1). Besides Trm cells, epithelial CD8+ effector and TCM cells were also enriched for a previously published Trm signature (1). CD8+ effector and γδ T cells from colitis patients had highest cytotoxicity gene enrichment scores (2), particularly those treated with cICI (Fig. 2A). While CD8+ effector T cells were more abundant in epithelium than lamina propria, those in lamina propria had higher cytotoxic potential (Fig. 2B). Colitis patients also had relatively more Tregs compared to HCs.

Conclusions
Activated CD8+ T(RM) cells, both in lamina propria and epithelium, are a hallmark of ICI-colitis. This could indicate that spatial segregation of lamina propria and epithelium is partly lost in ICI-colitis. T cells have higher cytotoxic capacity after combi-ICI than anti-PD-(L)1, but we found no evidence for ICI-mediated Treg depletion with either ICI-type. These molecular findings may partly explain the generally more acute and severe course of colitis observed with combi-ICI compared to anti-PD-(L)1 monotherapy.

Literature
1.Kumar,et al.Cell Rep 2017.doi:10.1016/j.celrep.2017.08.078
2.Nicolet,et al.PNAS 2020.doi:10.1073/pnas.1913940117

Funding for investigator-initiated study received from Bristol-Myers Squibb (CA209-6JY).

16:45

O2 Identification of individual volatile organic compounds in exhaled breath of advanced non-small cell lung cancer patients treated with (chemo-)immunotherapy: A proof-of-concept study

Alessandra Buma, Radboudumc

Introduction
Previously published results on exhaled breath analysis based on pattern recognition have shown that the SpiroNose allows for an accurate, non-invasive and low-cost identification of advanced non-small cell lung cancer (NSCLC) patients who benefit from immunotherapy early during treatment (1,2). Which individual volatile organic compounds (VOCs) and underlying biological pathways contribute to this discrimination between responders and non-responders, however, is still unknown. We hypothesize that VOCs arising from the microbiome could play a major role in this discrimination, since the SpiroNose sensor that showed the highest discriminative potential, is most sensitive to microbiome-specific VOCs (e.g. methane and natural gas) (2).

Aim
The primary aim of our study is to determine whether we can discriminate responders from non-responders early during treatment based on microbiome-specific VOCs detected in exhaled breath of advanced NSCLC patients treated with (chemo-)immunotherapy between baseline and six weeks after treatment start. The secondary aim of our study is to determine the correlation between microbiome-specific VOC dynamics and sensor dynamics of the SpiroNose sensor with the highest discriminative potential measured between baseline and six weeks after treatment start.

Methods
This is a proof-of-concept study in advanced NSCLC patients eligible for (chemo-)immunotherapy treatment. Efficacy of treatment will be assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 at 3-month follow-up. SpiroNose measurements will be performed at baseline, and after three and six weeks of treatment. In addition, breath and stool samples will be collected at each measurement moment for individual VOC identification and microbiome composition analysis, respectively. Analysis of the breath and stool samples will be performed using mass spectrometry and laser spectroscopy, and metagenomic analysis, respectively. Data analysis will involve statistics based on data reduction (e.g. Principal Component Analysis), Independent Samples T-test, Pearson correlation coefficient and Receiver Operating Characteristic (ROC) analysis.

Literature

  1. de Vries R, Muller M, van der Noort V, et al. Prediction of response to anti-PD-1 therapy in patients with non-small-cell lung cancer by electronic nose analysis of exhaled breath. Ann. Oncol. 2019; 30(10):1660-1666. doi: https://doi.org/10.1093/annonc/mdz279.
  2. Buma AIG, Muller M, de Vries R, et al. eNose analysis for early immunotherapy response monitoring in non-small cell lung cancer. Lung Cancer 2021; 160:36-43. doi: 1016/j.lungcan.2021.07.017.

 

16:55

O3 Role of mutational signatures in immunotherapy benefit in lung cancer

Hylke Donker, UMCG

Background
In advanced non-small cell lung cancer (NSCLC), response to immunotherapy is difficult to predict from pre-treatment information. We studied to what extent mutagenesis can explain the efficacy of immunotherapy in NSCLC through mutational signatures.

Methods
Cancer mutations were measured from m=101 whole genome sequenced (WGS) patients and a second cohort of m=126 patients analysed with targeted panel sequencing. COSMIC v3.3 weights were used to deconvolute non-silent mutations into signatures.

Results
Whole genome sequencing mutations attributed to a smoking (SBS4) and thiopurine chemotherapy exposure (SBS87) associated signatures were linked to durable benefit (DB) from immunotherapy. No doublet, indel, or copy number alteration signatures were linked to DBk. Single base substitution signature attributions could not be faithfully extracted from panel sequencing due to the limited panel size.

Conclusion
Mutational signatures inform about immunotherapy outcome in NSCLC, but should not be extracted from panel sequencing.

Literature
[1] Donker et al. “Using genomic scars to select immunotherapy beneficiaries in advanced non-small cell lung cancer.” Scientific Reports 13.1, 6581 (2023).
[2] Donker et al., “Reliability of panel-based mutational signatures for immune-checkpoint-inhibition efficacy prediction in non-small cell lung cancer”, Lung Cancer 182, 107286 (‘23).

17:05

O4 Cost-effectiveness of a Predictive Biomarker in Pembrolizumab-Containing Treatment for Advanced Non-Small Cell Lung Cancer in The Netherlands: An Early Health Technology Assessment

Leila-sophie Otte, Radboudumc

Methode
For each of the three pembrolizumab-containing treatments, a PB and SOC model was constructed with four health states: “First-line”, “second-line”, “best-supportive care”, and “death”. The PB scenario assumed 100% accuracy in identifying responders. Non-responders received alternative treatments. Six-week cycles were simulated over a lifetime horizon. Parameter inputs were based on literature, expert opinion, and registries, adopting a Dutch healthcare perspective. Real-world data were incorporated if available. Outcomes included mean differences in costs, life-years (LYs) and quality-adjusted life-years (QALYs) between the PB and SOC model per patient for each pembrolizumab-containing treatment.

Results
Implementing a PB in pembrolizumab monotherapy resulted in a mean loss of 0.31 QALYs and 0.39 LYs, and savings of €26.452 per patient. In the two pembrolizumab combination treatments, a mean loss of 0.22 and 0.06 QALYs and 0.31 and 0.11 LYs, and savings of €12,608 and €20,094 per patient were seen. Notably, all differences in LYs, QALYs, and costs were statistically significant, indicating a decline in treatment efficacy and concomitant cost savings.

Conclustions
Implementing a PB yields substantial cost savings for all pembrolizumab treatments but is associated with reductions in QALYs and LYs. The clinical relevance of these losses of treatment effects across all pembrolizumab-containing treatments requires further discussion. In-depth sensitivity analyses will reveal mechanisms contributing to treatment effectiveness loss. The results should be taken into consideration during decision-making processes of implementing a PB in pembrolizumab-containing treatments.

17:15

O5 Identifying oligoprogression with cell-free DNA-based next-generation sequencing in non-small cell lung cancer patients treated with Immune Checkpoint Inhibitors

Pim Rozendal, UMCG

Background
In the absence of targetable genomic alterations, advanced-stage non-small cell lung cancer (NSCLC) patients are typically treated with immune checkpoint inhibitors (ICIs) with proven long-lasting therapeutic responses in a subset of patients. In some patients with oligoprogression, ICI treatment can be prolonged after ablative therapy. However, differentiating between systemic progression and oligoprogression is often only possible upon follow-up. Therefore, in this study, molecular tumor profiling using ctDNA sequencing of longitudinally collected blood samples during ICI treatment was performed to evaluate mechanisms of systemic progression and distinguish between oligoprogression and systemic progression.

Methods
Twenty patients with advanced NSCLC treated with ICIs were included. Four subsequent blood samples were collected: before treatment initiation (t0), 1-2 months after the start of treatment and with clinical response (t1), after three months of treatment or at least three months prior to confirmed clinical progression and without clinical progression (t2), and at the time of confirmed progression (t3). Circulating cell free DNA (ccfDNA) was analyzed using the AVENIO ctDNA Expanded kit. CtDNA dynamics of recurring and acquired mutations were evaluated following international guidelines applied in routine molecular diagnostics.

Results
Based on preliminary results, in total 203 ctDNA variants were identified across the cohort. Of 17 patients (85%), ctDNA dynamics correlated with changes in the sum of longest target lesion diameters (RECIST v1.1). Remarkably, the three patients in whom the ctDNA levels remained stable at disease progression, survived 37-70 weeks after RECIST progression. Twenty-four variants solely detected at disease progression were observed in 13 patients (65%). Evaluation of differences in mutational profiles upon disease progression between oligoprogression and systemic progression is in progress.

Conclusions
CcfDNA-based next-generation sequencing (NGS) enables the detection of tumor-derived variants and monitoring ctDNA dynamics to potentially predict oligo- or systemic progression. Our findings contribute to the biological understanding of oligoprogression.

17:25

O6 Prognostic Value of Nivolumab Clearance in Non-Small Cell Lung Cancer Patients for Survival Early in Treatment

Leila-sophie Otten, Radboudumc

Background
Immune checkpoint inhibitors (ICIs) have greatly improved survival of non-small cell lung cancer patients, but the overall response rate remains low. A biomarker that identifies non-responders would be helpful to allow treatment decisions. Clearance of ICIs has shown to be related to treatment response, but the prognostic value early in treatment remains unknown. The aim of this research was to assess the prognostic value of nivolumab clearance to assess non-response early in treatment.

Methods
Individual estimates of nivolumab clearances at first dose, 6 and 12 weeks after treatment initiation were obtained via nonlinear mixed effects modelling using a previously validated population pharmacokinetic model[1]. The predictive value of nivolumab clearance was estimated using univariate Cox proportional hazards regression models at first dose and for the ratios between 6 and 12-weeks-to-first-dose. The cut-offs for nivolumab clearance at first dose and the 6 and 12-weeks-to-first-dose ratios were estimated using maximally rank statistics. For sensitivity and specificity calculations, a patient was considered a non-responder when they died within 6 months after start of nivolumab treatment.
RESULTS In total, 69 patients were included and the majority (86%) died during follow-up of 75 months. Patients with a nivolumab clearance ≥7.3 mL/h at first dose were more likely to die compared to patients with a nivolumab clearance <7.3 mL/h at first dose (HR=3.55, 95% CI=1.75-7.20). Nivolumab clearance ratios showed similar outcomes with HRs of 3.93 (95% CI=1.66-9.32) at a 0.953 cut-off for the 6-weeks-to-first-dose clearance ratio, and 2.96 (95% CI=1.32-6.64) at a 0.814 cut-off for the 12-weeks-to-first-dose clearance ratio. Despite high sensitivity (≥0.95), specificity was low for all three outcomes (0.29, 0.19, 0.11).

Conclusion
Nivolumab clearance distinguishes non-response within the first 12 weeks of nivolumab treatment. Our results encourage to further assess the prognostic potential of immunotherapy clearance.

Reference
[1] Zhang et al.CPT Pharmacometrics Syst Pharmacol.12-2019;8(12):962-970.doi:10.1002/psp4.12476

17:35

Diner buffet

Voorzitters: Sofie Wilgenhof & Hugo Horlings

18:30

casussen

19:00

Cancer vaccines

Prof. dr. Sjoerd van der Burg, immunoloog, hoofd research laboratorium, Leiden University

Biografie
Sjoerd H. van der Burg, Ph.D. is a professor in experimental cancer immunology and therapy at the department of medical oncology of the Leiden University Medical Center since 2010 and a Senior Investigator of the Oncode Institute since 2019. He leads the experimental cancer immunology and therapy group which performs fundamental, translational and clinical studies focusing on those factors of host-tumor interactions that determine the success and failure in immune control of cancer. His group has published several seminal studies on immunotherapy of cancer, in particular in the context of therapeutic vaccines and adoptive cell transfer and (co-)initiated a series of investigator-initiated clinical trials.

Samenvatting presentatie
Therapeutic cancer vaccines have undergone a resurgence in the past decade. A better understanding of the breadth of tumour-associated antigens, the native immune response and development of novel technologies for antigen delivery has facilitated improved vaccine design. The goal of therapeutic cancer vaccines is to induce tumour regression, eradicate minimal residual disease, establish lasting antitumour memory and avoid non-specific or adverse reactions. However, tumour-induced immunosuppression and immunoresistance pose significant challenges to achieving this goal. One such mechanism is the functional loss of the intracellular peptide transporter associated with Antigen Processing (TAP), which occurs frequently in many cancers including melanoma and non-small cell lung cancer (NSCLC).  We discovered the presentation of an alternative set of shared neo-antigens (TEIPPS) on such escaped cancers and developed a vaccine, called TEIPP24, to stimulate T-cell immunity against these escaped cancers. In a first-in-human multicenter dose-escalation study with extension cohort, 24 HLA-A*0201-positive patients with non-small cell lung cancer (NSCLC) were treated at three different dose levels. Patients in the extension cohort were treated with the highest dose TEIPP24 combined with pembrolizumab. In none of the patients dose limiting toxicity (DLT) occurred. After an introduction on the role and achievements of therapeutic vaccines in cancer, the development of TEIPP-directed therapy will be presented.

12-van_der_Burg-Sjoerd

19:30

Afsluiting voorzitters