ONCOTHESIS

Paving the way for immunotherapy in pancreatic cancer by exploring a novel combination immunotherapy consisting of a CD40 agonist and interleukin-15

BJMO - volume 15, issue 3, may 2021

E.L.J.M Smits PhD, G. Roeyen MD, PhD, J.R.M. Van Audenaerde PhD, M. Peeters MD, PhD

SUMMARY

Pancreatic Ductal Adenocarcinoma (PDAC) has the worst 5-year survival of all cancer types. Treatment options for these patients are limited and consist mainly of chemotherapy. However, the unique tumour microenvironment with its dense, fibrotic shield causes resistance to current and novel therapies. Tackling this stromal shield is therefore deemed crucial for making progress in PDAC treatment. We investigated in this thesis the potential of Natural Killer (NK) cells to address this high medical need. Firstly, our systematic review revealed strong evidence of their importance in PDAC and how the tumour renders them into a suppressed and less functional state. Based on this information, we sought to stimulate NK cells in such way that they attack both tumour and surrounding stroma. We show that, upon stimulation with IL-15, NK cells are capable of killing both pancreatic cancer and stellate cells, the drivers of the stromal reaction, in a contact-dependant manner. Increased expression of NKG2D and TIM-3 receptors was partially responsible for this enhanced killing. Furthermore, in our search to potentiate IL-15 stimulation, we combined this with an immune priming CD40 agonist and demonstrated profound anti-tumour effects and prolonged survival in PDAC mouse models. Increased intra-tumoral cytotoxic T cells, NK cells and reduced T regulatory cells combined with increased cross-presenting dendritic cells in the tumour draining lymph nodes are the main effectors of the observed anti-tumour effects. Summarised, our data provide a strong rationale for NK cell-driven cancer immunotherapy where immune stimulation is combined with immune priming. Initiation of an early-phase clinical trials with this novel combination immunotherapy for PDAC patients is warranted.

BELG J MED ONCOL 2021;15(3):128-31

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Optimising target volume definition and treatment accuracy in oesophageal cancer

BJMO - volume 15, issue 2, march 2021

M. Machiels MD, PhD

SUMMARY

On May 29th, 2020, M. Machiels defended her PhD thesis entitled ‘Optimising target volume definition and treatment accuracy in oesophageal cancer‘. The research was carried out at the Amsterdam UMC, location AMC under supervision of promotor prof. C.R.N. Rasch, MD, PhD, with dr. M.C.C.M. Hulshof, MD, PhD and Mrs. T. Alderliesten, PhD as co-promoters. Important findings are listed below. Full thesis is available at: http://hdl.handle.net/11245.1/2e692172-00cf-4565-b45c-04d1dffb951a.

(BELG J MED ONCOL 2021;15(2):83-6)

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Optimisation of the liquid biopsy workflow: From research to clinical practice

BJMO - volume 15, issue 1, january 2021

C. Rolfo MD, PhD, G. Roeyen MD, PhD, J. Jacobs PhD, K. Zwaenepoel PhD, L. Sorber PhD, P. Pauwels MD, PhD

SUMMARY

The general aim of this thesis was to determine the optimal workflow of circulating cell-free nucleic acid- (cfNA) based liquid biopsy for implementation in routine clinical practice. We started by evaluating several pre-analytical variables of the liquid biopsy workflow. We examined several cfDNA isolation kits, determined the optimal centrifugation protocol for both cfDNA and cfRNA, and determined the cfDNA stabilising efficiency of (specialised) blood collection tube (BCT). Next, we focused on the clinical applicability of liquid biopsy in non-small cell lung cancer (NSCLC). Based on this work, we specified recommendations regarding (pre-) analytical and biological variables to ensure successful liquid biopsy analysis.

(BELG J MED ONCOL 2021;15(1):48-50)

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Overcoming intrinsic and acquired resistance to EGFR-targeting agents in cancer treatment: focus on identification of predictive biomarkers and novel therapeutic strategies

BJMO - volume 14, issue 4, june 2020

A. Wouters PhD, F. Lardon PhD, I. De Pauw PhD, JB. Vermorken MD, PhD, M. Peeters MD, PhD

SUMMARY

Targeted therapies that inhibit oncogenic signalling pathways are the key for precision medicine in cancer treatment. Research over the past decades has revealed that deregulated or increased signalling of the epidermal growth factor receptor (EGFR) plays an integral role in the development of various cancer types, including colorectal cancer (CRC) and head and neck squamous cell carcinoma (HNSCC). After initially promising results of EGFR-targeted therapies, it became clear that therapeutic resistance is a major clinical problem. Moreover, as an increasing number of patients are currently considered as candidates for treatment with EGFR-targeted therapy, identification of predictive biomarkers is extremely important. The objective of this PhD project was to unravel and overcome resistance to the EGFR-targeting agent cetuximab in CRC and HNSCC. Hereby, we focused on the identification of drug resistance mechanisms, novel drug targets and therapeutic strategies as well as predictive biomarkers.

The present study demonstrated that afatinib, a second-generation irreversible inhibitor of EGFR, HER2 and HER4, has the potential to overcome cetuximab resistance in CRC and HNSCC cell lines. Therefore, these data support the hypothesis that afatinib may be a promising therapeutic agent to treat CRC and HNSCC patients experiencing intrinsic or acquired cetuximab resistance. Furthermore, we found that increased phosphorylation of Akt seems to be characteristic for acquired cetuximab resistance in HNSCC. Although further confirmation in tumour samples of HNSCC patients is imperative, Akt appears a novel drug target to improve outcome after cetuximab treatment as well as a potential predictive biomarker for EGFR-targeted therapies in HNSCC patients. In this view, we encourage further studies that focus on targeting Akt in combination with cetuximab, as this may be a promising strategy to overcome drug resistance in HNSCC patients. These findings can form a solid basis for further experiments with advanced in vitro and in vivo models.

(BELG J MED ONCOL 2020;14(4):155–8)

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Geriatric oncology: targeting older patients with cancer

BJMO - volume 14, issue 3, may 2020

C. Kenis PhD, H. Wildiers MD, PhD, J. De Grève MD, PhD, L. Decoster MD, PhD

SUMMARY

As the cancer population ages, treatment decisions in the older patients should not only be guided by the tumour characteristics but also by patient characteristics. The performance of a comprehensive geriatric assessment as well as a health related quality of life evaluation are important in order to deliver the optimal personalised care in older patients with cancer. The current PhD thesis focused on the use of screening tools, geriatric assessment and interventions as well as on health-related quality of life in older patients with cancer.

(BELG J MED ONCOL 2020;14(3):106–8)

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Boosting anticancer immunity with radiotherapy

BJMO - volume 14, issue 1, january 2020

K. Decaestecker PhD, N. Sundahl PhD, P. Ost MD, PhD, V. Kruse MD, PhD

SUMMARY

Preclinical and early clinical data indicate that stereotactic body radiotherapy (SBRT) could work synergistically with checkpoint inhibitors and increase response rates. Given the potential synergistic effect between both treatments, the associated toxicity might also be increased. We conducted two phase I trials combining SBRT with ipilimumab (n=13) or pembrolizumab (n=18) in metastatic/inoperable melanoma and metastatic urothelial carcinoma respectively. To evaluate the effect of SBRT timing, patients were randomised to either sequential or concurrent SBRT in the latter trial. To assess early efficacy, a phase II trial of SBRT and nivolumab was conducted in metastatic/inoperable melanoma (n=20). Our data shows that SBRT combined with ipilimumab, nivolumab or pembrolizumab is safe and might increase efficacy in a subset of patients.

(BELG J MED ONCOL 2020;14(1):28–30)

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HER2 overexpression in gastroesophageal adenocarcinoma, prognostic and predictive value and diagnostic approach

BJMO - volume 13, issue 4, june 2019

B. Maes MD, PhD, L. Thijs MD, P. Peeters MD, S. Tejpar MD, PhD

SUMMARY

Gastric (including gastroesophageal junction) adenocarcinoma ranks top three in global cancer mortality. Between 4–30% of patients have human epidermal growth factor receptor 2 (HER2) driven disease, and targeting HER2 receptor signalling improved prospects in metastatic setting. HER2 status is assessed by immunohistochemistry and in situ hybridisation. However, determination and interpretation of HER2 status remains challenging due to intra- and intertumoral heterogeneity and lack of data on the biological relevant cut-off. Currently, only trastuzumab is approved for treatment of HER2 amplified advanced gastric cancer. The strength of HER2 amplification at baseline and after progression should be integrated in future prospective randomised trials. HER2 loss occurs predominantly in cases with initial moderate immunostaining for HER2 and can lead to clinical resistance to trastuzumab. We review the use of liquid biopsies as an alternative to traditional tissue biopsies to overcome heterogeneity and to allow monitoring the dynamics of the plasma HER2 status. We believe that early detection of plasma HER2 loss can identify patients at risk for loss of response to anti-HER2 therapy. Based on a clinical case, we tried to define the implications and clinical relevance of HER2 positivity. We illustrate the usefulness of re-determination of the HER2 status in metastatic lesions after disease progression and provide the prospects of non-invasive testing.

(BELG J MED ONCOL 2019;13(4):135–141)

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