Clinical Proof of Concept

Clinical Proof of Concept fund

The fund

Oncode aims to link fundamental and clinical research to enable efficient translation of promising research findings into novel diagnostic methods and clinical treatment strategies. To fund these projects, Oncode launched the Clinical Proof of Concept fund. Via a rolling call, Oncode Investigators - together with a clinician - can submit proposals to start (pre)clinical projects.

The Oncode approach

To support researchers in the development of their proposals, Oncode is offering extra support through the Oncode Exploratory Development Expert Support (OEDES) team. This team consists of experts in pre-clinical and clinical development, with experience in academic, industry and clinical settings. They help to define the goal of the study in relation to the overall development trajectory and can support researchers by giving them specific advice on their proposals, like pre-clinical requirements for safe and efficacious human dosing, validation strategies for new diagnostics and ways to maximize valuable results. The OEDES team also provides Oncode Investigators and Researchers extra support with educational materials about the Clinical Proof of Concept. Please have a look at the informative video series.

Procedure

Together with a clinician, Oncode Investigators can submit a pre-proposal (expression of interest), which will be reviewed by the Clinical Advisory Board (CAB), including a patient representative, the OEDES team, the Research Management Committee (RMC) and the Valorization team. After a positive outcome, the Investigator will be invited to prepare a full proposal. To support the researchers in putting together such a proposal and contribute with their specific expertise, they will be invited for an OEDES workshop. The full proposal will be reviewed by the CAB, OEDES and Valorization team, followed by a final decision of the Oncode Managing Board.

To fund these projects, Oncode launched the clinical proof-of-concept (cPoC) fund. Via a rolling call, Oncode Investigators can submit proposals to start clinical projects.

What are the eligibility criteria?

  • Projects must be tied to the main research focus of the applying Oncode Investigator.
  • Projects must involve at least one lead clinician, who may be associated with any Dutch institution.
  • Projects are either 1) clinical studies, i.e. studies in man or 2) pre-clinical studies of which the results, when positive, can lead directly to a clinical trial.
  • The project contains clear milestones with well-defined go/no- go criteria based on results that were obtained as well as on feasibility (patient accrual for example). The project can only proceed upon a positive decision based on these pre-defined go-criteria.
  • A total of up to 800.000 euros will be available for clinical studies (and studies with a strong clinical component as well as pre-clinical component). The detailed budget (full proposals) needs to indicate the amount required to achieve each of the milestones. Positive decisions based on the go/no-go criteria releases the subsequent parts of the allocated funding.
  • A total of up to 200.000 euros will be available for pre-clinical studies. The budget needs to indicate the amount required to achieve each of the milestones, and positive decisions based on the go/no-go criteria will release the subsequent parts of the allocated funding.

Are you curious how the OEDES team can support your CPoC project and why the CPoC program is so unique? In the video below, Oncode Investigator Sjoerd van der Burg (LUMC) and Paul de Koning (Oncode Exploratory Development Expert Support Team) explain how this process has worked in practice for Sjoerd's TEIPP-targeting immunotherapy project.

Click to see the video

List of Approved Projects

HDAC inhibitor Vorinostat in resistant BRAF V600 mutated advanced melanoma

Oncode Investigator: René Bernards (NKI)

Clinician: Sophie Wilgenhof (NKI-AVL)

Starting year: 2018

Background of the project:

Patients with advanced BRAF V600 mutated (BRAFm) melanoma develop resistance to BRAF inhibitors (BRAFi) and/or MEK inhibitors (MEKi) in 6-14 months. This is often associated with secondary mutations in the MAPK pathway, e.g. NRAS/KRAS, leading to reactivation of the pathway. Preclinical studies in cell lines and mice showed that treatment of BRAFi-resistant BRAFm melanoma with Vorinostat leads to selective cell death of the BRAF inhibitor resistant cells only and to a remarkable reduction of tumor volume.

Outline & clinical need

The researchers work on a clinical Proof of Concept trial in patients with advanced BRAF V600 mutated melanoma who developed resistance to BRAF inhibitors and/or MEK inhibitors. For this patient group no rational treatment is available at the moment. ctDNA will be used as biomarker to detect emerging clones resistant to BRAF inhibitors and switch to a short-term purging treatment with Vorinostat after which BRAF-MEK inhibition will be reintroduced. The short-term treatment with Vorinostat leads to a killing of tumor cells harbouring a secondary mutation in the MAPK-pathway, e.g. KRAS and NRAS. The researchers expect that patients will have a longer progression free survival with this treatment schedule compared to BRAF inhibition alone.

Improving Peptide Receptor Radionuclide Therapy with PARP inhibitors: the PRRT-PARPi study

Oncode Investigator: Roland Kanaar (Erasmus MC)

Oncode researcher: Julie Nonnekens (Erasmus MC)

Clinicians: Hans Hofland, Ferry Eskens, Wouter de Herder, Astrid van der Veldt, Tessa Brabander (all Erasmus MC)

Others: Mark Konijnenberg, Stijn Koolen (both Erasmus MC)

Anticipated start date: January 2021

Background

PRRT with [177Lu]Lu-DOTA-[Tyr3]octreotate (177Lu-DOTATATE or Lutathera®) has been approved by the EMA and FDA in 2018 for the second-line treatment of metastatic or locally advanced irresectable somatostatin receptor (SST)-positive GEPNETs. Although effective in prolonging progression-free survival, cure has not been associated with this treatment. It is unfortunately not feasible to administer a higher PRRT dose, since this might lead to radiation-induced toxicity in healthy tissues, leading to morbidity and mortality. Therefore, improvement of tumor cell radiosensitization to PRRT is urgently needed.

This clinical project is guided by the results of a number of preclinical studies (in vitro, ex vivoand in vivo) in which we have shown that the PARPi olaparib (Lynparza®; approved by FDA/EMA as maintenance treatment of adults with recurrent BRCA-mutated ovarian and breast cancer) can be used to specifically sensitize SST-positive cells to PRRT (1 and unpublished data). Here, we will explore the first steps towards clinical implementation of the combination of PRRT with olaparib: a phase I dose escalation study of re-treatment with PRRT (R-PRRT) with increasing doses of PARPi olaparib to assess safety and to define a RP2D of olaparib, followed by a PoC study to assess the PRRT enhancing effect of the RP2D olaparib in combination with R-PRRT compared to R-PRRT monotherapy in historical controls.

Outline & Clinical Need

The overarching goal of the project is to evaluate the enhancing effect of the combination treatment of a PARP inhibitor (olaparib) and re-treatment with peptide receptor radionuclide therapy (R-PRRT) compared to treatment with R-PRRT alone in patients with well-differentiated advanced gastroenteropancreatic neuroendocrine tumors (GEPNETs).

The project consists of two parts: a phase I dose escalation study to determine the maximum tolerated dose, and a PoC study to assess the effect of the proposed combination treatment.

The first part will be focused on determining the maximum tolerated dose (MTD) of a PARP inhibitor in combination with peptide receptor radionuclide therapy (PRRT) re-treatment in patients with well-differentiated advanced gastroenteropancreatic neuroendocrine tumors (GEPNETs), progressive after 4 cycles of PRRT after an initial response. This study will be followed by a proof of concept (PoC) study to assess the PRRT enhancement effect of the PARP inhibitor using the recommended phase II dose (RP2D, equal to MTD) compared to PRRT monotherapy in historical controls.

We investigated mechanisms to overcome current limitations of PRRT by enlarging the therapeutic window. The mechanism of action of PRRT consists of specific targeting of the NET cells via binding to the SST and by subsequently inducing single-strand breaks (SSBs) and double-strand breaks (DSBs) in the tumor cell’s DNA during radioactive decay. While a certain amount of DNA damage can be repaired, a higher level of DNA damage will increase the level of induced cell death. In order to increase the accumulated level of DNA damage induced by PRRT, we will combine PRRT with a specific PARP-1 inhibitor (PARPi). PARP-1 is essential for SSB repair and when SSBs are not repaired, they will be converted into DSBs during cell division. The combination of PRRT with PARPi will increase the rate of PRRT-induced DSBs and thereby increase the tumor cell death rate (1 and unpublished data).

Towards clinical implementation of the MeD-seq assay

Oncode Investigator: Joost Gribnau (Erasmus MC)

Oncode researcher: Ruben Boers (Erasmus MC)

Clinicians: Stefan Sleijfer, Kees Verhoef (both Erasmus MC)

Others: John Martens, Saskia Wilting (both Erasmus MC)

Anticipated start date: January 2021

Background:

Colorectal cancer (CRC) is the second most common cancer in The Netherlands with >15,000 new cases in 2016. Approximately 40% of CRC patients develop colorectal liver metastases (CRLM). Currently about 30% of CRLM patients is treated with curative intent. Unfortunately, half of these patients develop recurrent disease within 1 year (defined as early recurrence). Previously described prognostic clinical risk scores (CRS) are unable to reliably predict early recurrence. Therefore, additional prognostic markers are urgently needed to reliably select patients at high risk for early recurrence that might benefit from adjuvant treatment after curative local treatment, which is not standard of care according to the current Dutch guidelines.

Circulating cell-free DNA (cfDNA) accurately reflects current disease state, is easily obtainable by a blood draw, and can be sampled repeatedly. Our recently developed MeD-seq technology is a low input (<1000 cells), high coverage (50% of all CpGs) assay that enables detection of CRLM-specific cfDNA methylation in a genome-wide fashion. This MeD-seq assay on cfDNA therefore has high potential as a minimally invasive test to estimate remaining tumor burden, which can be used to select CRLM patients at high risk of recurrence. If the clinical applicability can be demonstrated in this specific patient group, further development towards other tumor types and clinical applications (e.g. tumor detection, therapy response monitoring) is foreseen.

Outline & Clinical Need

The goal of the study is to deliver proof of concept of the clinical applicability of the MeD-seq assay, which is able to detect tumor-specific epigenetic patterns in the circulating cell-free DNA in the blood of patients. The assay will be evaluated whether it can predict early recurrence in colorectal cancer patients with surgically removable liver metastases. The MeD-seq assay provides the patients with a more accurate prognosis soon after their surgery. The test will also be evaluated whether it can enable a more personalized treatment, expected to improve outcome, by selecting those patients in need of additional treatment. This biomarker study will generate cfDNA methylation profiles from 240 patients with colorectal liver metastases participating in the MIRACLE study before and after surgery as well as from 50 healthy controls.

The MeD-seq assay examines epigenetic changes in tumor derived DNA, providing the patients with a more accurate prognosis soon after their surgery. The test will also enable a more personalized treatment, expected to improve outcome, by selecting those patients in need of additional treatment. In patients that have a low risk of early recurrence, the test may render follow up visits redundant, thereby reducing the amount of unnecessary anxiety for patients. The use of minimally invasively obtainable blood samples reduces the need for often painful tissue biopsies and burdensome imaging scans, thereby increasing the patient’s quality of life while enabling more frequent disease monitoring.

For the treating physicians the MeD-seq test will provide a reliable, objective and affordable tool to select CRLM patients at high risk of early recurrence. This will greatly improve current treatment decision-making for CRLM patients.

International Leukemia Target Board

Oncode Investigator: Monique den Boer (Princess Maxima Center)

Clinicians: Josef Vormoor, Peter Hoogerbrugge, Michel Zwaan (all Princess Maxima Center)

Other members of the team Judith Boer, Olaf Heidenreich (both Princess Maxima Center)

Starting year: 2020

Background:

Children with hematological malignancies are treated according to standardized treatment protocols monitored by national childhood oncology study groups. Over the past decades, improvements in outcome were driven by the optimization of multi-agent chemotherapy regimens, minimal residual disease (MRD) monitoring, and (cyto)genetic prognostic markers including IKZF1 deletion and BCR-ABL1 fusion. However, relapses still occur in 15% of all cases and up to 40-50% of high-risk cases, and the outcome after relapse is poor. Contradictory, children with relapsed leukemia and lymphoma are treated with virtually the same drugs as those used in initial treatment, simply because detection of target presence for precision medicines and/or knowledge about resistance-modifying agents is lacking. Hematopoietic stem cell transplantation is a potential cure for high risk cases. However, both intensive chemotherapy and conditioning for stem cell transplantation are highly toxic, with acute as well as long-term side effects.

Outline & Clinical need:

There is a need for new medicines which can improve outcome (long-term prognosis and reduced side-effects) for children with hematological malignancies. These new medicines have been, most often, not yet used in children and hence drug dosing and (partial) efficacy needs to be established in early clinical trials (phase I and II). To accelerate the more upfront use of new agents, these drugs need to be efficacious in some extend. To achieve this, patients should enrol in early clinical trials based on the most perfect fit between target presence, knowledge about targeted drug sensitivity and trials open to children. Given the limited number of eligible patients per national study group, lack of relevant expertise in both molecular profiling and clinical trial eligibility within individual groups, the researchers aim to set-up an international platform for the interpretation of molecular profiles AND trial eligibility of patients.

The researchers will work on an international proof of concept study in children with relapsed/refractory hematological malignancies in which the primary objectives are to 1) determine the actionable lesions in a uniform setting by a group of experts and 2) advice the treating physicians which trials are open in order to facilitate the enrolment of the right patient in the right early clinical trial. By this centralized approach, the researchers will also be able to address our secondary objectives in which they 1) want to identify the frequency and total number of the different types of lesions and 2) want to elucidate the reasons why patients are not been enrolled in trials. These secondary objectives are essential for discussions with regulatory authorities (like EMA) and pharma and will elucidate the hurdles in drug development for these patients.

Blood-borne assessments of stromal activation to guide therapy in esophageal adenocarcinoma– BASALT

Oncode Investigators: Jan Paul Medema (Amsterdam UMC)

Oncode researcher: Maarten Bijlsma (Amsterdam UMC)

Clinician: Hanneke van Laarhoven (Amsterdam UMC)

Starting year: 2019

Together with ZonMw Oncode fund this Affordable Healthcare Project

Background for the project:

Approximately 2.500 patients are diagnosed with esophageal adenocarcinoma in the Netherlands each year. Esophageal adenocarcinoma is a disease entity with a distinct etiology, molecular makeup, and poorer prognosis compared to squamous carcinomas of the esophagus. In patients eligible for resection, standard of care currently includes neoadjuvant chemotherapy and radiation followed by surgery (CROSS regimen). Despite this intense regimen, median overall survival is just over 3.5 years. Thus, there is a dire need of improvement.

In gastrointestinal cancers, including esophageal adenocarcinoma, non-tumor cells and material such as fibroblasts and extracellular matrix often comprise the bulk of tumor tissue (‘stroma’). This stroma is now well recognized to harbor significant tumor-promoting properties, and suspected to hamper response, for instance to neoadjuvant chemoradiation as recently shown by the Investigators. The research group has discovered the substance that is produced in the stroma and which prevents the effective treatment of esophageal adenocarcinoma patients. In addition, they have developed a so-called biomarker (a substance to be measured in the blood) that can demonstrate the amount of the treatment-inhibiting stroma in patients.

Outline & Clinical Need

This clinical study aims to find out how safe and effective the addition is of stroma-targeting agent Tocilizumab to the standard of care of esophageal cancer. Tocilizumab is already used as a standard in the treatment of other diseases, however the combination of Tocilizumab with chemotherapy and radiation in the treatment of esophageal cancer has not been studied before.

A positive outcome from this study will provide a much-needed stratification tool to improve outcome of currently available stroma-targeting compounds that have failed to demonstrate encouraging efficacy. These findings are not restricted to esophageal adenocarcinoma and can include other stroma-rich tumors with poor outcome, such as pancreatic and colorectal cancer. Gastrointestinal cancers belong to the deadliest cancers worldwide, with a five-year survival rate below 50%, underscoring the clinical need for improvement of treatment outcome and the potential impact of this stratification approach.

Head and neck cancer organoids and their potential to predict patient therapy response

Oncode Investigator: Hans Clevers (Hubrecht Institute, UMC Utrecht, PMC)

Oncode Scientist: Else Driehuis (Hubrecht Institute, UMC Utrecht)

Clinicians: Lot Devriese, Stefan Willems, Remco de Bree (all UMC Utrecht)

Starting year: 2018

Background of the project:

In the curative treatment of head and neck squamous cell carcinoma (HNSCC) patients with advanced disease, patients are either treated by radiotherapy (RT) combined with platinum-based chemotherapy (cisplatin or carboplatin), or with anti-EGFR antibody Cetuximab. Currently, the choice between these two treatments is made based on fitness and co-morbidity of the patient. RT + cisplatin is generally preferred because of a large body of evidence. RT + Cetuximab is given to patients with poor condition or when cisplatin is contra-indicated.

Until recently, no head-to head comparisons (randomized clinical trials) have been performed between platinum+radiotherapy and Cetuximab +radiotherapy. It has been noted that some patients respond strikingly well to cetuximab. Yet until now, no predictive biomarker for response to cetuximab has been described.
Strikingly, known predictive genetic alterations for response to anti-EGFR, such as RAS mutations for panitumumab in the treatment of colorectal cancer are currently not considered in clinical decision.

Outline & Clinical need:

At present, one cannot determine tumor drug sensitivity of individual patients upfront. To prevent the unnecessary exposure of patients to cytotoxic agents, it appears attractive to develop a method that predicts drug sensitivity, optimally guiding therapeutic decision making. Organoid technology allows the unique opportunity to expand both healthy and tumor tissue, providing an array of opportunities to improve health care.

The researchers work on a proof-of-concept study in which they will compare in vitro and in vivo data of the first-line treatment options of HNSCC patients that are currently available in the clinic: RT+Cisplatin, RT+Carboplatin and RT+ Cetuximab. After receiving the tissue obtained during surgery or biopsy, they will establish organoid lines, perform DNA/RNA sequencing and test their sensitivity to these therapies. Subsequently, they will link clinical patient response to in vitro drug response to determine its predictive value to therapy. They will also test organoids for sensitivity to drugs acting at non-EGFR molecular targets that are known to be mutationally activated in HNSCC but are currently not (yet) considered for treatment in standard clinical practice.

Point-of-care monitoring of head and neck cancer treatment response and recurrence development using nanopore-based ctDNA consensus sequencing

Oncode Investigator: Jeroen de Ridder (UMC Utrecht)

Clinicians: Stefan Willems, Lot Devriese, Manon Huibers, Lot Zuur (all UMC Utrecht)

Starting year: 2018

Background:

In the blood of cancer patients, circulating tumour DNA (ctDNA) contributes to the pool of cell-free DNA (cfDNA). Recent research demonstrated that ctDNA in ‘liquid biopsies’ (blood) may become a generic biomarker for non-invasive cancer diagnostics. However, it is difficult to detect cancer mutations in liquid biopsies, as the absolute and relative amounts of ctDNA among the total pool of cfDNA molecules in blood plasma is very low.

Outline & Clinical need:

Novel technology is required that can detect ctDNA mutations in a fast, sensitive and routine manner. The researchers found that single ctDNA molecules can be sequenced with high accuracy by a three-step process consisting of capturing, copying and concatenation of the original double-stranded ctDNA molecules. Real-time sequencing of the DNA products from this process using Oxford Nanopore MinION instruments, combined with appropriate bioinformatics, provides an unique assay for detection of somatic mutations in ctDNA samples. This innovative approach - called Cyclomics - is unparalleled by any other method in terms of sensitivity, cost-efficiency and speed, and it requires little capital investments, allowing point-of-care cancer diagnostics. In practice, this test can be used in every patient clinic without the need for a specialised lab. We have established a Cyclomics assay for mutation detection in TP53, enabling the monitoring of a large variety of cancers.

Within this clinical proof of concept project, the researchers will apply the Cyclomics ctDNA test in patients with advanced head and neck cancer squamous cell carcinoma (HNSCC). In the United States and Europe, HNSCC accounts for 3-4 percent of all malignancies and 380,000 patients worldwide die from this disease each year. Radiotherapy with or without concurrent chemotherapy is the primary treatment for advanced pharynx and larynxcancer and occasionally for oral cavity cancer. For patients that do not respond to primary curative (chemo)radiotherapy, salvage surgery is the final treatment for residual or recurrent disease.

There is one key unmet clinical need in HNSCC treatment: there is no reliable (individualized) biomarker that can be used to ascertain treatment response or disease recurrence. Such biomarker would help to identify patients that have a good treatment response and might benefit from treatment adaptation, e.g. dose (de)-escalation or other drugs (immunotherapy). Furthermore, it could aid in earlier detection of recurrences or residual disease, which is difficult using current imaging and pathology. Early recurrence detection is important as it will increase the chances of success of salvage therapy with improved quality of life for the patient as a result.

Selection of advanced breast cancer patients for carboplatin treatment using the functional repair capacity (RECAP) test: the CAREFUL study

Oncode Investigator: Roland Kanaar (Erasmus MC)

Clinicians: Agnes Jager, Stefan Sleijfer (both Erasmus MC)

Research team: Dik van Gent, Titia Meijer, Marjolijn Ladan, Nicole Verkaik, Esther Oomen-de Hoop, Carolien van Deurzen (all Erasmus MC)

Starting year: 2019

Background:

The continuous accumulation of various types of DNA damage in our DNA is counteracted by a broad spectrum of specific DNA repair mechanisms in normal cells. Interestingly, tumor cells often have defects in one or more DNA repair pathways. This particular feature of tumors can be exploited for treatment with DNA-damaging chemotherapies. The development of predictive assays to select tumors with defective DNA repair pathways would be a huge step forward in preselecting patients for precision medicine

DNA double strand breaks (DSB), a very toxic form of damage, can be inflicted by certain types of chemotherapy and radiation treatment. Tumor cells that harbor BRCA gene deficiencies show a defect in homologous recombination (HR), the DNA repair pathway necessary for error-free DSB repair. As a consequence, these cells are highly sensitive to DSB-inducing therapy like platinum, alkylating agents and PARP-inhibitors. Interestingly, sporadic breast cancers (i.e. non-mutated BRCA1/2) can also harbor HR deficiency (HRD).

Outline & Clinical need:

It is of great clinical interest to identify additional HRD tumors, without BRCA mutations, to enlarge the population of patients that could benefit from treatments targeting the HR pathway. Several different HRD tests have been designed, mostly based on genetic and epigenetic aberrations in a specific pattern throughout the genome. The researchers developed the RECAP (REpair CAPacity) test, a functional assay measuring accumulation of the repair protein RAD51 in so-called foci after ex vivo irradiation of fresh breast cancer tissue. The main advantages of the RECAP test compared to other HRD tests, is its functional character for exploring the HR phenotype rather than the static nature of DNA-based assays, that measure accumulation of mutations and chromosomal aberrations. This allows determining the HR status at the moment of testing. Therefore, the RECAP test can also detect reversion of the HRD phenotype in BRCA deficient tumors that developed resistance induced by prior treatments (manuscript in preparation).

In this proof of concept study, the researchers will investigate the predictive value of the RECAP test for the response to carboplatin (which induces DSB that require intact HR for their repair among TNBC or high-grade ER positive/HER2 negative advanced BC patients. This is a proof of concept for a broad class of HRD targeting drugs, including PARP inhibitors and (in the future) polymerase theta inhibitors. Besides the RECAP test, this study will also estimate the sensitivity and the specificity of the BRCA1-like classifier and the CHORD / HRDetect in a prospective study; the team will do a cross comparison between these three most promising HRD tests.

RASTRIC trial: Mutant Ras metastatic colorectal cancer triple drug combination therapy

Oncode Investigators: Hans Bos and Hugo Snippert (UMC Utrecht)

Clinicians: Jeanine Roodhart (project leader), Miriam Koopman, Eelke Gort (all UMC Utrecht)

Other members of the team: Sjoerd Elias (UMC Utrecht), Alwin Huitema (UMC Utrecht / NKI)

Starting year: 2020

Background:

Patients with mutant RAS metastatic colorectal cancer (mCRC) have a poorer overall survival compared to wildtype RAS mCRC. Mutant RAS mCRC have less treatment options because mutant RAS mCRC are resistant to anti-EGFR targeted therapy (cetuximab/ panitumumab). Furthermore, anti-EGFR-targeted therapy-treated patients develop resistance frequently due to the appearance of mutant Ras-containing tumor cells.

Outline & Clinical need:

As there are no targeted agents available to treat mutant RAS mCRC, there is an urgent clinical need for targeted drugs for which mutant RAS mCRC is sensitive.

Based on preclinical work with colorectal cancer organoids, the goal of this project is to evaluate whether the triplet combination of a MEK inhibitor, binimetinib, a pan-EGF receptor inhibitor, lapatinib, and a microtubule targeting agent, vinorelbine, will induce tumor regression in patients with mCRC having a mutation in RAS, resulting in an extended life-span with quality-of-life. If successful, the treatment may be extended to other tumor types harboring RAS mutations, e.g. non-small cell lung cancer and pancreatic cancer, and to EGFR-inhibitor resistant tumors, e.g. after treatment with an EGFR-inhibitor and right-sided colon cancer.

Validation of a novel 9-gene-classifier to guide adjuvant treatment for prostate cancer

Oncode Investigator: Wilbert Zwart (NKI)

Clinicians: Andre Bergman, Baukelien van Triest (both NKI-AVL)

Starting year: 2018

Background of the project:

250.000 prostate cancer patients die from the consequences of the disease each year, globally. Current clinical practice does not offer adjuvant therapy after radical prostatectomy for the entire patient population, as this has been proven unsuccessful in non-preselected cohorts. As a substantial percentage of these patients do however develop a recurrence, intensified treatment for these patients may prevent relapse, achieving a higher rate of cure for this population.

Outline & clinical need:

This project will put the 9-gene classifier to the test, previously identified by the researchers, validating the classifier on large historical cohorts representing thousands of prostate cancer patients. In re-analyzing these data computationally, we aim to establish whether our classifier can successfully identify those prostate cancer patients at very high risk of relapse without receiving any adjuvant treatment. In addition, the classifier is tested in data from an on-site clinical trial, to determine whether the outcome for these specific individuals may be improved by intensifying drug treatment in the adjuvant setting. As these patients would normally not receive any additional treatment after radical prostatectomy, this biomarker may identify those specific patients who would derive substantial benefit from additional treatment in the early disease setting, increasing chance for cure.

TEIPP-targeting immunotherapy

Oncode Investigator: Sjoerd van der Burg (LUMC)

Clinicians: Joachim Aerts (Erasmus MC)

Co-investigator: Thorbald van Hall (LUMC)

Starting year: 2019

Background:

Tumors have developed several escape mechanisms, including co-inhibitory molecule expression which is currently treated by checkpoint antibodies but also downregulation of the intracellular peptide transporter TAP1/TAP2, resulting in loss of the presentation of conventional T-cell epitopes in HLA class I, and hence in the failure of tumor-reactive CD8+ T-cells to recognize and kill tumor cells. This type of escape can occur in up to 50% of primary tumors and is increased in the metastatic lesions of such tumors. TAP defects correlate with worse clinico-pathological parameters and has been associated with loss of durable benefit to checkpoint inhibition.

Outline & Clinical need:

The unmet need is the development of a therapy that can reinforce effective tumor-immunity to cancers displaying TAP-defects for which conventional therapeutic cancer vaccines and/or checkpoint blockade will not work (anymore).

TEIPP therapy may fill this position by reinstalling an effective antitumor response to TAP-defective tumors thereby increasing the overall survival of patients failing first line therapy. While TAP defects result in a failure to present the conventional tumor antigens in HLA class I, a novel set of shared neoantigens - referred to as T-cell epitopes associated with impaired peptide processing or ‘TEIPP’ - becomes available for recognition by CD8+ T-cells. Spontaneous T-cell response to TEIPP antigens are rare and, therefore, exploitation of the TEIPP-specific T-cell repertoire for cancer treatment requires either specific stimulation of the immune system by vaccines or the adoptive transfer of TEIPP-specific TCR carrying T-cells.

Contact person

Marlinde Smit Programme Manager

Related news and events

Oncode Icons Square 22
First finalized Oncode Clinical Proof of Concept (CPoC) project
We are happy to announce that our first Oncode CPoC study - a collaboration between Oncode Investigator Jean Paul Medema (Amsterdam UMC) and clinician Henk Verheul (Radboud UMC) titled Pulsatile high dose Sunitinib as a specific drug for (a subset of) metastatic mesenchymal CRCs - is now finalized.
Bianca-OliviaNita