Professor W. Joost Lesterhuis

Kids are not small adults, Identifying age-dependent drug targets in paediatric oncology

Cancers in children are very different to cancers in adults. However, most therapeutic strategies are designed explicitly for adult cancers, and then used in children if proven safe.

Developing new immune based therapies for neuroblastoma

Neuroblastoma is a complex childhood cancer of the nerve cells and the most common solid tumour in children outside of the brain. The average age of diagnosis is 1-2 years and tragically 50% of children with high-risk neuroblastoma lose their battle within five years.

The interplay between sarcoma and surgery-induced wound healing

Local immunotherapy for sarcoma

Anti-metabolite chemotherapy increases LAG-3 expressing tumor-infiltrating lymphocytes which can be targeted by combination immune checkpoint blockade

Antibodies that target immune checkpoints such as cytotoxic T lymphocyte antigen 4, programmed cell death protein/ligand 1 are approved for treatment of multiple cancer types. 

Local therapy with combination TLR agonists stimulates systemic anti-tumor immunity and sensitizes tumors to immune checkpoint blockade

Time-course RNAseq data of murine AB1 mesothelioma and Renca renal cancer following immune checkpoint therapy

Time-critical transcriptional events in the immune microenvironment are important for response to immune checkpoint blockade (ICB), yet these events are difficult to characterise and remain incompletely understood. Here, we present whole tumor RNA sequencing data in the context of treatment with ICB in murine models of AB1 mesothelioma and Renca renal cell cancer. 

Immune checkpoint therapy responders display early clonal expansion of tumor infiltrating lymphocytes

Immune checkpoint therapy (ICT) causes durable tumour responses in a subgroup of patients, but it is not well known how T cell receptor beta (TCRβ) repertoire dynamics contribute to the therapeutic response. 

Protocol for delivery of intraoperative immunotherapy to mice by surgical debulking of subcutaneous tumors

Pre-clinical studies developing novel therapies to prevent cancer recurrence require appropriate surgical models. Here, we present a protocol for surgical debulking of subcutaneous tumors in mice, which allows for intraoperative application of immunotherapy-loaded biomaterials. 

Tretinoin improves the anti-cancer response to cyclophosphamide, in a model-selective manner

Chemotherapy is included in treatment regimens for many solid cancers, but when administered as a single agent it is rarely curative. The addition of immune checkpoint therapy to standard chemotherapy regimens has improved response rates and increased survival in some cancers. However, most patients do not respond to treatment and immune checkpoint therapy can cause severe side effects. Therefore, there is a need for alternative immunomodulatory drugs that enhance chemotherapy.

A surgically optimized intraoperative poly(I:C)-releasing hydrogel prevents cancer recurrence

Recurrences frequently occur following surgical removal of primary tumors. In many cancers, adjuvant therapies have limited efficacy. Surgery provides access to the tumor microenvironment, creating an opportunity for local therapy, in particular immunotherapy, which can induce local and systemic anti-cancer effects.

Geldanamycin treatment does not result in anti-cancer activity in a preclinical model of orthotopic mesothelioma

Mesothelioma is characterised by its aggressive invasive behaviour, affecting the surrounding tissues of the pleura or peritoneum. We compared an invasive pleural model with a non-invasive subcutaneous model of mesothelioma and performed transcriptomic analyses on the tumour samples.

CD4+ T cells drive an inflammatory, TNF-α/IFN-rich tumor microenvironment responsive to chemotherapy

While chemotherapy remains the first-line treatment for many cancers, it is still unclear what distinguishes responders from non-responders. Here, we characterize the chemotherapy-responsive tumor microenvironment in mice, using RNA sequencing on tumors before and after cyclophosphamide, and compare the gene expression profiles of responders with progressors.

Cancer chemotherapy: insights into cellular and tumor microenvironmental mechanisms of action

Chemotherapy has historically been the mainstay of cancer treatment, but our understanding of what drives a successful therapeutic response remains limited.

Comprehensive Testing of Chemotherapy and Immune Checkpoint Blockade in Preclinical Cancer Models Identifies Additive Combinations

Antibodies that target immune checkpoints such as cytotoxic T lymphocyte antigen 4 (CTLA‐4) and the programmed cell death protein 1/ligand 1 (PD-1/PD-L1) are now a treatment option for multiple cancer types. However, as a monotherapy, objective responses only occur in a minority of patients. Chemotherapy is widely used in combination with immune checkpoint blockade (ICB). Although a variety of isolated immunostimulatory effects have been reported for several classes of chemotherapeutics, it is unclear which chemotherapeutics provide the most benefit when combined with ICB.

Retinoic Acid Induces an IFN-Driven Inflammatory Tumour Microenvironment, Sensitizing to Immune Checkpoint Therapy

With immune checkpoint therapy (ICT) having reshaped the treatment of many cancers, the next frontier is to identify and develop novel combination therapies to improve efficacy. Previously, we and others identified beneficial immunological effects of the vitamin A derivative tretinoin on anti-tumour immunity.

Temporally restricted activation of IFNβ signaling determines response to immune checkpoint therapy

The biological determinants of the response to immune checkpoint blockade (ICB) in cancer remain incompletely understood. Little is known about dynamic biological events that underpin therapeutic efficacy due to the inability to frequently sample tumours in patients.

Protocol of DREAM3R: DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma-a phase 3 randomised trial

There is a strong theoretical rationale for combining checkpoint blockade with cytotoxic chemotherapy in pleural mesothelioma and other cancers.

PPARalpha and PPARgamma activation is associated with pleural mesothelioma invasion but therapeutic inhibition is ineffective

Mesothelioma is a cancer that typically originates in the pleura of the lungs. It rapidly invades the surrounding tissues, causing pain and shortness of breath. We compared cell lines injected either subcutaneously or intrapleurally and found that only the latter resulted in invasive and rapid growth.

A tipping point in cancer-immune dynamics leads to divergent immunotherapy responses and hampers biomarker discovery

Predicting treatment response or survival of cancer patients remains challenging in immuno-oncology. Efforts to overcome these challenges focus, among others, on the discovery of new biomarkers. Despite advances in cellular and molecular approaches, only a limited number of candidate biomarkers eventually enter clinical practice.

Malignant Pleural Effusions—A Window Into Local Anti-Tumor T Cell Immunity?

The success of immunotherapy that targets inhibitory T cell receptors for the treatment of multiple cancers has seen the anti-tumor immune response re-emerge as a promising biomarker of response to therapy. Longitudinal characterization of T cells in the tumor microenvironment (TME) helps us understand how to promote effective anti-tumor immunity. However, serial analyses at the tumor site are rarely feasible in clinical practice.

Tumor Infiltrating Effector Memory Antigen-Specific CD8(+) T Cells Predict Response to Immune Checkpoint Therapy

Immune checkpoint therapy (ICT) results in durable responses in individuals with some cancers, but not all patients respond to treatment. ICT improves CD8+ cytotoxic T lymphocyte (CTL) function, but changes in tumor antigen-specific CTLs post-ICT that correlate with successful responses have not been well characterized. Here, we studied murine tumor models with dichotomous responses to ICT.

Durvalumab with first-line chemotherapy in previously untreated malignant pleural mesothelioma (DREAM): a multicentre, single-arm, phase 2 trial with a safety run-in

There is a strong unmet need to improve systemic therapy in mesothelioma. Chemotherapy with cisplatin and pemetrexed improves survival in malignant pleural mesothelioma, and immune checkpoint inhibitors are an emerging treatment in this disease. We aimed to evaluate the activity of durvalumab, an anti-PD-L1 antibody, given during and after first-line chemotherapy with cisplatin and pemetrexed in patients with advanced malignant pleural mesothelioma.

Characteristics of TCR Repertoire Associated With Successful Immune Checkpoint Therapy Responses

Immunotherapies have revolutionized cancer treatment. In particular, immune checkpoint therapy (ICT) leads to durable responses in some patients with some cancers. However, the majority of treated patients do not respond. Understanding immune mechanisms that underlie responsiveness to ICT will help identify predictive biomarkers of response and develop treatments to convert non-responding patients to responding ones. ICT primarily acts at the level of adaptive immunity. The specificity of adaptive immune cells, such as T and B cells, is determined by antigen-specific receptors.

Bilateral murine tumor models for characterizing the response to immune checkpoint blockade

This protocol describes bilateral murine tumor models that display a symmetrical yet dichotomous response to immune checkpoint blockade

Sensitizing the Tumor Microenvironment to Immune Checkpoint Therapy

In this review we explore the current literature about the predictive characteristics of the tumor microenvironment and discuss therapeutic approaches

Sensitization to immune checkpoint blockade through activation of a STAT1/NK axis in the tumor microenvironment

Our results identify a pretreatment tumor microenvironment that predicts response to immune checkpoint blockade, which can be therapeutically attained

Functional genomics in cancer immunotherapy: Computational approaches for biomarker and drug discovery

This review explores computational strategies to yield biological insight into the processes involved in the immunotherapeutic response