Program Head, Cancer; Chronic and Severe Diseases RFA Deputy Head
Associate Professor Willem (Joost) Lesterhuis is an NHMRC EL2 Investigator. He has a background as a dual-trained medical oncologist and basic researcher in tumour immunology and cancer biology.
Joost obtained his MD at the Free University in Amsterdam 2001 and completed his medical oncology specialisation and his PhD in tumour immunology at the Radboud University in Nijmegen, The Netherlands in 2010. From 2011-2012 he was a visiting postdoc at the University of Western Australia, after which he worked as a medical oncologist/cancer researcher at the Academic Medical Centre at the University of Amsterdam in the Netherlands. Since 2013, when he and his family moved permanently to Australia, he has been a fulltime researcher, with a special focus on cancer immunology research, initially at the University of Western Australia, and since 2018 at Telethon Kids Institute, heading the Sarcoma Translational Research team.
His research combines several fields of science, including cancer biology, immunology, drug discovery, systems biology, and translational oncology.
Find Associate Professor Lesterhuis on Google Scholar and ORCID.
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Publications
February 2024
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.
Children's Cancers Published research Subsite: Cancer Sarcoma Translational ResearchJuly 2023A 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.
Children's Cancers Published research Subsite: Cancer Sarcoma Translational Research Translational GeneticsMay 2023Geldanamycin 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.
Children's Cancers Published research Systems Immunology Airway Epithelial Research Subsite: Cancer Sarcoma Translational ResearchDecember 2022CD4+ 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.
Children's Cancers Published research Computational Biology Sarcoma Translational Research Translational GeneticsJuly 2022Cancer 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.
Children's Cancers Published research Sarcoma Translational ResearchMay 2022Comprehensive 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.
Children's Cancers Published research Subsite: Cancer Sarcoma Translational ResearchMarch 2022Retinoic 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.
Children's Cancers Published research Pregnancy and Early Life Immunology Systems Immunology Subsite: Cancer Sarcoma Translational ResearchSeptember 2021Temporally 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.
Children's Cancers Published research Computational Biology Sarcoma Translational Research Translational GeneticsJanuary 2022Protocol 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.
Children's Cancers Published research Sarcoma Translational ResearchJanuary 2021PPARalpha 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.
Published research Systems Immunology Sarcoma Translational ResearchMay 2021A 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.
Children's Cancers Published research Sarcoma Translational ResearchApril 2021Malignant 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.
Children's Cancers Published research Sarcoma Translational ResearchNovember 2020Tumor 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.
Children's Cancers Published research Computational Biology Sarcoma Translational ResearchSeptember 2020Durvalumab 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.
Children's Cancers Published research Sarcoma Translational ResearchOctober 2020Characteristics 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.
Children's Cancers Published research Sarcoma Translational ResearchMay 2020Bilateral 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
Children's Cancers Published research Systems Immunology Computational Biology Sarcoma Translational ResearchFebruary 2020Sensitizing 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
Children's Cancers Published research Sarcoma Translational ResearchJuly 2019Sensitization 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
Children's Cancers Published research Systems Immunology Computational Biology Sarcoma Translational ResearchJune 2019Functional 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
Children's Cancers Published research Computational Biology Sarcoma Translational Research