ORCID Profile
0000-0002-2718-276X
Current Organisations
University of Western Australia
,
Telethon Kids Institute
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Dynamical Systems in Applications | Applied Mathematics | Cancer Genetics | Complex Physical Systems
ANZSRC Socio-Economic Objective (SEO)
Cancer and Related Disorders | Primary Mining and Extraction of Mineral Resources not elsewhere classified | Expanding Knowledge in the Mathematical Sciences |
Related Links
Publications
Cancer chemotherapy: insights into cellular and tumor microenvironmental mechanisms of action
Publisher: Frontiers Media SA
Date: 29-07-2022
Abstract: Chemotherapy has historically been the mainstay of cancer treatment, but our understanding of what drives a successful therapeutic response remains limited. The erse response of cancer patients to chemotherapy has been attributed principally to differences in the proliferation rate of the tumor cells, but there is actually very little experimental data supporting this hypothesis. Instead, other mechanisms at the cellular level and the composition of the tumor microenvironment appear to drive chemotherapy sensitivity. In particular, the immune system is a critical determinant of chemotherapy response with the depletion or knock-out of key immune cell populations or immunological mediators completely abrogating the benefits of chemotherapy in pre-clinical models. In this perspective, we review the literature regarding the known mechanisms of action of cytotoxic chemotherapy agents and the determinants of response to chemotherapy from the level of in idual cells to the composition of the tumor microenvironment. We then summarize current work toward the development of dynamic biomarkers for response and propose a model for a chemotherapy sensitive tumor microenvironment.
Tumour associated lymphocytes in the pleural effusions of patients with mesothelioma express high levels of inhibitory receptors 11 Medical and Health Sciences 1107 Immunology
Publisher: Springer Science and Business Media LLC
Date: 12-2018
CD4+T cells drive an inflammatory, TNF-a/IFN-rich tumor microenvironment responsive to chemotherapy
Publisher: Elsevier BV
Date: 12-2022
Early identification of antigen-specific immune responses in vivo by [ 18 F]-labeled 3′-fluoro-3′-deoxy-thymidine ([ 18 F]FLT) PET
Publisher: Proceedings of the National Academy of Sciences
Date: 24-10-2011
Abstract: Current biomarkers are unable to adequately predict vaccine-induced immune protection in humans with infectious disease or cancer. However, timely and adequate assessment of antigen-specific immune responses is critical for successful vaccine development. Therefore, we have developed a method for the direct assessment of immune responses in vivo in a clinical setting. Melanoma patients with lymph node (LN) metastases received dendritic cell (DC) vaccine therapy, injected intranodally, followed by [ 18 F]-labeled 3′-fluoro-3′-deoxy-thymidine ([ 18 F]FLT) PET at varying time points after vaccination. Control LNs received saline or DCs without antigen. De novo immune responses were readily visualized in treated LNs early after the prime vaccination, and these signals persisted for up to 3 wk. This selective [ 18 F]FLT uptake was markedly absent in control LNs, although tracer uptake in treated LNs increased profoundly with as little as 4.5 × 10 5 DCs. Immunohistochemical staining confirmed injected DC dispersion to T-cell areas and resultant activation of CD4 + and CD8 + T cells. The level of LN tracer uptake significantly correlates to the level of circulating antigen-specific IgG antibodies and antigen-specific proliferation of T cells in peripheral blood. Furthermore, this correlation was not observed with [ 18 F]-labeled fluoro-2-deoxy-2- d -glucose. Therefore, [ 18 F]FLT PET offers a sensitive tool to study the kinetics, localization, and involvement of lymphocyte subsets in response to vaccination. This technique allows for early discrimination of responding from nonresponding patients in anti-cancer vaccination and aid physicians in in idualized decisionmaking.
Temporally restricted activation of IFNβ signaling underlies response to immune checkpoint therapy in mice
Publisher: Springer Science and Business Media LLC
Date: 19-08-2022
DOI: 10.1038/S41467-022-32567-8
Abstract: 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 s le tumours in patients. Here, we map the transcriptional profiles of 144 responding and non-responding tumours within two mouse models at four time points during ICB. We find that responding tumours display on/fast-off kinetics of type-I-interferon (IFN) signaling. Phenocopying of this kinetics using time-dependent sequential dosing of recombinant IFNs and neutralizing antibodies markedly improves ICB efficacy, but only when IFNβ is targeted, not IFNα. We identify Ly6C + /CD11b + inflammatory monocytes as the primary source of IFNβ and find that active type-I-IFN signaling in tumour-infiltrating inflammatory monocytes is associated with T cell expansion in patients treated with ICB. Together, our results suggest that on/fast-off modulation of IFNβ signaling is critical to the therapeutic response to ICB, which can be exploited to drive clinical outcomes towards response.
Direct inhibition of STAT signaling by platinum drugs contributes to their anti-cancer activity
Publisher: Impact Journals, LLC
Date: 07-05-2017
Restoration of defective cross-presentation in tumors by gemcitabine
Publisher: Informa UK Limited
Date: 25-02-2015
Programmed Death Ligand 2 in Cancer-Induced Immune Suppression
Publisher: Hindawi Limited
Date: 2012
DOI: 10.1155/2012/656340
Abstract: Inhibitory molecules of the B7/CD28 family play a key role in the induction of immune tolerance in the tumor microenvironment. The programmed death-1 receptor (PD-1), with its ligands PD-L1 and PD-L2, constitutes an important member of these inhibitory pathways. The relevance of the PD-1/PD-L1 pathway in cancer has been extensively studied and therapeutic approaches targeting PD-1 and PD-L1 have been developed and are undergoing human clinical testing. However, PD-L2 has not received as much attention and its role in modulating tumor immunity is less clear. Here, we review the literature on the immunobiology of PD-L2, particularly on its possible roles in cancer-induced immune suppression and we discuss the results of recent studies targeting PD-L2 in cancer.
Retinoic Acid Induces an IFN-Driven Inflammatory Tumour Microenvironment, Sensitizing to Immune Checkpoint Therapy
Publisher: Frontiers Media SA
Date: 24-03-2022
Abstract: 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. Although it is known that tretinoin preferentially depletes myeloid derived suppressor cells in blood, little is known about the effects of tretinoin on the tumour microenvironment, h ering the rational design of clinical trials using tretinoin in combination with ICT. Here, we aimed to identify how tretinoin changed the tumour microenvironment in mouse tumour models, using flow cytometry and RNAseq, and we sought to use that information to establish optimal dosing and scheduling of tretinoin in combination with several ICT antibodies in multiple cancer models. We found that tretinoin rapidly induced an interferon dominated inflammatory tumour microenvironment, characterised by increased CD8+ T cell infiltration. This phenotype completely overlapped with the phenotype that was induced by ICT itself, and we confirmed that the combination further lified this inflammatory milieu. The addition of tretinoin significantly improved the efficacy of anti-CTLA4/anti-PD-L1 combination therapy, and staggered scheduling was more efficacious than concomitant scheduling, in a dose-dependent manner. The positive effects of tretinoin could be extended to ICT antibodies targeting OX40, GITR and CTLA4 monotherapy in multiple cancer models. These data show that tretinoin induces an interferon driven, CD8+ T cell tumour microenvironment that is responsive to ICT.
Polyinosinic polycytidylic acid prevents efficient antigen expression after mRNA electroporation of clinical grade dendritic cells
Publisher: Springer Science and Business Media LLC
Date: 19-11-2008
DOI: 10.1007/S00262-008-0626-Y
Abstract: Tumor-derived peptides are used frequently as antigen (Ag) source in dendritic cell (DC) therapy in cancer patients. An alternative is to load DC with tumor-associated Ag (TAA)-encoding RNA. RNA-loading obviates prior knowledge of CTL and Th epitopes in the Ag. Multiple epitopes for many HLA alleles (both MHC class I and class II) are encoded by the RNA and loading is independent of the patient's HLA make-up. Herein, we determined the optimal conditions for mRNA-electroporation of monocyte-derived DC for clinical application in relation to different maturation cocktails. The data demonstrate that TAA carcinoembryonic antigen, gp100 and tyrosinase are expressed already 30 min after electroporation with the encoding mRNA. Moreover, gp100-specific CTL are activated by gp100 mRNA-electroporated DC. Importantly, we show here that the presence of polyinosinic-polycytidylic acid [poly(I:C)] in the maturation cocktail prevents effective protein expression of the electroporated mRNA as well as subsequent CTL recognition. This effect of poly(I:C) correlates with the induction of IFN-induced genes and innate anti-viral effector molecules in DC. Together these data show that electroporation of mature DC with TAA-encoding mRNA is attractive for use in DC vaccination protocols in cancer patients, but protein expression should be tested for each maturation cocktail.
Sensitization to immune checkpoint blockade through activation of a STAT1/NK axis in the tumor microenvironment
Publisher: American Association for the Advancement of Science (AAAS)
Date: 17-07-2019
DOI: 10.1126/SCITRANSLMED.AAV7816
Abstract: A STAT1-driven inflammatory phenotype associated with response to checkpoint blocking antibodies sensitizes cancers to immunotherapy.
Phenotypical and Functional Characterization of Clinical Grade Dendritic Cells
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2002
DOI: 10.1097/00002371-200209000-00007
Abstract: Dendritic cells (DC) are the professional antigen presenting cells of the immune system. Therefore, several clinical studies have been initiated in which tumor antigen-loaded DC are used as a vaccine to boost an immune response against malignant tumors in patients with cancer. A prerequisite for DC used in these vaccination studies is not only that they are grown under "Good Manufacturing Practice" but equally important that they retain their functional properties. In an extensive study, various conditions were tested to optimize the maturation and yield of DC grown for clinical use. DC grown in XVIVO-15 medium supplemented with 5% HS yielded the best results, morphologically and phenotypically. Mature DC expressed significant amounts of mature DC markers (CD83) and the costimulatory molecules CD80 and CD86. It was shown that mature and immature DC can be frozen and retain their phenotype and function after thawing. These clinical grade DC secreted high levels of the chemokines dendritic cell chemokine 1 (DC-CK1), interleukin-8 (IL-8), macrophage-derived chemokine (MDC), and thymus and activation-regulated chemokine (TARC). This implicates that these DC can attract naïve T and B cells as well as natural killer cells and memory T cells. Finally, to test their migratory capacity in vivo, (111)In-labeled DC were injected into tumor-free lymph nodes of patients with melanoma. Autoradiographic analysis of the dissected lymph nodes indicated that these DC could migrate into the T cell area of adjacent lymph nodes. In conclusion, a culture procedure was established to generate large numbers of monocyte-derived immature and mature DC that retain their morphologic, phenotypic, and functional characteristics in vitro and can be visualized in situ.
Durvalumab with first-line chemotherapy in previously untreated malignant pleural mesothelioma (DREAM): a multicentre, single-arm, phase 2 trial with a safety run-in
Publisher: Elsevier BV
Date: 09-2020
Vascular Endothelial Growth Factor in Systemic Capillary Leak Syndrome
Publisher: Elsevier BV
Date: 06-2009
Tumor-infiltrating dendritic cells exhibit defective cross-presentation of tumor antigens, but is reversed by chemotherapy
Publisher: Wiley
Date: 15-12-2015
Abstract: Cross-presentation defines the unique capacity of an APC to present exogenous Ag via MHC class I molecules to CD8(+) T cells. DCs are specialized cross-presenting cells and as such have a critical role in antitumor immunity. DCs are routinely found within the tumor microenvironment, but their capacity for endogenous or therapeutically enhanced cross-presentation is not well characterized. In this study, we examined the tumor and lymph node DC cross-presentation of a nominal marker tumor Ag, HA, expressed by the murine mesothelioma tumor AB1-HA. We found that tumors were infiltrated by predominantly CD11b(+) DCs with a semimature phenotype that could not cross-present tumor Ag, and therefore, were unable to induce tumor-specific T-cell activation or proliferation. Although tumor-infiltrating DCs were able to take up, process, and cross-present exogenous cell-bound and soluble Ags, this was significantly impaired relative to lymph node DCs. Importantly, however, systemic chemotherapy using gemcitabine reversed the defect in Ag cross-presentation of tumor DCs. These data demonstrate that DC cross-presentation within the tumor microenvironment is defective, but can be reversed by chemotherapy. These results have important implications for anticancer therapy, particularly regarding the use of immunotherapy in conjunction with cytotoxic chemotherapy.
Vaccination with mRNA-Electroporated Dendritic Cells Induces Robust Tumor Antigen-Specific CD4+ and CD8+ T Cells Responses in Stage III and IV Melanoma Patients
Publisher: American Association for Cancer Research (AACR)
Date: 30-09-2012
DOI: 10.1158/1078-0432.CCR-11-3368
Abstract: Purpose: Electroporation of dendritic cells (DC) with mRNA encoding tumor-associated antigens (TAA) has multiple advantages compared to peptide loading. We investigated the immunologic and clinical responses to vaccination with mRNA-electroporated DC in stage III and IV melanoma patients. Experimental design: Twenty-six stage III HLA*02:01 melanoma patients scheduled for radical lymph node dissection (stage III) and 19 melanoma patients with irresectable locoregional or distant metastatic disease (referred to as stage IV) were included. Monocyte-derived DC, electroporated with mRNA encoding gp100 and tyrosinase, were pulsed with keyhole limpet hemocyanin and administered intranodally. TAA-specific T-cell responses were monitored in blood and skin-test infiltrating lymphocyte (SKIL) cultures. Results: Comparable numbers of vaccine-induced CD8+ and/or CD4+ TAA-specific T-cell responses were detected in SKIL cultures 17/26 stage III patients and 11/19 stage IV patients. Strikingly, in this population, TAA-specific CD8+ T cells that recognize multiple epitopes and produce elevated levels of IFNγ upon antigenic challenge in vitro, were significantly more often observed in stage III patients 15/17 versus 3/11 stage IV patients, P = 0.0033. In stage IV patients, one mixed and one partial response were documented. The presence or absence of IFNγ-producing TAA-specific CD8+ T cells in stage IV patients was associated with marked difference in median overall survival of 24.1 months versus 11.0 months, respectively. Conclusion: Vaccination with mRNA-electroporated DC induces a broad repertoire of IFNγ producing TAA-specific CD8+ and CD4+ T-cell responses, particularly in stage III melanoma patients. Clin Cancer Res 18(19) 5460–70. ©2012 AACR.
Immunomonitoring Tumor-Specific T Cells in Delayed-Type Hypersensitivity Skin Biopsies After Dendritic Cell Vaccination Correlates With Clinical Outcome
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-08-2005
Abstract: Tumor-specific immunomonitoring is essential to evaluate the efficacy of vaccination against cancer. In this study, we investigated the predictive value of the presence or absence of antigen-specific T cells in biopsies from delayed-type hypersensitivity (DTH) sites. In our ongoing clinical trials, HLA-A2.1+ melanoma patients were vaccinated with mature dendritic cells (DC) pulsed with melanoma-associated peptides (gp100 and tyrosinase) and keyhole limpet hemocyanin. After intradermal administration of a DTH challenge with gp100- and tyrosinase peptide-loaded DC, essentially all patients showed a positive induration. In clinically responding patients, T cells specific for the antigen preferentially accumulated in the DTH site, as visualized by in situ tetramer staining. Furthermore, significant numbers of functional gp100 and tyrosinase tetramer-positive T cells could be isolated from these DTH biopsies, in accordance with the applied antigen in the DTH challenge. We observed a direct correlation between the presence of DC vaccine-related T cells in the DTH biopsies of stage IV melanoma patients and a positive clinical outcome (P = .0012). These findings demonstrate the potency of this novel approach in the monitoring of vaccination studies in cancer patients.
The chemotherapeutic drug oxaliplatin differentially affects blood DC function dependent on environmental cues
Publisher: Springer Science and Business Media LLC
Date: 23-12-2011
PD-L2 is predominantly expressed by Th2 cells
Publisher: Elsevier BV
Date: 10-2011
DOI: 10.1016/J.MOLIMM.2011.09.014
Abstract: In response to a recently published article by Messal et al. (2011) in which the authors show that PD-L2 is expressed by activated T cells and ligation results in suppression of T cell proliferation and cytokine secretion, we here report that PD-L2 is differentially expressed by the erse Th subsets, with predominant expression by Th2 cells.
Route of Administration Modulates the Induction of Dendritic Cell Vaccine–Induced Antigen-Specific T Cells in Advanced Melanoma Patients
Publisher: American Association for Cancer Research (AACR)
Date: 09-2011
DOI: 10.1158/1078-0432.CCR-11-1261
Abstract: Purpose: It is unknown whether the route of administration influences dendritic cell (DC)-based immunotherapy. We compared the effect of intradermal versus intranodal administration of a DC vaccine on induction of immunologic responses in melanoma patients and examined whether concomitant administration of interleukin (IL)-2 increases the efficacy of the DC vaccine. Experimental Design: HLA-A2.1+ melanoma patients scheduled for regional lymph node dissection were vaccinated four times biweekly via intradermal or intranodal injection with 12 × 106 to 17 × 106 mature DCs loaded with tyrosinase and gp100 peptides together with keyhole limpet hemocyanin (KLH). Half of the patients also received low-dose IL-2 (9 MIU daily for 7 days starting 3 days after each vaccination). KLH-specific B- and T-cell responses were monitored in blood. gp100- and tyrosinase-specific T-cell responses were monitored in blood by tetramer analysis and in biopsies from delayed-type hypersensitivity (DTH) skin tests by tetramer and functional analyses with 51Cr release assays or IFNγ release, following coculture with peptide-pulsed T2 cells or gp100- or tyrosinase-expressing tumor cells. Results: In 19 of 43 vaccinated patients, functional tumor antigen–specific T cells could be detected. Although significantly more DCs migrated to adjacent lymph nodes upon intranodal vaccination, this was also highly variable with a complete absence of migration in 7 of 24 intranodally vaccinated patients. Intradermal vaccinations proved superior in inducing functional tumor antigen–specific T cells. Coadministration of IL-2 did not further augment the antigen-specific T-cell response but did result in higher regulatory T-cell frequencies. Conclusion: Intradermal vaccination resulted in superior antitumor T-cell induction when compared with intranodal vaccination. No advantage of additional IL-2 treatment could be shown. Clin Cancer Res 17(17) 5725–35. ©2011 AACR.
Isolated acral dermatitis due to graft‐versus‐host disease
Publisher: Wiley
Date: 19-02-2009
EBV-related lymphoproliferative disorders in immunocompetent patients
Publisher: Springer Science and Business Media LLC
Date: 02-10-2003
Dexamethasone differentially depletes tumour and peripheral blood lymphocytes and can impact the efficacy of chemotherapy/checkpoint blockade combination treatment
Publisher: Informa UK Limited
Date: 13-07-2019
Platinum-based drugs disrupt STAT6-mediated suppression of immune responses against cancer in humans and mice
Publisher: American Society for Clinical Investigation
Date: 08-2011
DOI: 10.1172/JCI43656
Immune Stimulatory Features of Classical Chemotherapy
Publisher: Elsevier
Date: 2007
Combining chemotherapy and checkpoint blockade in thoracic cancer: how to proceed?
Publisher: Future Medicine Ltd
Date: 12-2014
DOI: 10.2217/LMT.14.37
Abstract: SUMMARY Given the impressive efficacy of immune checkpoint blockade in thoracic malignancies, and the recently discovered immune-stimulating properties of many cytotoxic drugs, a logical next step would be to combine these treatments. However, the rational design of clinical trials investigating these combinations is h ered by a lack of knowledge regarding the overall immunogenic effects of the different chemotherapeutics. Here, we give an overview of the field with regard to checkpoint blockade and the immunological effects of cytotoxic chemotherapeutics, with particular focus on preclinical and clinical studies investigating the combination of these two treatment modalities. We discuss the hurdles that need to be overcome in order to optimally exploit chemotherapy and immune checkpoint blockade combinations in thoracic cancers.
Skin-Test Infiltrating Lymphocytes Early Predict Clinical Outcome of Dendritic Cell–Based Vaccination in Metastatic Melanoma
Publisher: American Association for Cancer Research (AACR)
Date: 29-11-2012
DOI: 10.1158/0008-5472.CAN-12-2479
Abstract: The identification of responding patients early during treatment would improve the capability to develop effective new immunotherapies more rapidly. Here, we describe a bioassay that may link early T-cell–mediated immune responses to later clinical benefits. This bioassay rests upon the tenet of immunotherapy that tumor-specific effector T cells capable of invading peripheral tissue can recognize tumor antigens and exert cytotoxic functions there. To show its utility, we conducted a retrospective study of a large cohort of metastatic melanoma patients (n = 91) enrolled in dendritic cell (DC)-based vaccination protocols to examine a hypothesized correlation of posttreatment skin-infiltrating lymphocytes (SKIL) with overall survival (OS). Stringent immunologic criteria were defined to identify long-term survivors. The presence of tumor-associated antigen (TAA)-specific CD8+ T cell populations within SKILs (criterion I) was highly predictive for long-term survival. Further restriction by selecting for the presence of TAA-specific CD8+ T cells specifically recognizing tumor peptide (criterion II) was also associated with improved OS. Recognition of naturally processed antigen (criterion III) maximized the accuracy of the test, with a median OS of 24.1 versus 9.9 months (P = 0.001). Our results show that detailed characterization of SKILs can permit an accurate selection of metastatic melanoma patients who benefit most from DC-based vaccination. This simple and robust bioassay integrates multiple aspects of cellular functions that mediate effective immune responses, thereby offering an effective tool to rapidly identify patients who are responding to immunotherapy at an early stage of treatment. Cancer Res 72(23) 6102–10. ©2012 AACR.
Acute arterial occlusion after chemotherapy for testicular cancer
Publisher: Elsevier BV
Date: 11-2005
Combination immune checkpoint blockade as an effective therapy for mesothelioma
Publisher: Informa UK Limited
Date: 30-07-2018
Transient Treg depletion enhances therapeutic anti‐cancer vaccination
Publisher: Wiley
Date: 21-11-2016
DOI: 10.1002/IID3.136
Synergistic Effect of CTLA-4 Blockade and Cancer Chemotherapy in the Induction of Anti-Tumor Immunity
Publisher: Public Library of Science (PLoS)
Date: 23-04-2013
STATing the importance of immune modulation by platinum chemotherapeutics
Publisher: Informa UK Limited
Date: 03-2012
Strong spontaneous tumor neoantigen responses induced by a natural human carcinogen
Publisher: Informa UK Limited
Date: 11-05-2015
Recovery of symptomatic extravasation of liposomal doxorubicin after dexrazoxane treatment
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2012
Malignant Pleural Effusions—A Window Into Local Anti-Tumor T Cell Immunity?
Publisher: Frontiers Media SA
Date: 27-04-2021
Abstract: 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. Malignant pleural effusions (MPE) associated with thoracic cancers are an abnormal accumulation of fluid in the pleural space that is routinely drained for patient symptom control. This fluid contains tumor cells and immune cells, including lymphocytes, macrophages and dendritic cells, providing a window into the local tumor microenvironment. Recurrent MPE is common, and provides an opportunity for longitudinal analysis of the tumor site in a clinical setting. Here, we review the phenotype of MPE-derived T cells, comparing them to tumor and blood T cells. We discuss the benefits and limitations of their use as potential dynamic biomarkers of response to therapy.
Comprehensive Testing of Chemotherapy and Immune Checkpoint Blockade in Preclinical Cancer Models Identifies Additive Combinations
Publisher: Frontiers Media SA
Date: 11-05-2022
DOI: 10.3389/FIMMU.2022.872295
Abstract: 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. We investigated 10 chemotherapies from the main canonical classes dosed at the clinically relevant maximum tolerated dose in combination with anti‐CTLA-4/anti-PD-L1 ICB. We screened these chemo-immunotherapy combinations in two murine mesothelioma models from two different genetic backgrounds, and identified chemotherapies that produced additive, neutral or antagonistic effects when combined with ICB. Using flow cytometry and bulk RNAseq, we characterized the tumor immune milieu in additive chemo-immunotherapy combinations. 5-fluorouracil (5-FU) or cisplatin were additive when combined with ICB while vinorelbine and etoposide provided no additional benefit when combined with ICB. The combination of 5-FU with ICB augmented an inflammatory tumor microenvironment with markedly increased CD8 + T cell activation and upregulation of IFNγ, TNFα and IL-1β signaling. The effective anti‐tumor immune response of 5-FU chemo-immunotherapy was dependent on CD8 + T cells but was unaffected when TNFα or IL-1β cytokine signaling pathways were blocked. Our study identified additive and non-additive chemotherapy/ICB combinations and suggests a possible role for increased inflammation in the tumor microenvironment as a basis for effective combination therapy.
Acute generalised exanthematous pustulosis mimicking septic shock
Publisher: Elsevier BV
Date: 04-2004
Dendritic cell vaccines in melanoma: From promise to proof?
Publisher: Elsevier BV
Date: 05-2008
DOI: 10.1016/J.CRITREVONC.2007.12.007
Abstract: Dendritic cells (DC) are the directors of the immune system, capable of inducing tumour antigen-specific T- and B-cell responses. As such, they are currently applied in clinical studies in cancer patients. Early small clinical trials showed promising results, with frequent induction of anti-cancer immune reactivity and clinical responses. In recent years, additional trials have been carried out in melanoma patients, and although immunological responses are often reported, objective clinical responses remain anecdotal with objective response rates not exceeding 5-10%. Thus, DC vaccination research has now entered a stage in between 'proof of principle' and 'proof of efficacy' trials. Crucial questions to answer at this moment are why the clinical responses remain scarce and what can be done to improve the efficacy of vaccination. The answers to these questions probably lie in the preparation and administration of the DC vaccines. Predominantly, cytokine-matured DC are used in clinical studies, while from preclinical studies it is evident that DC that are activated by pathogen-associated molecules are much more potent T cell activators. For sake of easy accessibility monocyte-derived DC are often used, but are these cells also the most potent type of DC? Other yet unsettled issues include the optimal antigen-loading strategy and route of administration. In addition, trials are needed to investigate the value of manipulating tolerizing mechanisms, such as depletion of regulatory T cells or blockade of the inhibitory T cell molecule CTLA-4. These issues need to be addressed in well-designed comparative clinical studies with biological endpoints in order to determine the optimal vaccine characteristics. DC vaccination can then be put to the ultimate test of randomized clinical trials. Here, we review the immunobiology of DC with emphasis on the different aspects that are most relevant for the induction of anti-tumour responses in vivo. The different variables in preparing and administering DC vaccines are discussed in this context and the immunological and clinical results of studies with DC vaccines in melanoma patients are summarized.
Functional genomics in cancer immunotherapy
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C9ME00029A
Abstract: A hitchhiker's guide to biomarker discovery in immune checkpoint blockade.
Bilateral murine tumor models for characterizing the response to immune checkpoint blockade
Publisher: Springer Science and Business Media LLC
Date: 04-2020
DOI: 10.1038/S41596-020-0299-3
Abstract: The therapeutic response to immune checkpoint blockade (ICB) is highly variable, not only between different cancers but also between patients with the same cancer type. The biological mechanisms underlying these differences in response are incompletely understood. Identifying correlates in patient tumor s les is challenging because of genetic and environmental variability. Murine studies usually compare different tumor models or treatments, introducing potential confounding variables. This protocol describes bilateral murine tumor models, derived from syngeneic cancer cell lines, that display a symmetrical yet dichotomous response to ICB. These models enable detailed analysis of whole tumors in a highly homogeneous background, combined with knowledge of the therapeutic outcome within a few weeks, and could potentially be used for mechanistic studies using other (immuno-)therapies. We discuss key considerations and describe how to use two cell lines as fully optimized models. We discuss experimental details, including proper inoculation technique to achieve symmetry and one-sided surgical tumor removal, which takes only 5 min per mouse. Furthermore, we outline the preparation of bulk tissue or single-cell suspensions for downstream analyses such as bulk RNA-seq, immunohistochemistry, single-cell RNA-seq and flow cytometry.
New directions in mesothelioma treatment
Publisher: Future Medicine Ltd
Date: 12-2015
DOI: 10.2217/LMT.15.32
Abstract: For most patients with mesothelioma, symptom control and palliative chemotherapy are mainstays of care. First-line cisplatin emetrexed chemotherapy has demonstrated survival and quality-of-life benefits. A randomized controlled trial adding bevacizumab to cisplatin and pemetrexed recently reported improved survival and time to progression, and may constitute a new standard of care where economically viable. Immunotherapy is under active investigation and positive results have been reported from single-arm studies of the anti-CTLA4 antibody tremelimumab the anti-PD-1 antibody pembrolizumab and mesothelin-targeting strategies. Symptom control remains critical for patient well-being, and includes management of pleural effusion, analgesia, treatment of symptomatic masses and management of systemic symptoms. There is increasing evidence that tunneled pleural catheters are preferred over talc pleurodesis for recurrent pleural effusion.
Sensitizing the Tumor Microenvironment to Immune Checkpoint Therapy
Publisher: Frontiers Media SA
Date: 18-02-2020
Neoadjuvant anti-tumor vaccination prior to surgery enhances survival
Publisher: Springer Science and Business Media LLC
Date: 04-09-2014
Mouse models of mesothelioma: Strengths, limitations and clinical translation
Publisher: Future Medicine Ltd
Date: 10-2014
DOI: 10.2217/LMT.14.27
Abstract: SUMMARY Mouse models of cancer are invaluable for obtaining detailed knowledge about tumor development and for screening therapeutic and preventive approaches. Mesothelioma is an unusual cancer because the same carcinogen, asbestos, causes a similar disease in both humans and animals. Unlike most other cancers, murine mesothelioma can therefore be regarded as a disease homolog, rather than a model as such. However, because asbestos-induced cancer has low penetrance and a long lag time, most translational studies have utilized more efficient models such as tumor transplantation. In consequence, many promising results have not translated into positive findings in patients. Here, we describe the widely used murine mesothelioma models and critically discuss their relative advantages and disadvantages. We emphasize the use of the appropriate model for the specific research question and the need to use multiple models in order to obtain robust and translatable data.
Network analysis of immunotherapy-induced regressing tumours identifies novel synergistic drug combinations
Publisher: Springer Science and Business Media LLC
Date: 21-07-2015
DOI: 10.1038/SREP12298
Abstract: Cancer immunotherapy has shown impressive results, but most patients do not respond. We hypothesized that the effector response in the tumour could be visualized as a complex network of interacting gene products and that by mapping this network we could predict effective pharmacological interventions. Here, we provide proof of concept for the validity of this approach in a murine mesothelioma model, which displays a dichotomous response to anti-CTLA4 immune checkpoint blockade. Network analysis of gene expression profiling data from responding versus non-responding tumours was employed to identify modules associated with response. Targeting the modules via selective modulation of hub genes or alternatively by using repurposed pharmaceuticals selected on the basis of their expression perturbation signatures dramatically enhanced the efficacy of CTLA4 blockade in this model. Our approach provides a powerful platform to repurpose drugs and define contextually relevant novel therapeutic targets.
A systematic investigation of the maximum tolerated dose of cytotoxic chemotherapy with and without supportive care in mice
Publisher: Springer Science and Business Media LLC
Date: 16-10-2017
Dendritic cell-based vaccines in cancer immunotherapy: an update on clinical and immunological results
Publisher: Elsevier BV
Date: 10-2004
Esophageal Adenocarcinoma Cells and Xenograft Tumors Exposed to Erb-b2 Receptor Tyrosine Kinase 2 and 3 Inhibitors Activate Transforming Growth Factor Beta Signaling, Which Induces Epithelial to Mesen
Publisher: Elsevier BV
Date: 07-2017
DOI: 10.1053/J.GASTRO.2017.03.004
Abstract: Drugs that inhibit the erb-b2 receptor tyrosine kinase 2 (ERBB2 or HER2) are the standard treatment of patients with different types of cancer, including HER2-overexpressing gastroesophageal tumors. Unfortunately, cancer cells become resistant to these drugs, so overall these drugs provide little benefit to patients with these tumors. We investigated mechanisms that mediate resistance of esophageal adenocarcinoma (EAC) cells and patient-derived xenograft tumors to ERBB inhibitors. We cultured primary tumor cells, isolated from EAC patient s les, and OE19 and OE33 EAC cell lines with trastuzumab (an inhibitor of HER2), with or without pertuzumab (which inhibits dimerization of HER2 with HER3) or a specific antibody against HER3 (anti-HER3). HER2 was knocked down by expression of small hairpin RNAs. In addition, cells were incubated with NRG1-β, a mediator of HER2-HER3 signaling, or A83-01, an inhibitor of transforming growth factor beta (TGFβ) signaling. Cells were analyzed for markers of the epithelial to mesenchymal transition (EMT) using flow cytometry, immunofluorescence, and quantitative reverse transcription polymerase chain reaction. We performed limiting dilution, transwell, and cell viability assays to study the functional effects of HER2 and HER3 inhibition and reactivation. We analyzed publicly available EAC gene expression datasets to correlate expression of ERBB genes with genes encoding epithelial and mesenchymal proteins. NOD.Cg-Prkdc EAC cells incubated with trastuzumab decreased expression of epithelial markers (CD24, CD29, and CDH1) and increased expression of mesenchymal markers (CXCR4, VIM, ZEB1, SNAI2, and CDH2), compared with cells not exposed to trastuzumab, indicating induction of EMT. Addition of NRG1-β to these cells restored their epithelial phenotype. Incubation of EAC cells with trastuzumab and pertuzumab accelerated the expression of EMT markers, compared with cells incubated with trastuzumab alone. EAC cells cultured for 2 months with a combination of trastuzumab and pertuzumab became resistant to chemotherapeutic agents (5-fluoruracil, carboplatin, cisplatin, eribulin, and paclitaxel), based on their continued viability, which was accompanied with an enhanced migratory capacity in transwell assays and clonogenicity in limiting dilution analyses. In comparisons of EAC gene expression patterns, we associated high expression of ERBB3 with an epithelial gene expression signature expression of TGFβ correlated with expression of EMT-related genes, and we found an inverse correlation between expression of TGFB1 and ERBB3. EAC cells incubated with ERBB inhibitors began to secrete ligands for the TGFβ receptor and underwent EMT. Incubation of EAC cells with trastuzumab, followed by 10 days of incubation with the TGFβ receptor inhibitor in the presence of trastuzumab, caused cells to regain an epithelial phenotype. EAC patient-derived xenograft tumors grew more slowly in mice given the combination of trastuzumab, pertuzumab, and the TGFβ inhibitor than in mice given single agents or a combination of trastuzumab and pertuzumab. Tumors exposed to trastuzumab and pertuzumab expressed EMT markers and were poorly differentiated, whereas tumors exposed to the combination of trastuzumab, pertuzumab, and the TGFβ inhibitor expressed epithelial markers and were more differentiated. EAC cells become resistant to trastuzumab and pertuzumab by activating TGFβ signaling, which induces EMT. Agents that block TGFβ signaling can increase the anti-tumor efficacies of trastuzumab and pertuzumab.
Autologous monocyte-derived DC vaccination combined with cisplatin in stage III and IV melanoma patients: a prospective, randomized phase 2 trial
Publisher: Springer Science and Business Media LLC
Date: 24-01-2020
DOI: 10.1007/S00262-019-02466-X
Abstract: Autologous dendritic cell (DC) vaccines can induce tumor-specific T cells, but their effect can be counteracted by immunosuppressive mechanisms. Cisplatin has shown immunomodulatory effects in vivo which may enhance efficacy of DC vaccination. This is a prospective, randomized, open-label phase 2 study (NCT02285413) including stage III and IV melanoma patients receiving 3 biweekly vaccinations of gp100 and tyrosinase mRNA-loaded monocyte-derived DCs with or without cisplatin. Primary objectives were to study immunogenicity and feasibility, and secondary objectives were to assess toxicity and survival. Twenty-two stage III and 32 stage IV melanoma patients were analyzed. Antigen-specific CD8 + T cells were found in 44% versus 67% and functional T cell responses in 28% versus 19% of skin-test infiltrating lymphocytes in patients receiving DC vaccination with and without cisplatin, respectively. Four patients stopped cisplatin because of toxicity and continued DC monotherapy. No therapy-related grade 3 or 4 adverse events occurred due to DC monotherapy. During combination therapy, one therapy-related grade 3 adverse event, decompensated heart failure due to fluid overload, occurred. The clinical outcome parameters did not clearly suggest significant differences. Combination of DC vaccination and cisplatin in melanoma patients is feasible and safe, but does not seem to result in more tumor-specific T cell responses or improved clinical outcome, when compared to DC vaccination monotherapy.
Characteristics of TCR Repertoire Associated With Successful Immune Checkpoint Therapy Responses
Publisher: Frontiers Media SA
Date: 14-10-2020
A pilot study on the immunogenicity of dendritic cell vaccination during adjuvant oxaliplatin/capecitabine chemotherapy in colon cancer patients
Publisher: Springer Science and Business Media LLC
Date: 10-2010
Cancer immunotherapy – revisited
Publisher: Springer Science and Business Media LLC
Date: 08-2011
DOI: 10.1038/NRD3500
Abstract: Our insight into antitumour immune responses has increased considerably during the past decades, yet the development of immunotherapy as a treatment modality for cancer has been h ered by several factors. These include difficulties in the selection of the optimal dose and schedule, the methods of evaluation, and financial support. Although durable clinical remissions have been observed with various immunotherapeutic strategies, the percentage of patients who benefited from these interventions has remained too small to justify the general use of such strategies. However, the recent positive results of clinical trials with novel immunoactive drugs as well as the unexpected finding of a positive interaction between immunotherapy and chemotherapy may herald a new era for the immunotherapy of cancer.
Dynamic versus static biomarkers in cancer immune checkpoint blockade
Publisher: Springer Science and Business Media LLC
Date: 06-01-2017
DOI: 10.1038/NRD.2016.233
Abstract: Recently, there has been a coordinated effort from academic institutions and the pharmaceutical industry to identify biomarkers that can predict responses to immune checkpoint blockade in cancer. Several biomarkers have been identified however, none has reliably predicted response in a sufficiently rigorous manner for routine use. Here, we argue that the therapeutic response to immune checkpoint blockade is a critical state transition of a complex system. Such systems are highly sensitive to initial conditions, and critical transitions are notoriously difficult to predict far in advance. Nevertheless, warning signals can be detected closer to the tipping point. Advances in mathematics and network biology are starting to make it possible to identify such warning signals. We propose that these dynamic biomarkers could prove to be useful in distinguishing responding from non-responding patients, as well as facilitate the identification of new therapeutic targets for combination therapy.
A Mouse Model of Incompletely Resected Soft Tissue Sarcoma for Testing (Neo)adjuvant Therapies
Publisher: MyJove Corporation
Date: 28-07-2020
DOI: 10.3791/60882
A surgically optimized intraoperative poly(I:C)-releasing hydrogel prevents cancer recurrence
Publisher: Elsevier BV
Date: 07-2023
PPARα and PPARγ activation is associated with pleural mesothelioma invasion but therapeutic inhibition is ineffective
Publisher: Elsevier BV
Date: 2022
A tipping point in cancer-immune dynamics leads to divergent immunotherapy responses and hampers biomarker discovery
Publisher: BMJ
Date: 05-2021
Abstract: 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. A computational modeling approach based on ordinary differential equations was used to simulate the fundamental mechanisms that dictate tumor-immune dynamics and to investigate its implications on responses to immune checkpoint inhibition (ICI) and patient survival. Using in silico biomarker discovery trials, we revealed fundamental principles that explain the erging success rates of biomarker discovery programs. Our model shows that a tipping point—a sharp state transition between immune control and immune evasion—induces a strongly non-linear relationship between patient survival and both immunological and tumor-related parameters. In patients close to the tipping point, ICI therapy may lead to long-lasting survival benefits, whereas patients far from the tipping point may fail to benefit from these potent treatments. These findings have two important implications for clinical oncology. First, the apparent conundrum that ICI induces substantial benefits in some patients yet completely fails in others could be, to a large extent, explained by the presence of a tipping point. Second, predictive biomarkers for immunotherapy should ideally combine both immunological and tumor-related markers, as a patient’s distance from the tipping point can typically not be reliably determined from solely one of these. The notion of a tipping point in cancer-immune dynamics helps to devise more accurate strategies to select appropriate treatments for patients with cancer.
Protocol of DREAM3R
Publisher: BMJ
Date: 2022
DOI: 10.1136/BMJOPEN-2021-057663
Abstract: There is a strong theoretical rationale for combining checkpoint blockade with cytotoxic chemotherapy in pleural mesothelioma and other cancers. Two recent single-arm, phase 2 trials [DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma (DREAM) and Phase II multicenter study of anti-PD-L1, durvalumab, in combination with cisplatin and pemetrexed for the first-line treatment of unresectable malignant pleural mesothelioma (PrE0505)] combining the programmed death ligand-1 (PD-L1) inhibitor durvalumab with standard first-line chemotherapy exceeded prespecified safety and activity criteria to proceed to a phase 3 confirmatory trial to assess this combination. We present the protocol of the DREAM3R trial. This multicentre open-label randomised trial will recruit 480 treatment-naïve adults with advanced pleural mesothelioma, randomised (2:1) to either 3-weekly durvalumab 1500 mg plus 3-weekly doublet chemotherapy (cisplatin 75 mg/m 2 or carboplatin, Area Under the Curve,AUC 5 and pemetrexed 500 mg/m 2 ) 4–6 cycles, followed by 4-weekly durvalumab 1500 mg until disease progression, unacceptable toxicity or patient withdrawal OR doublet chemotherapy alone for 4–6 cycles, followed by observation. The target accrual time is 27 months, with follow-up for an additional 24 months. This provides over 85% power if the true HR for overall survival (OS) is 0.70, with two-sided alpha of 0.05, assuming a median OS of 15 months in the control group. Randomisation is stratified by age (18–70 years vs ), sex, histology (epithelioid vs non-epithelioid), platinum agent (cisplatin vs carboplatin) and region (USA vs Australia/New Zealand vs Other). The primary endpoint is OS. Secondary endpoints include progression-free survival, objective tumour response (by mRECIST V.1.1 and iRECIST), adverse events, health-related quality of life and healthcare resource use. Tertiary correlative objectives are to explore and validate potential prognostic and/or predictive biomarkers (including features identified in the DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma (DREAM) and PrE0505 studies, PD-L1 expression, tumour mutational burden, genomic characteristics and human leukocyte antigen subtypes) in tissue and serial blood s les. An imaging databank will be assembled for validation of radiological measures of response, and studies of possible radiomic biomarkers in mesothelioma. The protocol was approved by human research ethics review committees for all participating sites. Results will be disseminated in peer-reviewed journals and at scientific conferences. AstraZeneca. CTC 0231 / TOGA 18/001 / PrE0506 3.0, 29 July 2021. ClinicalTrials.gov Identifier: NCT04334759 ACTRN 12620001199909.
Favorable overall survival in stage III melanoma patients after adjuvant dendritic cell vaccination
Publisher: Informa UK Limited
Date: 05-06-2015
Colitis in an alcohol-dependent woman
Publisher: Elsevier BV
Date: 06-2007
Tumor infiltrating effector memory Antigen-Specific CD8+ T Cells predict response to immune checkpoint therapy
Publisher: Frontiers Media SA
Date: 12-11-2020
Targeting CD4+ T-Helper Cells Improves the Induction of Antitumor Responses in Dendritic Cell–Based Vaccination
Publisher: American Association for Cancer Research (AACR)
Date: 2013
DOI: 10.1158/0008-5472.CAN-12-1127
Abstract: To evaluate the relevance of directing antigen-specific CD4+ T helper cells as part of effective anticancer immunotherapy, we investigated the immunologic and clinical responses to vaccination with dendritic cells (DC) pulsed with either MHC class I (MHC-I)–restricted epitopes alone or both MHC class I and II (MHC-I/II)–restricted epitopes. We enrolled 33 stage III and IV HLA-A*02:01–positive patients with melanoma in this study, of whom 29 were evaluable for immunologic response. Patients received intranodal vaccinations with cytokine-matured DCs loaded with keyhole limpet hemocyanin and MHC-I alone or MHC-I/II–restricted tumor-associated antigens (TAA) of tyrosinase and gp100, depending on their HLA-DR4 status. In 4 of 15 patients vaccinated with MHC-I/II–loaded DCs and 1 of 14 patients vaccinated with MHC-I–loaded DCs, we detected TAA-specific CD8+ T cells with maintained IFN-γ production in skin test infiltrating lymphocyte (SKIL) cultures and circulating TAA-specific CD8+ T cells. If TAA-specific CD4+ T-cell responses were detected in SKIL cultures, it coincided with TAA-specific CD8+ T-cell responses. In 3 of 13 patients tested, we detected TAA-specific CD4+CD25+FoxP3− T cells with high proliferative capacity and IFN-γ production, indicating that these were not regulatory T cells. Vaccination with MHC-I/II–loaded DCs resulted in improved clinical outcome compared with matched control patients treated with dacarbazine (DTIC), median overall survival of 15.0 versus 8.3 months (P = 0.089), and median progression-free survival of 5.0 versus 2.8 months (P = 0.0089). In conclusion, coactivating TAA-specific CD4+ T-helper cells with DCs pulsed with both MHC class I and II–restricted epitopes augments TAA-specific CD8+ T-cell responses, contributing to improved clinical responses. Cancer Res 73(1) 19–29. ©2012 AACR.
Vaccination of colorectal cancer patients with CEA-loaded dendritic cells: antigen-specific T cell responses in DTH skin tests
Publisher: Elsevier BV
Date: 06-2006
Abstract: Dendritic cells (DCs) are the professional antigen-presenting cells of the immune system. As such they are currently used in clinical vaccination protocols in cancer patients. We evaluated the ability of mature DCs pulsed with carcinoembryonic antigen (CEA)-peptide to induce CEA-specific T cell responses in patients with resectable liver metastases from colorectal cancer. CEA-specific T cell reactivity was monitored in peripheral blood, biopsies of vaccination sites and post-treatment DTH skin tests, and when available also in resected abdominal lymph nodes and tumor tissue. Ten patients were vaccinated intradermally and intravenously with CEA-peptide pulsed mature DCs three times prior to resection of liver metastases. High numbers of CEA-specific T cells were detected in post-treatment DTH biopsies in seven out of 10 patients, which produced high amounts of interferon (IFN)-gamma upon stimulation with CEA-loaded target cells. These responses were not found in biopsies of first vaccination sites, indicating a de novo T cell induction or at least a strong potentiation by the vaccine. In addition, CEA-specific T cells were detected in a resected lymph node in one patient, but not in peripheral blood or tumor tissue. Vaccination with CEA-peptide loaded mature DCs induced potent CEA-specific T cell responses in advanced colorectal cancer patients. In this study, antigen-specific T cell responses were readily detected in DTH skin tests, much less in abdominal lymph nodes, and not in peripheral blood and tumor tissue.
Molecular Pathways: The Immunogenic Effects of Platinum-Based Chemotherapeutics
Publisher: American Association for Cancer Research (AACR)
Date: 29-05-2014
DOI: 10.1158/1078-0432.CCR-13-3141
Abstract: The platinum-based drugs cisplatin, carboplatin, and oxaliplatin belong to the most widely used chemotherapeutics in oncology, showing clinical efficacy against many solid tumors. Their main mechanism of action is believed to be the induction of cancer cell apoptosis as a response to their covalent binding to DNA. In recent years, this picture has increased in complexity, based on studies indicating that cellular molecules other than DNA may potentially act as targets, and that part of the antitumor effects of platinum drugs occurs through modulation of the immune system. These immunogenic effects include modulation of STAT signaling induction of an immunogenic type of cancer cell death through exposure of calreticulin and release of ATP and high-mobility group protein box-1 (HMGB-1) and enhancement of the effector immune response through modulation of programmed death receptor 1-ligand and mannose-6-phosphate receptor expression. Both basic and clinical studies indicate that at least part of the antitumor efficacy of platinum chemotherapeutics may be due to immune potentiating mechanisms. Clinical studies exploiting this novel mechanism of action of these old cancer drugs have been initiated. Here, we review the literature on the immunogenic effects of platinum, summarize the clinical advances using platinum as a cytotoxic compound with immune adjuvant properties, and discuss the limitations to these studies and the gaps in our understanding of the immunologic effects of these drugs. Clin Cancer Res 20(11) 2831–7. ©2014 AACR.
Comment on “Drug Discovery: Turning the Titanic”
Publisher: American Association for the Advancement of Science (AAAS)
Date: 26-03-2014
DOI: 10.1126/SCITRANSLMED.3008763
Abstract: Molecular and cellular events that govern a disease resolution may pinpoint new druggable pathways.
Chemoimmunotherapy: still waiting for the magic to happen
Publisher: Elsevier BV
Date: 07-2014
Dendritic cell immunotherapy: mapping the way
Publisher: Springer Science and Business Media LLC
Date: 30-04-2004
DOI: 10.1038/NM1039
Geldanamycin treatment does not result in anti-cancer activity in a preclinical model of orthotopic mesothelioma
Publisher: Public Library of Science (PLoS)
Date: 05-05-2023
DOI: 10.1371/JOURNAL.PONE.0274364
Abstract: 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 s les. Invasive pleural tumours were characterised by a transcriptomic signature enriched for genes associated with MEF2C and MYOCD signaling, muscle differentiation and myogenesis. Further analysis using the CMap and LINCS databases identified geldanamycin as a potential antagonist of this signature, so we evaluated its potential in vitro and in vivo . Nanomolar concentrations of geldanamycin significantly reduced cell growth, invasion, and migration in vitro . However, administration of geldanamycin in vivo did not result in significant anti-cancer activity. Our findings show that myogenesis and muscle differentiation pathways are upregulated in pleural mesothelioma which may be related to the invasive behaviour. However, geldanamycin as a single agent does not appear to be a viable treatment for mesothelioma.
Immune Stimulatory Features of Classical Chemotherapy
Publisher: Elsevier
Date: 2013
Dendritic Cell Vaccination in Combination with Anti-CD25 Monoclonal Antibody Treatment: A Phase I/II Study in Metastatic Melanoma Patients
Publisher: American Association for Cancer Research (AACR)
Date: 13-10-2010
DOI: 10.1158/1078-0432.CCR-10-1757
Abstract: Purpose: The success of cancer immunotherapy depends on the balance between effector T cells and suppressive immune regulatory mechanisms within the tumor microenvironment. In this study we investigated whether transient monoclonal antibody–mediated depletion of CD25high regulatory T cells (Treg) is capable of enhancing the immunostimulatory efficacy of dendritic cell vaccines. Experimental Design: Thirty HLA-A2.1+ metastatic melanoma patients were vaccinated with mature dendritic cells pulsed with tumor peptide and keyhole limpet hemocyanin (KLH). Half of the patients were pretreated with daclizumab, a humanized antibody against the interleukin-2 (IL-2) receptor α-chain (CD25), either four or eight days before dendritic cell vaccinations. Clinical and immunologic parameters were determined. Results: Daclizumab efficiently depleted all CD25high immune cells, including CD4+FoxP3+CD25high cells, from the peripheral blood within four days of administration. Thirty days after administration, daclizumab was cleared from the circulation and all CD25+ cells reappeared. The presence of daclizumab during dendritic cell vaccinations prevented the induction of specific antibodies in vivo but not the presence of antigen-specific T cells. Daclizumab, however, did prevent these CD25+ T cells from acquiring effector functions. Consequently, significantly less patients pretreated with daclizumab developed functional, vaccine-specific effector T cells and antibodies compared with controls. Daclizumab pretreatment had no significant effect on progression-free survival compared with the control group. Conclusions: Although daclizumab depleted the CD4+FoxP3+CD25high Tregs from the peripheral circulation, it did not enhance the efficacy of the dendritic cell vaccine. Residual daclizumab functionally suppressed de novo induced CD25+ effector cells during dendritic cell vaccinations. Our results indicate that for immunotherapeutic benefit of transient Treg depletion, timing and dosing as well as Treg specificity are extremely important. Clin Cancer Res 16(20) 5067–78. ©2010 AACR.
Wild-type and modified gp100 peptide-pulsed dendritic cell vaccination of advanced melanoma patients can lead to long-term clinical responses independent of the peptide used
Publisher: Springer Science and Business Media LLC
Date: 11-11-2010
DOI: 10.1007/S00262-010-0942-X
Abstract: Dendritic cell (DC)-based immunotherapy is explored worldwide in cancer patients. Several strategies have been employed to load DC with antigen, including peptide loading. To increase immunogenicity of peptides, major histocompatibility complex (MHC) class I binding affinity and stability of peptide-MHC complexes at the cell surface may be improved by modification of the amino acid sequence. In this study, we compared the capacity of DC loaded with wild-type versus modified gp100 peptides with higher binding affinities to induce an immune and clinical response in advanced melanoma patients. Metastatic HLA-A2.1(+) melanoma patients were vaccinated intravenously (on average 25 × 10(6) DC) and intradermally (on average 11 × 10(6) DC) with mature DC loaded with keyhole limpet hemocyanin (KLH) together with tyrosinase peptide and either wild-type (15 patients) or modified (12 patients) gp100 peptides. All vaccinated patients showed a pronounced proliferative T cell or humoral response against KLH. Gp100-specific T cell responses were monitored in post-treatment delayed type hypersensitivity (DTH) skin biopsies by tetramer and functional analysis. Antigen-specific T cells were found in 2 of 15 patients vaccinated with wild-type gp100-loaded DC, versus 1 of 12 patients vaccinated with modified peptide-loaded DC. These three patients also had the best clinical response, with long-term (>8 years) complete responses in two patients, one in each group. We conclude that vaccination with peptide-loaded DC can result in long-term clinical responses in a minority of metastatic melanoma patients, and that the use of modified as compared to wild-type gp100 peptides for DC loading does not result in a relevant enhanced immune responses.
In situ detection of antigen-specific T cells in cryo-sections using MHC class I tetramers after dendritic cell vaccination of melanoma patients
Publisher: Springer Science and Business Media LLC
Date: 18-04-2007
DOI: 10.1007/S00262-007-0304-5
Abstract: Application of tetrameric MHC class I-peptide complexes has significantly improved the monitoring of antigen-specific T cell immune responses in mouse models as well as in clinical studies. Especially MHC class I tetramer analysis of tumor-specific T cells in suspension or on thick vibratome sections from viable tissue has been proven extremely useful. Using the well-characterized mouse tyrosinase-related-protein-2 specific cytotoxic T cell (CTL) clone LP9, we now developed a method that allows for specific identification of T cells with MHC class I tetramers in 8 mum thick, chemically fixed cryosections. The protocol was validated in a murine influenza virus-infection model. Moreover, analysis of delayed type hypersensitivity (DTH) skin biopsies from melanoma patients vaccinated with peptide-loaded mature dendritic cells, revealed the presence and location of anti-tumor CTLs. The specificity of the CTLs detected in situ correlated with both the DTH challenge specificity and reactivity of cell suspensions derived from the same biopsies. Collectively, our data demonstrate that in situ MHC class I tetramer staining provides a valuable tool to reveal the presence and anatomical location of specific CTLs in frozen tissue following immune-based treatment strategies in cancer patients.
Chemotherapy and immunotherapy: Mapping the road ahead
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.COI.2015.12.003
Abstract: Cancer immunotherapy, and in particular checkpoint blockade, is now standard clinical care for a growing number of cancers. Cytotoxic drugs have been the primary weapon against cancer for a long time and have typically been understood because of their capacity to directly kill tumour cells. It is now clear that these drugs are potential partners for checkpoint blockade and different drugs can influence the immune response to cancer through a wide variety of mechanisms. Some of these relate to immunogenic cell death, whilst others relate to changes in antigen-presentation, tumour cell targeting, or depletion of immunosuppressive cells. Here, we review some recent advances in our understanding of the immunological changes associated with chemotherapy, discuss progress in combining chemotherapy with checkpoint blockade, and comment on the difficulties encountered in translating promising preclinical data into successful treatments for cancer patients.
A tipping point in cancer-immune dynamics leads to divergent immunotherapy responses and hampers biomarker discovery
Publisher: Cold Spring Harbor Laboratory
Date: 03-11-2020
DOI: 10.1101/2020.10.29.20222455
Abstract: 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. A computational modeling approach based on ordinary differential equations was used to simulate the fundamental mechanisms that dictate tumor-immune dynamics and to investigate its implications on responses to immune checkpoint inhibition (ICI) and patient survival. Using in silico biomarker discovery trials, we revealed fundamental principles that explain the erging success rates of biomarker discovery programs. Our model shows that a tipping point – a sharp state transition between immune control and immune evasion – induces a strongly non-linear relationship between patient survival and both immunological and tumor-related parameters. In patients close to the tipping point, ICI therapy may lead to long-lasting survival benefits, whereas patients far from the tipping point may fail to benefit from these potent treatments. These findings have two important implications for clinical oncology. First, the apparent conundrum that ICI induces substantial benefits in some patients yet completely fails in others could be, to a large extent, explained by the presence of a tipping point. Second, predictive biomarkers for immunotherapy should ideally combine both immunological and tumor-related markers, as a patient’s distance from the tipping point can typically not be reliably determined from solely one of these. The notion of a tipping point in cancer-immune dynamics helps to devise more accurate strategies to select appropriate treatments for cancer patients.
Related Organisations
University Of Amsterdam, Academic Medical Centre
Location: Netherlands
Related Funding Activities
Discovery Projects - Grant ID: DP180100718
Start Date: 2018
End Date: 12-2021
Amount: $461,218.00
Funder: Australian Research Council
View Funded Activity