Sir Peter MacCallum Department of Oncology - Research Publications
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ItemChallenges of PD-L1 testing in non-small cell lung cancer and beyond(AME PUBL CO, 2020-08-01)
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ItemNo Preview AvailableBlockade of the co-inhibitory molecule PD-1 unleashes ILC2-dependent antitumor immunity in melanoma(NATURE RESEARCH, 2021-06-07)Group 2 innate lymphoid cells (ILC2s) are essential to maintain tissue homeostasis. In cancer, ILC2s can harbor both pro-tumorigenic and anti-tumorigenic functions, but we know little about their underlying mechanisms or whether they could be clinically relevant or targeted to improve patient outcomes. Here, we found that high ILC2 infiltration in human melanoma was associated with a good clinical prognosis. ILC2s are critical producers of the cytokine granulocyte-macrophage colony-stimulating factor, which coordinates the recruitment and activation of eosinophils to enhance antitumor responses. Tumor-infiltrating ILC2s expressed programmed cell death protein-1, which limited their intratumoral accumulation, proliferation and antitumor effector functions. This inhibition could be overcome in vivo by combining interleukin-33-driven ILC2 activation with programmed cell death protein-1 blockade to significantly increase antitumor responses. Together, our results identified ILC2s as a critical immune cell type involved in melanoma immunity and revealed a potential synergistic approach to harness ILC2 function for antitumor immunotherapies.
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ItemChimeric Antigen Receptor T cell Therapy and the Immunosuppressive Tumor Microenvironment in Pediatric Sarcoma(MDPI, 2021-09-01)Sarcomas are a diverse group of bone and soft tissue tumors that account for over 10% of childhood cancers. Outcomes are particularly poor for children with refractory, relapsed, or metastatic disease. Chimeric antigen receptor T (CAR T) cells are an exciting form of adoptive cell therapy that potentially offers new hope for these children. In early trials, promising outcomes have been achieved in some pediatric patients with sarcoma. However, many children do not derive benefit despite significant expression of the targeted tumor antigen. The success of CAR T cell therapy in sarcomas and other solid tumors is limited by the immunosuppressive tumor microenvironment (TME). In this review, we provide an update of the CAR T cell therapies that are currently being tested in pediatric sarcoma clinical trials, including those targeting tumors that express HER2, NY-ESO, GD2, EGFR, GPC3, B7-H3, and MAGE-A4. We also outline promising new CAR T cells that are in pre-clinical development. Finally, we discuss strategies that are being used to overcome tumor-mediated immunosuppression in solid tumors; these strategies have the potential to improve clinical outcomes of CAR T cell therapy for children with sarcoma.
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ItemMelanoma brain metastases that progress on BRAF-MEK inhibitors demonstrate resistance to ipilimumab-nivolumab that is associated with the Innate PD-1 Resistance Signature (IPRES)(BMJ PUBLISHING GROUP, 2021-10-01)BACKGROUND: Melanoma brain metastases (MBMs) are a challenging clinical problem with high morbidity and mortality. Although first-line dabrafenib-trametinib and ipilimumab-nivolumab have similar intracranial response rates (50%-55%), central nervous system (CNS) resistance to BRAF-MEK inhibitors (BRAF-MEKi) usually occurs around 6 months, and durable responses are only seen with combination immunotherapy. We sought to investigate the utility of ipilimumab-nivolumab after MBM progression on BRAF-MEKi and identify mechanisms of resistance. METHODS: Patients who received first-line ipilimumab-nivolumab for MBMs or second/third line ipilimumab-nivolumab for intracranial metastases with BRAFV600 mutations with prior progression on BRAF-MEKi and MRI brain staging from March 1, 2015 to June 30, 2018 were included. Modified intracranial RECIST was used to assess response. Formalin-fixed paraffin-embedded samples of BRAFV600 mutant MBMs that were naïve to systemic treatment (n=18) or excised after progression on BRAF-MEKi (n=14) underwent whole transcriptome sequencing. Comparative analyses of MBMs naïve to systemic treatment versus BRAF-MEKi progression were performed. RESULTS: Twenty-five and 30 patients who received first and second/third line ipilimumab-nivolumab, were included respectively. Median sum of MBM diameters was 13 and 20.5 mm for the first and second/third line ipilimumab-nivolumab groups, respectively. Intracranial response rate was 75.0% (12/16), and median progression-free survival (PFS) was 41.6 months for first-line ipilimumab-nivolumab. Efficacy of second/third line ipilimumab-nivolumab after BRAF-MEKi progression was poor with an intracranial response rate of 4.8% (1/21) and median PFS of 1.3 months. Given the poor activity of ipilimumab-nivolumab after BRAF-MEKi MBM progression, we performed whole transcriptome sequencing to identify mechanisms of drug resistance. We identified a set of 178 differentially expressed genes (DEGs) between naïve and MBMs with progression on BRAF-MEKi treatment (p value <0.05, false discovery rate (FDR) <0.1). No distinct pathways were identified from gene set enrichment analyses using Kyoto Encyclopedia of Genes and Genomes, Gene Ontogeny or Hallmark libraries; however, enrichment of DEG from the Innate Anti-PD1 Resistance Signature (IPRES) was identified (p value=0.007, FDR=0.03). CONCLUSIONS: Second-line ipilimumab-nivolumab for MBMs after BRAF-MEKi progression has poor activity. MBMs that are resistant to BRAF-MEKi that also conferred resistance to second-line ipilimumab-nivolumab showed enrichment of the IPRES gene signature.
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ItemEnhancing the Potential of Immunotherapy in Paediatric Sarcomas: Breaking the Immunosuppressive Barrier with Receptor Tyrosine Kinase Inhibitors(MDPI, 2021-12-01)Despite aggressive surgery, chemotherapy, and radiotherapy, survival of children and adolescents and young adults (AYAs) with sarcoma has not improved significantly in the past four decades. Immune checkpoint inhibitors (ICIs) are an exciting type of immunotherapy that offer new opportunities for the treatment of paediatric and AYA sarcomas. However, to date, most children do not derive a benefit from this type of treatment as a monotherapy. The immunosuppressive tumour microenvironment is a major barrier limiting their efficacy. Combinations of ICIs, such as anti-PD-1 therapy, with targeted molecular therapies that have immunomodulatory properties may be the key to breaking through immunosuppressive barriers and improving patient outcomes. Preclinical studies have indicated that several receptor tyrosine kinase inhibitors (RTKi) can alter the tumour microenvironment and boost the efficacy of anti-PD-1 therapy. A number of these combinations have entered phase-1/2 clinical trials, mostly in adults, and in most instances have shown efficacy with manageable side-effects. In this review, we discuss the status of ICI therapy in paediatric and AYA sarcomas and the rationale for co-treatment with RTKis. We highlight new opportunities for the integration of ICI therapy with RTK inhibitors, to improve outcomes for children with sarcoma.
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ItemNo Preview AvailableThe unexplored immune landscape of high-risk pediatric cancers.(AMER ASSOC CANCER RESEARCH, 2021-07-01)Abstract In adult cancer, immune signatures such as the T cell-inflamed gene expression profile (GEP) have been developed to predict which patients are likely to respond to immune checkpoint inhibitors (ICIs) beyond high tumor mutation burden (TMB) and PD-L1 expression. The GEP infers T cell infiltration and activation in the tumor microenvironment (TME) from transcriptomic data. However, it is not known whether tools such as GEP are applicable in pediatric cancer, as the TME in childhood cancers is largely unexplored and response to ICIs are rare. We have undertaken an integrated analysis of the pediatric TME using RNA-sequencing (RNA-seq) and immunohistochemistry (IHC). Our goal is to identify patients with T cell-inflamed or “hot” tumors who may benefit from ICIs. Through Australia's ZERO childhood cancer precision medicine program we performed RNA-seq on 347 high-risk pediatric cancers (estimated <30% chance of survival) and performed IHC for CD4, CD8, CD45 and PD-L1 on 112 matching samples. Using both informatic assessments and IHC as independent measures of immune infiltration, we mapped the immune landscape of the TME across a broad range of high-risk pediatric cancers. As RNA-seq is increasingly used in the analysis of patient tumors, we investigated numerous molecular correlates of immune infiltration, tailored specifically to pediatric patients. RNA-seq was used to generate the GEP and map expression profiles of immune checkpoint genes, and deconvolution algorithms were used to extract the immune cell composition for every tumor. The correlation analysis between IHC, deconvolution of cell mixture composition and GEP were assessed, including PD-L1 protein and mRNA expression. We observed significant correlation between PD-L1 protein and mRNA expression and a weak correlation of CD8+ T cells with GEP. Deconvoluted TME estimates were most tightly correlated with the presence of T cell infiltrates (CD4 and CD8) with IHC. TMB and tumor purity estimates were derived from whole genome sequencing for each case. No correlation was observed between TMB and immune infiltration, however, tumor purity was negatively correlated with immune infiltration. Using IHC as an independent marker of a T cell-inflamed TME, we have identified a novel pediatric immune signature that includes markers of CD4 and CD8 T cells, T cell cytotoxicity, T and NK cell recruitment and activation, MHC Class II molecules and immune checkpoints. This is the first study to comprehensively analyze the pediatric TME in a cohort of this size and diversity, with matching IHC for orthogonal validation. Through the combination of RNA-seq and IHC, we have devised a novel immune signature specific to pediatrics and these techniques have identified a subset of patients that are immune “hot” and may potentially respond to ICIs. Conversely, we also highlight the potential of identifying immune “cold” patients who may need immunomodulatory combination strategies to maximize immune response. Citation Format: Chelsea Mayoh, Rachael L. Terry, Marie Wong, Loretta M. Lau, Dong Anh Khuong-Quang, Marion K. Mateos, Vanessa Tyrrell, Michelle Haber, David S. Ziegler, Mark J. Cowley, Joseph A. Trapani, Paul J. Neeson, Paul G. Ekert. The unexplored immune landscape of high-risk pediatric cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3044.
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ItemMAIT cells regulate NK cell-mediated tumor immunity(NATURE PORTFOLIO, 2021-08-06)The function of MR1-restricted mucosal-associated invariant T (MAIT) cells in tumor immunity is unclear. Here we show that MAIT cell-deficient mice have enhanced NK cell-dependent control of metastatic B16F10 tumor growth relative to control mice. Analyses of this interplay in human tumor samples reveal that high expression of a MAIT cell gene signature negatively impacts the prognostic significance of NK cells. Paradoxically, pre-pulsing tumors with MAIT cell antigens, or activating MAIT cells in vivo, enhances anti-tumor immunity in B16F10 and E0771 mouse tumor models, including in the context of established metastasis. These effects are associated with enhanced NK cell responses and increased expression of both IFN-γ-dependent and inflammatory genes in NK cells. Importantly, activated human MAIT cells also promote the function of NK cells isolated from patient tumor samples. Our results thus describe an activation-dependent, MAIT cell-mediated regulation of NK cells, and suggest a potential therapeutic avenue for cancer treatment.
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ItemTranscriptome sequencing and multi-plex imaging of prostate cancer microenvironment reveals a dominant role for monocytic cells in progression(BMC, 2021-07-22)BACKGROUND: Prostate cancer is caused by genomic aberrations in normal epithelial cells, however clinical translation of findings from analyses of cancer cells alone has been very limited. A deeper understanding of the tumour microenvironment is needed to identify the key drivers of disease progression and reveal novel therapeutic opportunities. RESULTS: In this study, the experimental enrichment of selected cell-types, the development of a Bayesian inference model for continuous differential transcript abundance, and multiplex immunohistochemistry permitted us to define the transcriptional landscape of the prostate cancer microenvironment along the disease progression axis. An important role of monocytes and macrophages in prostate cancer progression and disease recurrence was uncovered, supported by both transcriptional landscape findings and by differential tissue composition analyses. These findings were corroborated and validated by spatial analyses at the single-cell level using multiplex immunohistochemistry. CONCLUSIONS: This study advances our knowledge concerning the role of monocyte-derived recruitment in primary prostate cancer, and supports their key role in disease progression, patient survival and prostate microenvironment immune modulation.
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ItemNo Preview AvailablePreclinical Evidence of the Efficacy of Lewis Y Car T Cells in Patient-Derived Models of Prostate Cancer(The Endocrine Society, 2021-05-03)Abstract Chimeric antigen receptor T (CAR T) cell therapy is an adoptive immunotherapy that has led to new treatments for lymphoma, leukemia, and other blood cancers; however, its efficacy for prostate cancer remains unproven. Here we report pre-clinical evidence of the efficacy of CAR T cell therapy against the Lewis Y antigen (LeY) using patient-derived models of prostate cancer. To assess the expression of LeY on prostate tumours, we performed immunohistochemistry on a cohort of 41 patient-derived xenografts (PDXs). Cytoplasmic and membrane expression were separately assessed and quantified, for each patient. Overall, 61% (25/41) of PDXs were positive for membrane LeY expression, of which 18 PDXs had greater than 50% membrane-positive cells, and considered most suitable to detection and stable binding by anti-LeY CAR T’s. To determine the in vitro sensitivity to CAR T cytotoxicity, we selected 4 PDXs with high and 2 PDXs with low LeY expression using 3 androgen receptor (AR)-positive adenocarcinomas and 3 AR-negative tumors expressing neuroendocrine markers. Next we established organoids for in vitro co-culture assays where organoids were co-incubated with an equal number of anti-LeY+ CAR T cells or Empty vector control CAR T cells (Ev CAR T). Using time-lapse microscopy we reported destruction of organoids by LeY+ CAR T cells as indicated by their morphological collapse and uptake of propidium iodide from the culture medium; control Ev CAR T cells produced no cytotoxicity. Over the 48h assay, the level of target cell death of the LeY+ organoids was correlated to the intensity LeY surface expression. Target cell death mediated by the CAR T cells required perforin and granzyme B, as potent and highly specific small molecule inhibitors of perforin (SN34960) and granzyme B (C20) applied alone or in combination greatly decreased PI uptake, indicating organoid survival. Neither inhibitor adversely affected CAR T cell viability as measured by PI and Annexin V staining. This demonstrated canonical activation of granule exocytosis pathway by the CAR T cells, leading to organoid cell death. To assess CAR T cell efficacy in vivo, we selected one PDX with high LeY expression. Monotherapy with CAR T cells failed to decrease tumour volume compared to vehicle control. However, CAR T cells given after a single dose of the chemotherapeutic agent carboplatin greatly and durably reduced tumour burden, with residual tumour mass being less than 1% of their original size (0.56 ± 0.23% of tumour volume at the start of treatment). Overall, these data provide preclinical evidence that: i) high membrane expression of LeY correlates with in vitro and in vivo CAR T cell-induced tumour cell death via the canonical perforin/granzyme B mechanism; and, ii) membrane LeY can be used as a biomarker for patient selection.
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ItemNo Preview AvailableMyeloma natural killer cells are exhausted and have impaired regulation of activation(FERRATA STORTI FOUNDATION, 2021-09-01)Not available.