Publications

Immunotherapy with checkpoint inhibitors has revolutionised the outcomes for melanoma patients. In the metastatic setting, patients treated with nivolumab and ipilimumab have an expected 5-year survival of> 50%. For patients with resected high-risk stage III disease, adjuvant pembrolizumab, nivolumab or dabrafenib and trametinib are associated with a significant improvement in both relapse-free survival (RFS) and distant metastasis-free survival (DMFS). More recently neoadjuvant immunotherapy has shown very promising outcomes in patients with clinically detectable nodal disease and is likely to become a new standard of care. For stage IIB/C disease, two pivotal adjuvant trials of pembrolizumab and nivolumab have also reported a significant improvement in both RFS and DMFS. However, the absolute benefit is low and there are concerns about the risk of severe toxicities as well as long-term morbidity from endocrine toxicity. Ongoing registration phase III trials are currently evaluating newer immunotherapy combinations and the role of BRAF/MEK-directed targeted therapy for stage II melanoma. However, our ability to personalise therapy based on molecular risk stratification has lagged behind the development of novel immune therapies. There is a critical need to evaluate the use of tissue and blood-based biomarkers, to better select patients that will recur and avoid unnecessary treatment for the majority of patients cured by surgery alone.

Bacillus Calmette-Guerin (BCG) is a live attenuated vaccine against tuberculosis (TB) and remains the most commonly used vaccine worldwide. However, BCG has varied protective efficiency in adults and has safety concerns in immunocompromised population. Thus effective vaccines are necessary for preventing the prevalence of TB. Cyclic di-AMP (c-di-AMP) is a bacterial second messenger which regulates various cellular processes and host immune response. Previous work found that c-di-AMP regulates bacterial physiological function, pathogenicity and host type I IFN response. In this study, we constructed a recombinant BCG (rBCG) by overexpressing DisA, the diadenylate cyclase of Mycobacterium tuberculosis (Mtb), and observed the physiological changes of rBCG-DisA. The immunological characteristics of rBCG-DisA were investigated on humoral and cellar immune responses in a mice infection model. Our study demonstrated that overexpression of DisA in BCG does not affect the growth but reduces the length of BCG. rBCG-DisA-immunized mice show similar humoral and cellar immune responses in BCG-immunized mice. After Mtb infection, the splenic lymphocytes from both BCG and rBCG-DisA-immunized mice produced more IFN-γ, IL-2, and IL-10 than the un-immunized (UN) mice, while the cytokine levels of the rBCG-DisA group increased significantly than those of the BCG group. The transcription of IFN-β, IL-1β and autophagy related genes (Atgs) were up-regulated in macrophages after treated with c-di-AMP or bacterial infection. The productions of IL-6 were increased after Mtb challenge, especially in the rBCG-DisA-immunized mice. Strikingly, H3K4me4, the epigenetic marker of innate immune memory, was found in both two immunized groups, and the rBCG-DisA group showed stronger expression of H3K4me4 than that of BCG. In addition, the pathological changes of rBCG-DisA immunized mice were similar to that of BCG-immunized mice. The bacterial burdens in the lungs and spleens of BCG- and rBCG-DisA-immunized mice were significantly decreased, but there was no significant difference between the two immunized groups. Together, these results suggested that compared to BCG, rBCG-DisA vaccination, induces stronger immune responses but did not provided additional protection against Mtb infection in this study, which may be related to the innate immunity memory. Hence, c-di-AMP is a promising immunomodulator for a further developed BCG as a better vaccine.

TPS180 Background: 177 Lu‐PSMA-617 (Lu-PSMA) is a radiolabeled small-molecule that binds with high affinity to PSMA enabling highly targeted delivery of beta radiation to prostate cancer cells. In metastatic castration-resistant prostate cancer, Lu-PSMA showed superior activity to Cabazitaxel in the TheraP trial. Although androgen deprivation therapy (ADT) + Docetaxel is a standard of care for de novo high-volume mHNPC, outcomes remain sub-optimal for many patients. We hypothesize that Lu-PSMA prior to docetaxel will achieve a higher undetectable PSA rate at 12 months compared to docetaxel alone in men with newly-diagnosed high-volume mHNPC. Methods: UpFrontPSMA is an open label, randomized, stratified, 2-arm, multi-center, phase 2 clinical trial recruiting 140 patients at 11 Australian centers. Key eligibility criteria include histological diagnosis of prostate cancer within 12 weeks, PSA > 10ng/ml at diagnosis, < 4 weeks on ADT, and high-volume (≥ 4 bone metastases with ≥ 1 outside the axial skeleton, and/or visceral metastases), PSMA-avid disease on 68 Ga-PSMA-11 PET/CT with no major discordance on 18 FDG-PET/CT. Patients will be randomized 1:1 to the experimental arm (Lu-PSMA 7.5 GBq q6w x 2 cycles followed 6 weeks later by docetaxel 75mg/m 2 q3w x 6 cycles), or standard-of-care Arm (docetaxel alone). All patients will receive continuous ADT. Assessments will be done every 3 weeks during study treatment, and then every 6-12 weeks until unequivocal disease progression. CT and whole body bone scan will be performed at baseline and every 12 weeks, 68 Ga-PSMA-11 PET/CT at baseline and 12 weeks, and 18 FDG-PET/CT at baseline and 12 weeks (if applicable). Correlative samples will include optional tumour tissue (baseline and disease progression), and serial plasma/whole blood collection. The primary endpoint is undetectable PSA (≤ 0.2 ng/ml) at 12 months. Secondary endpoints are safety, time to castration resistance, PSA-progression-free-survival (PSA-PFS), radiographic PFS, radiographic response rates, early PSMA-PET response rates, quality of life and overall survival. Exploratory endpoints are prognostic and predictive value of PET-derived parameters and of biomarkers identified in plasma/whole blood/tumour tissue. The study will have 85% power to reject the null hypothesis if the true 12 month undetectable PSA rate in the experimental Arm is 50%. The power calculation assumes no more than 10 patients (7%) of the 140 patients will be unevaluable or lost to follow-up in 1 year, 5% alpha and two-sided test for proportions. As of October 13, 2020, accrual stands at 4. UpFrontPSMA is an investigator-led, academic trial sponsored by Peter MacCallum Cancer Centre in collaboration with ANZUP Cancer Trials Group with study coordination provided by the Centre for Biostatistics and Clinical Trials (BaCT) Clinical trial information: NCT04343885.

<p>Consort diagram describing samples disposition in the study.</p>

Abstract Primary cutaneous lymphomas represent a heterogeneous group of T‐ and B‐cell lymphomas with distinct clinical presentations, histopathologic features, treatment approaches and outcomes. The cutaneous T‐cell lymphomas, which include mycosis fungoides and Sézary syndrome, account for the majority of the cutaneous lymphomas. This Clinical Practice Statement is reflective of the current clinical practice in Australia. An expanded form of the Clinical Practice Statement (and updates), along with helpful patient resources and access to support groups, can be found at the following ( http://www.australasianlymphomaalliance.org.au ).

Abstract Despite the success of therapies targeting oncogenes in cancer, clinical outcomes are limited by a residual disease that results in relapse. This residual disease is characterized by drug-induced adaptation, that in melanoma includes altered metabolism. Here, we examined how targeted therapy reprograms metabolism in BRAF-mutant melanoma cells using a genome-wide RNAi screen and global gene expression profiling. This systematic approach revealed post-transcriptional regulation of metabolism following BRAF inhibition, involving selective mRNA transport and translation. As proof of concept we demonstrate the RNA binding kinase UHMK1 interacts with mRNAs that encode metabolic proteins and selectively controls their transport and translation during adaptation to BRAF targeted therapy. Inactivation of UHMK1 improves metabolic response to BRAF targeted therapy and delays resistance to BRAF and MEK combination therapy in vivo . Our data support a model wherein post-transcriptional gene expression pathways regulate metabolic adaptation underpinning targeted therapy response and suggest inactivation of these pathways may delay disease relapse.

Summary Marizomib ( MRZ ) is an irreversible, pan‐subunit proteasome inhibitor ( PI ) in clinical development for relapsed/refractory multiple myeloma ( RRMM ) and glioma. This study analysed MRZ , pomalidomide ( POM ) and low‐dose dexamethasone (Lo‐ DEX ) [ PMD ] in RRMM to evaluate safety and determine the maximum tolerated dose ( MTD ) and/or recommended Phase 2 dose ( RP 2D). Intravenous MRZ (0·3–0·5 mg/m 2 ) was administered over 2 h on days 1, 4, 8, 11; POM (3–4 mg) on days 1–21; and Lo‐ DEX (5 or 10 mg) on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 16, 22 and 23 of every 28‐day cycle. Thirty‐eight patients were enrolled that had received a median of 4 (range 1–10) prior lines of therapy; all patients received prior lenalidomide and bortezomib. No dose‐limiting toxicities ( DLT s) were observed and 0·5 mg/m 2 MRZ was determined to be the RP 2D. The most common treatment‐related ≥Grade 3 adverse events were: neutropenia (11/38 patients: 29%), pneumonia (4/38 patients 11%), anaemia (4/38 patients; 11%) and thrombocytopenia (4/38 patients; 11%). The overall response rate and clinical benefit rate was 53% (19/36) and 64% (23/36), respectively. In conclusion, PMD was well tolerated and demonstrated promising activity in heavily pre‐treated, high‐risk RRMM patients.

We recently cared for a 48-year-old male patient with stage IIIC (pT2aN3), BRAF V600E melanoma. After progression of disease on combination BRAF and MEK inhibitor therapy, he received combination immune checkpoint inhibitor (ICI) therapy with ipilimumab (anti- cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) monoclonal antibody) and nivolumab (anti- programmed cell death protein (PD-1) monoclonal antibody). He developed treatment-limiting immune related colitis, managed with steroids and anti-TNF therapy, in addition to multiply relapsed C. difficile colitis, ultimately responsive to oral fidaxomicin. Whilst awaiting a clinical response to fidaxomicin, the infectious diseases and oncology team considered the role of faecal microbiota transplant (FMT) for the management of the multiply relapsed Clostridioides difficile colitis and of ICI-associated colitis and to improve responsiveness to further immunotherapy. The medical decision not to pursue FMT was based on recovery from C. difficile infection, absence of evidence as to the most favourable microbiome to optimise responsiveness to ICI and the lack of validated screening processes for donor stool to characterise the donated microbiome and exclude unintended consequences such as transfer of potential pathogens. During this time, the patient developed a belief that he needed to 'optimise' his microbiome via FMT. His decision was based on widely cited reports in the popular press about potential for improving the anti-cancer immune effects of ICI therapy via augmentation of the microbiome. Our patient was determined to seek an FMT and pursued this against medical advice, at a significant out-of-pocket expense. Unfortunately, despite FMT, the patient developed explosive disease shortly after FMT and the focus of his care was shifted to palliation. The interactions between the host immune system and the colonising microbiota play an important role in both symbiosis and pathogenesis [[1]Rajagopala SV, Vashee S, Oldfield LM, Suzuki Y, Venter JC, Telenti A, et al. The human microbiome and cancer. Cancer prevention research (Philadelphia, Pa). 2017;10(4):226–34.Google Scholar]. The gastrointestinal (gut) microbiome is implicated in immune modulation both locally and at distant sites [[1]Rajagopala SV, Vashee S, Oldfield LM, Suzuki Y, Venter JC, Telenti A, et al. The human microbiome and cancer. Cancer prevention research (Philadelphia, Pa). 2017;10(4):226–34.Google Scholar]. We have seen explosive interest in microbiome modulation to treat gut diseases, such as Clostridioides difficile colitis and inflammatory bowel disease. There is also mounting evidence to support the role of the gut microbiome in shaping systemic ICI responses and modulation of immune related adverse events (irAEs) [[2]Gopalakrishnan V. Helmink B.A. Spencer C.N. Reuben A. Wargo J.A. The influence of the gut microbiome on cancer, immunity, and cancer immunotherapy.Cancer Cell. 2018; 33: 570-580Summary Full Text Full Text PDF PubMed Scopus (597) Google Scholar]. In pre-clinical murine models, Sivan et al. demonstrated that the gut microbiome can independently influence antitumor immunity and improve responsiveness to immunotherapy [[3]Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science (New York, NY). 2015;350(6264):1084–9.Google Scholar]. Further, Vetizou et al. demonstrated that disruption of the microbiome through the administration of broad-spectrum antibiotics reduced the antitumor efficacy of anti-CTLA-4 antibodies, but when followed by oral gavage with certain bacteria, was associated with restoration of anti-cancer responsiveness to ICIs. [[4]Vetizou M, Pitt JM, Daillere R, Lepage P, Waldschmitt N, Flament C, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science (New York, NY). 2015;350(6264):1079–84.Google Scholar] Providing further support for the role of the microbiome modulating the anti-cancer systemic immune responses, Sivan et al. and Vetizou et al. both went on to demonstrate that mice that received FMT with human ICI responder microbiomes experienced superior intrinsic anti-tumour immunity and improved response to ICIs compared to mice that received non-responder FMT. While there are significant differences between murine cancer models and patients, there is a growing body of evidence to suggest that findings from pre-clinical studies might be reproducible in humans. Gopalakrishnan et al. and others showed an association between a high diversity faecal microbiome and improved responsiveness to ICI therapy, which translated to prolonged progression-free and overall survival in a number of different cancer subtypes [5Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science (New York, NY). 2018;359(6371):97–103.Google Scholar, 6Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre ML, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science (New York, NY). 2018;359(6371):104–8.Google Scholar, 7Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillere R, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science (New York, NY). 2018;359(6371):91–7.Google Scholar]. While these results are promising, there are important limitations too, including conflicting data regarding what organisms constitute a 'favourable' microbiome and inconsistencies between the various sampling, analytic and quantitation methods for interrogation of the microbiome, making comparisons between reports difficult. Furthermore, mechanistic insights into the role of the microbiome in anti-tumour immunity are lacking. Finally, the paucity of human data makes it impossible to make any meaningful recommendations to patients about the current role for augmentation of the gut microbiomes through FMT or other methods. So, while these findings highlight the therapeutic potential of gut microbiome modulating therapy for augmentation of anti-tumour immunity, this science is in its infancy. The composition of the gut microbiome also appears to be linked to the development of irAEs. Vetizou et al. demonstrated that in mice with ICI-induced colitis, oral gavage with Bacteroides species led to reduced histological features of colonic inflammation [[4]Vetizou M, Pitt JM, Daillere R, Lepage P, Waldschmitt N, Flament C, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science (New York, NY). 2015;350(6264):1079–84.Google Scholar]. In humans, certain bacterial phyla have been linked with both resistance to and the development of irAE, particularly those involving the gastrointestinal tract [8Dubin K. Callahan M.K. Ren B. Khanin R. Viale A. Ling L. et al.Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis.Nat Commun. 2016; 710391Crossref PubMed Scopus (623) Google Scholar, 9Chaput N. Lepage P. Coutzac C. Soularue E. Le Roux K. Monot C. et al.Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab.Ann. Oncol. 2017; 28: 1368-1379Summary Full Text Full Text PDF PubMed Scopus (657) Google Scholar]. There is significant overlap between organisms that are associated with higher rates of tumour response and higher rates of colitis; further understanding of the role of the microbiome in autoimmunity could translate into therapeutic strategies that uncouple toxicity from anti-tumour immunity. Wang et al. have been the first to describe two cancer patients with treatment refractory ICI-related colitis successfully managed with FMT from a single healthy donor [[10]Wang Y. Wiesnoski D.H. Helmink B.A. Gopalakrishnan V. Choi K. DuPont H.L. et al.Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis.Nat Med. 2018; 24: 1804-1808Crossref PubMed Scopus (374) Google Scholar]. However, on interrogation of the microbiome at the time of colitis and post FMT, the microbiomes of these patients were disparate, making it impossible to conclude which bacterial strains were responsible for either the colitis or its resolution. As important as it is to seek to define the ideal 'responder' microbiome it is equally important to define the 'at-risk-of-irAE' microbiome. Trials are underway to assess the role for FMT and other microbiome modulating therapies in cancer patients. For example, a phase 1, single centre study of FMT from ICI responders into ICI refractory patients (NCT03353402). However, it is important to emphasise that there is currently insufficient clinical evidence to recommend any microbiome augmenting therapy to improve cancer outcomes outside of an investigational setting. Systematic, prospective interrogation of the gut microbiome using validated genomic assays in larger human cohorts is required before this knowledge can be translated into clinical practice [[2]Gopalakrishnan V. Helmink B.A. Spencer C.N. Reuben A. Wargo J.A. The influence of the gut microbiome on cancer, immunity, and cancer immunotherapy.Cancer Cell. 2018; 33: 570-580Summary Full Text Full Text PDF PubMed Scopus (597) Google Scholar]. Importantly, there is currently no clinical data to support the safety and efficacy of faecal transplantation for the purpose of achieving anti-tumour immunity. It is critical that both oncology and infectious disease clinicians have knowledge of this rapidly evolving area in order to carry out informed conversations regarding the limitations of current knowledge and potential for unintended consequences of FMT with this potentially vulnerable patient population. Olivia C. Smibert: contributed to the structure, literature search and writing of the manuscript. Christina W. Guo: contributed to the structure, literature search and writing of the manuscript. Chloe Khoo: contributed to the structure, literature search and writing of the manuscript. Karin A Thursky: contributed to the structure, literature search and writing of the manuscript. Shahneen Sandhu: contributed to the structure, literature search and writing of the manuscript. Monica A. Slavin: contributed to the structure, literature search and writing of the manuscript.

The kinase activity of mTOR involves 2 multiprotein complexes, (mTORC1-mTORC2). Targeting mTORC1 with rapalogues induces compensatory feedback loops resulting in AKT/ERK activation, which may be abrogated by mTORC2 inhibition. A first-in-human trial evaluating tolerability, pharmacokinetics and pharmacodynamics of the dual TORC1/TORC2 inhibitor OSI-027 was conducted. Dose escalation was pursued for three schedules of administration (three consecutive days per week (S1), once a week (S2) and daily dosing (S3)), until dose-limiting toxicities (DLT) were identified. Expansion cohorts with paired tumour biopsies were initiated based on tolerability and pharmacodynamics. One hundred and twenty eight patients with advanced cancer were enrolled. DLT consisted predominantly of fatigue, renal function disturbances and cardiac events. OSI-027 exposure was dose proportional, with Tmax within 4 h and a half-life of ∼14 h. Expansion cohorts were initiated for S1 and S2, as MTD for S3 was overall considered suboptimal. Target modulation in peripheral blood mononuclear cells were observed from 30 mg, but in tumour biopsies 120 mg QD were needed, which was a non-tolerable dose due to renal toxicity. No RECIST responses were recorded, with stable disease >6 months in six (5%) patients. OSI-027 inhibits mTORC1/2 in patients with advanced tumour s in a dose-dependent manner but doses above the tolerable levels in S1 and S3 are required for a sustained biological effect in tumour biopsies.