Publications by authors named "Andrew M Scott"

266 Publications

Bintrafusp alfa (M7824), a bifunctional fusion protein targeting TGF-β and PD-L1: results from a phase I expansion cohort in patients with recurrent glioblastoma.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab058. Epub 2021 Apr 9.

Austin Brain Tumor Center, Austin, Texas, USA.

Background: For patients with recurrent glioblastoma (rGBM), there are few options following treatment failure with radiotherapy plus temozolomide. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β "trap") fused to a human IgG1 antibody blocking PD-L1.

Methods: In this phase I, open-label expansion cohort (NCT02517398), patients with rGBM that progressed after radiotherapy plus temozolomide received bintrafusp alfa 1200 mg Q2W until disease progression, unacceptable toxicity, or trial withdrawal. Response was assessed per RANO criteria. The primary endpoint was disease control rate (DCR); secondary endpoints included safety.

Results: As of August 24, 2018, 35 patients received bintrafusp alfa for a median of 1.8 (range, 0.5-20.7) months. Eight patients (22.9%) experienced disease control as assessed by an independent review committee: 2 had a partial response, 4 had stable disease, and 2 had non-complete response/non-progressive disease. Median progression-free survival (PFS) was 1.4 (95% confidence interval [CI], 1.2-1.6) months; 6- and 12-month PFS rates were 15.1% and 11.3%, respectively. Median overall survival (OS) was 5.3 (95% CI, 2.6-9.4) months; 6- and 12-month OS rates were 44.5% and 30.8%, respectively. The DCR (95% CI) was 66.7% (22.3-95.7%) for patients with -mutant GBM ( = 6) and 13.8% (3.9-31.7%) for patients with -wild-type GBM ( = 29). Disease control was seen regardless of PD-L1 expression. Twenty-five patients (71.4%) experienced treatment-related adverse events (grade ≥3; 17.1% [ = 6]).

Conclusions: The percentage of patients achieving disease control and the manageable safety profile may warrant further investigation of bintrafusp alfa in GBM.
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http://dx.doi.org/10.1093/noajnl/vdab058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156979PMC
April 2021

EGFRvIII Promotes Cell Survival during Endoplasmic Reticulum Stress through a Reticulocalbin 1-Dependent Mechanism.

Cancers (Basel) 2021 Mar 10;13(6). Epub 2021 Mar 10.

Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Parkville, VIC 3050, Australia.

Reticulocalbin 1 (RCN1) is an endoplasmic reticulum (ER)-residing protein, involved in promoting cell survival during pathophysiological conditions that lead to ER stress. However, the key upstream receptor tyrosine kinase that regulates RCN1 expression and its potential role in cell survival in the glioblastoma setting have not been determined. Here, we demonstrate that RCN1 expression significantly correlates with poor glioblastoma patient survival. We also demonstrate that glioblastoma cells with expression of EGFRvIII receptor also have high RCN1 expression. Over-expression of wildtype EGFR also correlated with high RCN1 expression, suggesting that EGFR and EGFRvIII regulate RCN1 expression. Importantly, cells that expressed EGFRvIII and subsequently showed high RCN1 expression displayed greater cell viability under ER stress compared to EGFRvIII negative glioblastoma cells. Consistently, we also demonstrated that RCN1 knockdown reduced cell viability and exogenous introduction of RCN1 enhanced cell viability following induction of ER stress. Mechanistically, we demonstrate that the EGFRvIII-RCN1-driven increase in cell survival is due to the inactivation of the ER stress markers ATF4 and ATF6, maintained expression of the anti-apoptotic protein Bcl-2 and reduced activity of caspase 3/7. Our current findings identify that EGFRvIII regulates RCN1 expression and that this novel association promotes cell survival in glioblastoma cells during ER stress.
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http://dx.doi.org/10.3390/cancers13061198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999088PMC
March 2021

GPA33 is expressed on multiple human blood cell types and distinguishes CD4 central memory T cells with and without effector function.

Eur J Immunol 2021 Jun 4;51(6):1377-1389. Epub 2021 May 4.

Department of Hematopoiesis and Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

The Ig superfamily protein glycoprotein A33 (GPA33) has been implicated in immune dysregulation, but little is known about its expression in the immune compartment. Here, we comprehensively determined GPA33 expression patterns on human blood leukocyte subsets, using mass and flow cytometry. We found that GPA33 was expressed on fractions of B, dendritic, natural killer and innate lymphoid cells. Most prominent expression was found in the CD4 T cell compartment. Naïve and CXCR5 regulatory T cells were GPA33 , and naïve conventional CD4 T cells expressed intermediate GPA33 levels. The expression pattern of GPA33 identified functional heterogeneity within the CD4 central memory T cell (Tcm) population. GPA33 CD4 Tcm cells were fully undifferentiated, bona fide Tcm cells that lack immediate effector function, whereas GPA33 Tcm cells exhibited rapid effector functions and may represent an early stage of differentiation into effector/effector memory T cells before loss of CD62L. Expression of GPA33 in conventional CD4 T cells suggests a role in localization and/or preservation of an undifferentiated state. These results form a basis to study the function of GPA33 and show it to be a useful marker to discriminate between different cellular subsets, especially in the CD4 T cell lineage.
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http://dx.doi.org/10.1002/eji.202048744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251590PMC
June 2021

Medical imaging and nuclear medicine: a Lancet Oncology Commission.

Lancet Oncol 2021 04 4;22(4):e136-e172. Epub 2021 Mar 4.

Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, VIC, Australia; Department of Molecular Imaging and Therapy, Austin Health, Melbourne, VIC, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC, Australia; Department of Medicine, University of Melbourne, Melbourne, VIC, Australia.

The diagnosis and treatment of patients with cancer requires access to imaging to ensure accurate management decisions and optimal outcomes. Our global assessment of imaging and nuclear medicine resources identified substantial shortages in equipment and workforce, particularly in low-income and middle-income countries (LMICs). A microsimulation model of 11 cancers showed that the scale-up of imaging would avert 3·2% (2·46 million) of all 76·0 million deaths caused by the modelled cancers worldwide between 2020 and 2030, saving 54·92 million life-years. A comprehensive scale-up of imaging, treatment, and care quality would avert 9·55 million (12·5%) of all cancer deaths caused by the modelled cancers worldwide, saving 232·30 million life-years. Scale-up of imaging would cost US$6·84 billion in 2020-30 but yield lifetime productivity gains of $1·23 trillion worldwide, a net return of $179·19 per $1 invested. Combining the scale-up of imaging, treatment, and quality of care would provide a net benefit of $2·66 trillion and a net return of $12·43 per $1 invested. With the use of a conservative approach regarding human capital, the scale-up of imaging alone would provide a net benefit of $209·46 billion and net return of $31·61 per $1 invested. With comprehensive scale-up, the worldwide net benefit using the human capital approach is $340·42 billion and the return per dollar invested is $2·46. These improved health and economic outcomes hold true across all geographical regions. We propose actions and investments that would enhance access to imaging equipment, workforce capacity, digital technology, radiopharmaceuticals, and research and training programmes in LMICs, to produce massive health and economic benefits and reduce the burden of cancer globally.
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http://dx.doi.org/10.1016/S1470-2045(20)30751-8DOI Listing
April 2021

Global costs, health benefits, and economic benefits of scaling up treatment and imaging modalities for survival of 11 cancers: a simulation-based analysis.

Lancet Oncol 2021 03;22(3):341-350

Department of Global Health and Population, Harvard TH Chan School of Public Health, Harvard University, Boston, MA, USA; Department of Global Health and Social Medicine, Harvard Medical School, Harvard University, Boston, MA, USA.

Background: In addition to increased availability of treatment modalities, advanced imaging modalities are increasingly recommended to improve global cancer care. However, estimates of the costs and benefits of investments to improve cancer survival are scarce, especially for low-income and middle-income countries (LMICs). In this analysis, we aimed to estimate the costs and lifetime health and economic benefits of scaling up imaging and treatment modality packages on cancer survival, both globally and by country income group.

Methods: Using a previously developed model of global cancer survival, we estimated stage-specific cancer survival and life-years gained (accounting for competing mortality) in 200 countries and territories for patients diagnosed with one of 11 cancers (oesophagus, stomach, colon, rectum, anus, liver, pancreas, lung, breast, cervix uteri, and prostate) representing 60% of all cancer diagnoses between 2020 and 2030 (inclusive of full years). We evaluated the costs and health and economic benefits of scaling up packages of treatment (chemotherapy, surgery, radiotherapy, and targeted therapy), imaging modalities (ultrasound, x-ray, CT, MRI, PET, single-photon emission CT), and quality of care to the mean level of high-income countries, separately and in combination, compared with no scale-up. Costs and benefits are presented in 2018 US$ and discounted at 3% annually.

Findings: For the 11 cancers studied, we estimated that without scale-up (ie, with current availability of treatment, imaging, and quality of care) there will be 76·0 million cancer deaths (95% UI 73·9-78·6) globally for patients diagnosed between 2020 and 2030, with more than 70% of these deaths occurring in LMICs. Comprehensive scale-up of treatment, imaging, and quality of care could avert 12·5% (95% UI 9·0-16·3) of these deaths globally, ranging from 2·8% (1·8-4·3) in high-income countries to 38·2% (32·6-44·5) in low-income countries. Globally, we estimate that comprehensive scale-up would cost an additional $232·9 billion (95% UI 85·9-422·0) between 2020 and 2030 (representing a 6·9% increase in cancer treatment costs), but produce $2·9 trillion (1·8-4·0) in lifetime economic benefits, yielding a return of $12·43 (6·47-33·23) per dollar invested. Scaling up treatment and quality of care without imaging would yield a return of $6·15 (2·66-16·71) per dollar invested and avert 7·0% (3·9-10·3) of cancer deaths worldwide.

Interpretation: Simultaneous investment in cancer treatment, imaging, and quality of care could yield substantial health and economic benefits, especially in LMICs. These results provide a compelling rationale for the value of investing in the global scale-up of cancer care.

Funding: Harvard TH Chan School of Public Health and National Cancer Institute.
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http://dx.doi.org/10.1016/S1470-2045(20)30750-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033570PMC
March 2021

A clinical trial of non-invasive imaging with an anti-HIV antibody labelled with copper-64 in people living with HIV and uninfected controls.

EBioMedicine 2021 Mar 25;65:103252. Epub 2021 Feb 25.

Department of Molecular Imaging and Therapy, Austin Health, and University of Melbourne, Melbourne, Australia; Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, School of Cancer Medicine, La Trobe University, Melbourne, Australia.

Background: A research priority in finding a cure for HIV is to establish methods to accurately locate and quantify where and how HIV persists in people living with HIV (PLWH) receiving suppressive antiretroviral therapy (ART). Infusing copper-64 (Cu) radiolabelled broadly neutralising antibodies targeting HIV envelope (Env) with CT scan and positron emission tomography (PET) identified HIV Env in tissues in SIV infected non-human primates . We aimed to determine if a similar approach was effective in people living with HIV (PLWH).

Methods: Unmodified 3BNC117 was compared with 3BNC117 bound to the chelator MeCOSar and Cu (Cu-3BNC117) in vitro to assess binding and neutralization. In a clinical trial Cu-3BNC117 was infused into HIV uninfected (Group 1), HIV infected and viremic (viral load, VL >1000 c/mL; Group 2) and HIV infected aviremic (VL <20 c/mL; Group 3) participants using two dosing strategies: high protein (3mg/kg unlabeled 3BNC117 combined with <5mg Cu-3BNC117) and trace (<5mg Cu-3BNC117 only). All participants were screened for 3BNC117 sensitivity from virus obtained from viral outgrowth. Magnetic resonance imaging (MRI)/PET and pharmacokinetic assessments (ELISA for serum 3BNC117 concentrations and gamma counting for Cu) were performed 1, 24- and 48-hours post dosing. The trial (clincialtrials.gov NCT03063788) primary endpoint was comparison of PET standard uptake values (SUVs) in regions of interest (e.g lymph node groups and gastrointestinal tract).

Findings: Comparison of unmodified and modified 3BNC117 in vitro demonstrated no difference in HIV binding or neutralisation. 17 individuals were enrolled of which 12 were dosed including Group 1 (n=4, 2 high protein, 2 trace dose), Group 2 (n=6, 2 high protein, 4 trace) and Group 3 (n=2, trace only). HIV+ participants had a mean CD4 of 574 cells/microL and mean age 43 years. There were no drug related adverse effects and no differences in tissue uptake in regions of interest (e.g lymph node gut, pharynx) between the 3 groups. In the high protein dosing group, serum concentrations of 3BNC117 and gamma counts were highly correlated demonstrating that Cu-3BNC117 remained intact in vivo.

Interpretation: In PLWH on or off ART, the intervention of infusing Cu-3BNC117 and MRI/PET imaging over 48 hours, was unable to detect HIV-1 env expression in vivo. Future studies should investigate alternative radiolabels such as zirconium which have a longer half-life in vivo.

Funding: Funded by the Alfred Foundation, The Australian Centre for HIV and Hepatitis Virology Research with additional support from the Division of AIDS, National Institute of Allergy and Infectious Disease, US National Institutes of Health (USAI126611). JHM and SRL are supported by the Australian National Health and Medical Research Council.
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http://dx.doi.org/10.1016/j.ebiom.2021.103252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921458PMC
March 2021

[Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial.

Lancet 2021 Feb 11;397(10276):797-804. Epub 2021 Feb 11.

Prostate Cancer Theranostics and Imaging Centre of Excellence, Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.

Background: Lutetium-177 [Lu]Lu-PSMA-617 is a radiolabelled small molecule that delivers β radiation to cells expressing prostate-specific membrane antigen (PSMA), with activity and safety in patients with metastatic castration-resistant prostate cancer. We aimed to compare [Lu]Lu-PSMA-617 with cabazitaxel in patients with metastatic castration-resistant prostate cancer.

Methods: We did this multicentre, unblinded, randomised phase 2 trial at 11 centres in Australia. We recruited men with metastatic castration-resistant prostate cancer for whom cabazitaxel was considered the next appropriate standard treatment. Participants were required to have adequate renal, haematological, and liver function, and an Eastern Cooperative Oncology Group performance status of 0-2. Previous treatment with androgen receptor-directed therapy was allowed. Men underwent gallium-68 [Ga]Ga-PSMA-11 and 2-flourine-18[F]fluoro-2-deoxy-D-glucose (FDG) PET-CT scans. PET eligibility criteria for the trial were PSMA-positive disease, and no sites of metastatic disease with discordant FDG-positive and PSMA-negative findings. Men were randomly assigned (1:1) to [Lu]Lu-PSMA-617 (6·0-8·5 GBq intravenously every 6 weeks for up to six cycles) or cabazitaxel (20 mg/m intravenously every 3 weeks for up to ten cycles). The primary endpoint was prostate-specific antigen (PSA) response defined by a reduction of at least 50% from baseline. This trial is registered with ClinicalTrials.gov, NCT03392428.

Findings: Between Feb 6, 2018, and Sept 3, 2019, we screened 291 men, of whom 200 were eligible on PET imaging. Study treatment was received by 98 (99%) of 99 men randomly assigned to [Lu]Lu-PSMA-617 versus 85 (84%) of 101 randomly assigned to cabazitaxel. PSA responses were more frequent among men in the [Lu]Lu-PSMA-617 group than in the cabazitaxel group (65 vs 37 PSA responses; 66% vs 37% by intention to treat; difference 29% (95% CI 16-42; p<0·0001; and 66% vs 44% by treatment received; difference 23% [9-37]; p=0·0016). Grade 3-4 adverse events occurred in 32 (33%) of 98 men in the [Lu]Lu-PSMA-617 group versus 45 (53%) of 85 men in the cabazitaxel group. No deaths were attributed to [Lu]Lu-PSMA-617.

Interpretation: [Lu]Lu-PSMA-617 compared with cabazitaxel in men with metastatic castration-resistant prostate cancer led to a higher PSA response and fewer grade 3 or 4 adverse events. [Lu]Lu-PSMA-617 is a new effective class of therapy and a potential alternative to cabazitaxel.

Funding: Prostate Cancer Foundation of Australia, Endocyte (a Novartis company), Australian Nuclear Science and Technology Organization, Movember, The Distinguished Gentleman's Ride, It's a Bloke Thing, and CAN4CANCER.
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http://dx.doi.org/10.1016/S0140-6736(21)00237-3DOI Listing
February 2021

ELOVL5 Is a Critical and Targetable Fatty Acid Elongase in Prostate Cancer.

Cancer Res 2021 04 5;81(7):1704-1718. Epub 2021 Feb 5.

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, New York.

The androgen receptor (AR) is the key oncogenic driver of prostate cancer, and despite implementation of novel AR targeting therapies, outcomes for metastatic disease remain dismal. There is an urgent need to better understand androgen-regulated cellular processes to more effectively target the AR dependence of prostate cancer cells through new therapeutic vulnerabilities. Transcriptomic studies have consistently identified lipid metabolism as a hallmark of enhanced AR signaling in prostate cancer, yet the relationship between AR and the lipidome remains undefined. Using mass spectrometry-based lipidomics, this study reveals increased fatty acyl chain length in phospholipids from prostate cancer cells and patient-derived explants as one of the most striking androgen-regulated changes to lipid metabolism. Potent and direct AR-mediated induction of ELOVL fatty acid elongase 5 (ELOVL5), an enzyme that catalyzes fatty acid elongation, was demonstrated in prostate cancer cells, xenografts, and clinical tumors. Assessment of mRNA and protein in large-scale data sets revealed ELOVL5 as the predominant ELOVL expressed and upregulated in prostate cancer compared with nonmalignant prostate. ELOVL5 depletion markedly altered mitochondrial morphology and function, leading to excess generation of reactive oxygen species and resulting in suppression of prostate cancer cell proliferation, 3D growth, and tumor growth and metastasis. Supplementation with the monounsaturated fatty acid cis-vaccenic acid, a direct product of ELOVL5 elongation, reversed the oxidative stress and associated cell proliferation and migration effects of ELOVL5 knockdown. Collectively, these results identify lipid elongation as a protumorigenic metabolic pathway in prostate cancer that is androgen-regulated, critical for metastasis, and targetable via ELOVL5. SIGNIFICANCE: This study identifies phospholipid elongation as a new metabolic target of androgen action that is critical for prostate tumor metastasis.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2511DOI Listing
April 2021

A Phase 1 and Biodistribution Study of ABT-806i, an In-Radiolabeled Conjugate of the Tumor-Specific Anti-EGFR Antibody ABT-806.

J Nucl Med 2021 Jun 28;62(6):787-794. Epub 2021 Jan 28.

Olivia Newton-John Cancer Research Institute, Austin Health, Melbourne, Australia.

ABT-806 is a tumor-specific antibody targeting the epidermal growth factor receptor (EGFR). This study assessed safety, biodistribution, and pharmacokinetics of In-radiolabeled ABT-806 (ABT-806i) and effects of repeated doses of ABT-806 on receptor occupancy. Eligible patients had advanced tumors likely to express EGFR/EGFRvIII; adequate performance status and organ function; and measurable disease by RECIST 1.1. In cohort 1, 6 patients received a bolus administration of ABT-806i and underwent SPECT followed by whole-body planar scans. In cohort 2, 12 patients were imaged similarly as in 1 initially; thereafter, they received 3 doses of unlabeled ABT-806, before another dose of ABT-806i with associated SPECT and whole-body planar scans. At the end of both cohorts, patients who had stable or responding disease were able to enroll into an extension study (M12-326) in which they received unlabeled ABT-806 every 2 wk until disease progression, withdrawal of consent, or intolerable toxicity. No toxicity related to ABT-806i infusion was observed. ABT-806i showed minimal uptake in normal tissues and cleared gradually from blood with a half-life of 6.0 ± 1.5 d. The mean effective dose of ABT-806i was 0.137 mSv/MBq for males and 0.183 mSv/MBq for females. ABT-806i tumor uptake varied and did not correlate with archived tumor EGFR expression. No change in ABT-806i uptake was observed after interval ABT-806 treatment, indicating stable EGFR expression in tumor. The patient with highest tumor uptake of ABT-806i had advanced head and neck cancer and experienced a partial response. ABT-806i allows for real-time imaging of EGFR conformational expression in tumors, has an acceptable radiation dosimetry, and provides important additional information about antigen expression compared with standard approaches using archival tissue. Its role to assist in patient selection for EGFR-based therapeutics and investigate treatment resistance should be further investigated.
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http://dx.doi.org/10.2967/jnumed.120.253146DOI Listing
June 2021

Sensitization of Cancers Resistant to HER2 Antibodies.

Crit Rev Oncog 2020 ;25(3):175-207

Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia; School of Cancer Medicine, La Trobe University, Melbourne, Australia; Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Australia; Department of Medicine, University of Melbourne, Melbourne, Australia.

Human epidermal growth factor receptor 2 (HER2) oncogene addiction has led to the development of anti-HER2 therapies which have revolutionized the management of patients with HER2-positive cancers, with trastuzumab being the cornerstone of treatment of HER2-positive breast cancer. Despite the success of these biologics in breast cancer patients, not all patients with HER2-positive tumors respond to treatment, and many eventually develop resistance to therapy. Developing therapies that that circumvent current resistance mechanisms and improve patient outcomes further remains an area of unmet clinical need. Based on insights gained from established anti-HER2 therapies and our understanding of known resistance mechanisms a number of novel anti-HER2 treatments are being developed. These include novel HER2 antibody-drug conjugates that have shown activity in HER2 high and low tumors, novel HER2 antibodies, T cell bispecific antibodies, and HER2 antibodies in combination with phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors, immunotherapy and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. In this article, we review resistance mechanisms to approved HER2 antibodies and provide an overview of emerging therapeutic agents.
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http://dx.doi.org/10.1615/CritRevOncog.2020036080DOI Listing
January 2020

Expression of EGFR and conformational forms of EGFR in malignant pleural mesothelioma and its impact on survival.

Lung Cancer 2021 03 31;153:35-41. Epub 2020 Dec 31.

Department of Medical Oncology, Austin Health, Melbourne, Australia; Olivia-Newton John Cancer Research Institute, Melbourne, Australia; Faculty of Medicine, University of Melbourne, Melbourne, Australia; School of Cancer Medicine, La Trobe University, Melbourne, Australia.

Aim: Conformational forms of the epidermal growth factor receptor (EGFR) are pro-tumorigenic. The prevalence and impact of conformational forms of EGFR in malignant mesothelioma (MM) is unknown. We investigated expression of EGFR and conformational forms of EGFR by immunohistochemistry using EGFR-targeting monoclonal antibodies (mAb). In addition, EGFR gene amplification was investigated by fluorescent in-situ hybridization (FISH). Findings were correlated with survival.

Methods: Patients treated between 1988 and 2014 were identified from the thoracic surgery database of the Austin Hospital, Melbourne, Australia. Tissue microarrays (TMAs) were constructed, subjected to wild type (wt) EGFR IHC staining and FISH analysis. Conformational and mutation forms of EGFR were detected by IHC using mAb806, and LMH-151 which detects EGFRVIII. `H-scores` were derived and EGFR expression correlated with survival by Kaplan-Meier and log rank analysis.

Results: WtEGFR expression was seen in 93 % (299/321) of cases with overexpression (defined as an H-score ≥200) seen in more than half of cases (64 %). EGFR overexpression in MM was seen more commonly in the epithelioid subtype. EGFR overexpression was not associated with true EGFR amplification, although multiple copies were appreciated in samples with polysomy. EGFR expression did not correlate with survival. A conformational form of EGFR associated with EGFR dysregulation was found in 8.2 % of cases, and patients with these tumors had a trend towards a poorer outcome. No cases of the EGFRVIII mutation were identified.

Conclusion: MM consistently demonstrated high expression of EGFR, with a subset of tumors showing conformational EGFR forms consistent with EGFR dysregulation, but withoutEGFR amplification or EGFR VIII mutation. wtEGFR expression did not influence survival. The impact of EGFR conformation on survival warrants further investigation.
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http://dx.doi.org/10.1016/j.lungcan.2020.12.028DOI Listing
March 2021

The Australasian Radiopharmaceutical Trials Network: Clinical Trials, Evidence, and Opportunity.

J Nucl Med 2021 Jun 31;62(6):755-756. Epub 2020 Dec 31.

Department of Molecular Imaging and Therapy at Austin Health, Olivia Newton-John Cancer Research Institute and School of Cancer Medicine at La Trobe University, and Faculty of Medicine at University of Melbourne, Melbourne, Australia

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http://dx.doi.org/10.2967/jnumed.120.258152DOI Listing
June 2021

Pharmacogenomics in Radionuclide Therapy: Impact on Response to Theranostics.

J Nucl Med 2021 Jul 31;62(7):884-885. Epub 2020 Dec 31.

Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.

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http://dx.doi.org/10.2967/jnumed.120.254995DOI Listing
July 2021

Ventilation perfusion lung SPECT/CT in pregnancy during COVID-19.

Intern Med J 2020 12;50(12):1588-1590

Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1111/imj.15089DOI Listing
December 2020

2020 SNMMI Highlights Lecture: Oncology and Therapy, Part 2.

Authors:
Andrew M Scott

J Nucl Med 2021 Jan;62(1):14N-19N

Director, Department of Molecular Imaging and Therapy, Austin Health; Head, Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute; Professor, School of Cancer Medicine, La Trobe University; Professor, University of Melbourne; Melbourne, Australia.

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January 2021

Synthesis and fluorine-18 radiolabeling of a phospholipid as a PET imaging agent for prostate cancer.

Nucl Med Biol 2021 02 28;93:37-45. Epub 2020 Nov 28.

Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Australia; School of Cancer Medicine, La Trobe University, Melbourne, Australia; Department of Molecular Imaging and Therapy, Austin Health, Heidelberg, Australia; Department of Medicine, Melbourne University, Melbourne, Australia. Electronic address:

Introduction: Altered lipid metabolism and subsequent changes in cellular lipid composition have been observed in prostate cancer cells, are associated with poor clinical outcome, and are promising targets for metabolic therapies. This study reports for the first time on the synthesis of a phospholipid radiotracer based on the phospholipid 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine (PC44:12) to allow tracking of polyunsaturated lipid tumor uptake via PET imaging. This tracer may aid in the development of strategies to modulate response to therapies targeting lipid metabolism in prostate cancer.

Methods: Lipidomics analysis of prostate tumor explants and LNCaP tumor cells were used to identify PC44:12 as a potential phospholipid candidate for radiotracer development. Synthesis of phosphocholine precursor and non-radioactive standard were optimised using click chemistry. The biodistribution of a fluorine-18 labeled analogue, N-{[4-(2-[F]fluoroethyl)-2,3,4-triazol-1-yl]methyl}-1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine ([F]2) was determined in LNCaP prostate tumor-bearing NOD SCID gamma mice by ex vivo biodistribution and PET imaging studies and compared to biodistribution of [F]fluoromethylcholine.

Results: [F]2 was produced with a decay-corrected yield of 17.8 ± 3.7% and an average radiochemical purity of 97.00 ± 0.89% (n = 6). Molar activity was 85.1 ± 3.45 GBq/μmol (2300 ± 93 mCi/μmol) and the total synthesis time was 2 h. Ex vivo biodistribution data demonstrated high liver uptake (41.1 ± 9.2%ID/g) and high splenic uptake (10.9 ± 9.1%ID/g) 50 min post-injection. Ex vivo biodistribution showed low absolute tumor uptake of [F]2 (0.8 ± 0.3%ID/g). However, dynamic PET imaging demonstrated an increase over time of the relative tumor-to-muscle ratio with a peak of 2.8 ± 0.5 reached 1 h post-injection. In contrast, dynamic PET of [F]fluoromethylcholine demonstrated no increase in tumor-to-muscle ratios due to an increase in both tumor and muscle over time. Absolute uptake of [F]fluoromethylcholine was higher and peaked at 60 min post injection (2.25 ± 0.29%ID/g) compared to [F]2 (1.44 ± 0.06%ID/g) during the 1 h dynamic scan period.

Conclusions And Advances In Knowledge: This study demonstrates the ability to radiolabel phospholipids and indicates the potential to monitor the in vivo distribution of phospholipids using fluorine-18 based PET.
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http://dx.doi.org/10.1016/j.nucmedbio.2020.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071757PMC
February 2021

2020 SNMMI Highlights Lecture: Oncology and Therapy, Part 1.

Authors:
Andrew M Scott

J Nucl Med 2020 12;61(12):31N-40N

Director, Department of Molecular Imaging and Therapy, Austin Health; Head, Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute; Professor, School of Cancer Medicine, La Trobe University; Professor, University of Melbourne; Melbourne, Australia.

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December 2020

Response Evaluation and Survival Prediction After PD-1 Immunotherapy in Patients with Non-Small Cell Lung Cancer: Comparison of Assessment Methods.

J Nucl Med 2021 Jul 27;62(7):926-933. Epub 2020 Nov 27.

Department of Molecular Imaging and Therapy, Austin Health, Heidelberg, Victoria, Australia.

Immunotherapy using programmed death-1 blockers is a promising modality for non-small cell lung cancer (NSCLC). Therefore, defining the most accurate response criteria for immunotherapy monitoring is of great importance in patient management. This study aimed to compare the correlation between survival outcome and response assessment by PERCIST, version 1.0; immunotherapy-modified PERCIST (imPERCIST); RECIST, version 1.1; and immunotherapy-modified RECIST (iRECIST) in NSCLC patients. Seventy-two patients with NSCLC who were treated with nivolumab or pembrolizumab and had baseline and follow-up F-FDG PET/CT data were analyzed. The patients were categorized into responders (complete or partial response) and nonresponders (stable or progressive disease) according to PERCIST1 and PERCIST5 (analyzing the peak SUV normalized by lean body mass [SUL] of 1 or up to 5 lesions), imPERCIST1, imPERCIST5, RECIST, and iRECIST. The correlation between achieved response and overall survival (OS) was compared. The overall response rate and the overall disease control rate of the study population were 29% and 74%, respectively. The OS and progression-free survival (PFS) of patients with complete and partial response were statistically comparable. The OS and PFS were significantly different between responders and nonresponders (20.3 vs. 10.6 mo, = 0.001, for OS and 15.5 vs. 2.2 mo, < 0.001, for PFS, respectively). Twenty-three (32%) patients with progressive disease according to PERCIST5 had controlled disease according to imPERCIST5; follow-up of patients showed that 22% of these patients had pseudoprogression. The overall incidence of pseudoprogression was 7%. The response rate was 25% and 24% according to PERCIST1 and PERCIST5 ( = 0.2) and 32% and 29% according to imPERCIST1 and imPERCIST5 ( = 0.5), respectively, indicating no significant difference between analyzing the SUL of only the most F-FDG-avid lesion and analyzing up to the 5 most F-FDG-avid lesions. The achieved response by all conventional and immunotherapy-modified methods correlated strongly with patients' survival outcome, with significantly longer OS and PFS in responders than in nonresponders according to all assessed definitions. The most F-FDG-avid lesion according to PERCIST and imPERCIST accurately reflects the overall metabolic response.
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http://dx.doi.org/10.2967/jnumed.120.254508DOI Listing
July 2021

Eph Receptors in the Immunosuppressive Tumor Microenvironment.

Cancer Res 2021 02 11;81(4):801-805. Epub 2020 Nov 11.

Tumour Targeting Program, Olivia Newton-John Cancer Institute/La Trobe University School of Cancer Medicine, Victoria, Melbourne, Australia.

The tumor microenvironment (TME) promotes tumor development via complex intercellular signaling, aiding tumor growth and suppressing immunity. Eph receptors (Eph) and their ephrin ligands control cell interactions during normal development, and reemerge in tumors and the TME, where they are implicated in invasion, metastasis, and angiogenesis. Recent studies also indicate roles for Ephs in suppressing immune responses by controlling tumor interactions with innate and adaptive immune cells within the TME. Accordingly, inhibiting these functions can promote immune response and efficacy of immune checkpoint inhibition. This research highlights Ephs as potential targets to enhance efficacy of immune-based therapies in patients with cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3047DOI Listing
February 2021

Automated synthesis of F radiolabelled indole containing Oncrasin-like molecules; a comparison of iodonium salts and boronic ester chemistry.

EJNMMI Radiopharm Chem 2020 Nov 9;5(1):23. Epub 2020 Nov 9.

The Olivia Newton-John Cancer Research Insititute, and School of Cancer Medicine, La Trobe University, Heidelberg, 3084, Australia.

Background: Oncrasin-1 is a small molecule which was identified from a screen of KRAS mutant cancer cells and has shown specificity for KRAS mutant cell killing. We aimed to develop a radiolabelled form of Oncrasin-1 to enable in-vivo imaging of mutant KRAS expression in malignant tumours. This work outlines the synthesis of 3 fluorinated derivatives and development of iodonium salt and boronic ester precursors for radiolabelling with the F isotope.

Results: In our hands, synthesis of iodonium salts were not easily accessible due to the 3-carbaldehyde indole structure being preferentially oxidized by conditions required for iodonium salt formation, rather than benzyl iodide. Synthesis and radiolabelling of boronic acid pinacol ester precursors were successful, with the products being obtained in yields of 10.76% ± 0.96% (n = 5), 14.7% ±8.58% (n = 3) and 14.92% ±3.9% (n = 3) for F KAM001, F KAM002 and F KAM003 respectively, with radiochemical purity of greater than 99%.

Conclusions: The successful synthesis of these tracers has been undertaken utilizing boronic ester radio-fluorination methods and will allow for investigation of Oncrasin based molecules as potential diagnostics for cancers expressing mutant KRAS protein.
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http://dx.doi.org/10.1186/s41181-020-00104-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652984PMC
November 2020

Antibody-Drug Conjugates for Cancer Therapy.

Molecules 2020 Oct 16;25(20). Epub 2020 Oct 16.

Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, VIC 3084, Australia, (U.H.).

Antibody-drug conjugates (ADCs) are novel drugs that exploit the specificity of a monoclonal antibody (mAb) to reach target antigens expressed on cancer cells for the delivery of a potent cytotoxic payload. ADCs provide a unique opportunity to deliver drugs to tumor cells while minimizing toxicity to normal tissue, achieving wider therapeutic windows and enhanced pharmacokinetic/pharmacodynamic properties. To date, nine ADCs have been approved by the FDA and more than 80 ADCs are under clinical development worldwide. In this paper, we provide an overview of the biology and chemistry of each component of ADC design. We briefly discuss the clinical experience with approved ADCs and the various pathways involved in ADC resistance. We conclude with perspectives about the future development of the next generations of ADCs, including the role of molecular imaging in drug development.
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http://dx.doi.org/10.3390/molecules25204764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587605PMC
October 2020

Automated radiosynthesis of [ Ga]Ga-PSMA-11 and [ Lu]Lu-PSMA-617 on the iPHASE MultiSyn module for clinical applications.

J Labelled Comp Radiopharm 2021 Mar 2;64(3):140-146. Epub 2020 Nov 2.

Tumor Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia.

Prostate-specific membrane antigen (PSMA)-targeted imaging and therapy of prostate cancer using theranostic pairs is rapidly changing clinical practice. To facilitate clinical trials, fully automated procedures for the radiosyntheses of [ Ga]Ga-PSMA-11 and [ Lu]Lu-PSMA-617 were developed from commercially available precursors using the cassette based iPHASE MultiSyn module. Formulated and sterile radiopharmaceuticals were obtained in 76 ± 3% (n = 20) and 91 ± 4% (n = 15) radiochemical yields after 17 and 20 min, respectively. Radiochemical purity was always >95% and molar activities exceeded 792 ± 100 and 88 ± 6 GBq/μmol, respectively. Quality control showed conformity with all relevant release criteria and radiopharmaceuticals were used in the clinic.
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http://dx.doi.org/10.1002/jlcr.3889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048907PMC
March 2021

First clinical study of a pegylated diabody I-labeled PEG-AVP0458 in patients with tumor-associated glycoprotein 72 positive cancers.

Theranostics 2020 15;10(25):11404-11415. Epub 2020 Sep 15.

Avipep Pty Ltd and the Victorian Cancer Biologics Consortium, Parkville, Victoria 3052, Australia.

Through protein engineering and a novel pegylation strategy, a diabody specific to tumor-associated glycoprotein 72 (TAG-72) (PEG-AVP0458) has been created to optimize pharmacokinetics and bioavailability to tumor. We report the preclinical and clinical translation of PEG-AVP0458 to a first-in-human clinical trial of a diabody. Clinical translation followed characterization of PEG-AVP0458 drug product and preclinical biodistribution and imaging assessments of Iodine-124 trace labeled PEG-AVP0458 (I-PEG-AVP0458). The primary study objective of the first-in-human study was the safety of a single protein dose of 1.0 or 10 mg/mI-PEG-AVP0458 in patients with TAG-72 positive relapsed/ metastatic prostate or ovarian cancer. Secondary study objectives were evaluation of the biodistribution, tumor uptake, pharmacokinetics and immunogenicity. Patients were infused with a single-dose of I labeled PEG-AVP0458 (3-5 mCi (111-185 MBq) for positron emission tomography (PET) imaging, performed sequentially over a one-week period. Safety, pharmacokinetics, biodistribution, and immunogenicity were assessed up to 28 days after infusion. PEG-AVP0458 was radiolabeled with I and shown to retain high TAG-72 affinity and excellent targeting of TAG-72 positive xenografts by biodistribution analysis and PET imaging. In the first-in-human trial, no adverse events or toxicity attributable to I-PEG-AVP0458 were observed. Imaging was evaluable in 5 patients, with rapid and highly specific targeting of tumor and minimal normal organ uptake, leading to high tumor:blood ratios. Serum concentration values of I-PEG-AVP0458 showed consistent values between patients, and there was no significant difference in T½α and T½β between dose levels with mean (± SD) results of T½α = 5.10 ± 4.58 hours, T½β = 46.19 ± 13.06 hours. These data demonstrates the safety and feasibility of using pegylated diabodies for selective tumor imaging and potential delivery of therapeutic payloads in cancer patients.
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http://dx.doi.org/10.7150/thno.49422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545991PMC
June 2021

Neutrophil to lymphocyte ratio predicts glucocorticoid resistance in polymyalgia rheumatica.

Int J Rheum Dis 2021 Jan 12;24(1):56-62. Epub 2020 Oct 12.

Department of Rheumatology, Austin Health, Heidelberg, VIC, Australia.

Aim: Neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) correlate with disease activity in several rheumatic diseases; however, their utility in polymyalgia rheumatica (PMR) remains unclear. This study evaluated their relationship with disease activity and glucocorticoid resistance in PMR.

Method: Data for disease activity (PMR-AS) and full blood examination was obtained from a prospective observational cohort comprising newly diagnosed, steroid-naïve PMR patients treated with low-dose glucocorticoid therapy. Glucocorticoid resistance was defined as non-response to prednisolone 15 mg/d or initial response followed by flare (PMR-AS ≥ 9.35 or ∆ ≥6.6) upon weaning to 5 mg/d. Univariable Bayesian linear regression analysis of the relationship between PMR-AS (baseline and mean) and NLR and PLR was performed. Predictors of glucocorticoid resistance were identified using a multivariable outcome model, with variables derived from Bayesian model selection.

Results: Of the 32 included patients, 16 (50%) fulfilled the primary outcome measure of glucocorticoid resistance. These participants were older, typically female, and had higher baseline C-reactive protein than their glucocorticoid-responsive counterparts. A statistically significant relationship was identified between PMR-AS and both NLR (odds ratio [OR] 28.1; 95% CI 1.6-54.7) and PLR (OR 40.6; 95% CI 10.1-71.4) at baseline, with PLR also found to correlate with disease activity during follow-up (OR 15.6; 95% CI 2.7-28.2). Baseline NLR proved a statistically significant predictor of glucocorticoid-resistant PMR (OR 14.01; 95% CI 1.49-278.06).

Conclusion: Baseline NLR can predict glucocorticoid resistance in newly diagnosed PMR patients. Both NLR and PLR may be reliable biomarkers of disease activity in PMR.
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http://dx.doi.org/10.1111/1756-185X.14000DOI Listing
January 2021

Analysis of angiogenic and stromal biomarkers in a large malignant mesothelioma cohort.

Lung Cancer 2020 12 1;150:1-8. Epub 2020 Oct 1.

Department of Medical Oncology, Austin Health, Melbourne, Australia; Olivia-Newton John Cancer Research Institute, Melbourne, Australia; School of Cancer Medicine, La Trobe University, Melbourne, Australia.

Background: Malignant mesothelioma (MM) is an aggressive malignancy of the pleura and other mesothelial membranes. Agents targeting vascular endothelial growth factor (VEGF) such as bevacizumab; and multi-kinase inhibitors such as nintedanib [angiokinase inhibitor of VEGF, platelet-derived growth factor (PDGF) receptor and fibroblast growth factor receptor (FGFR)] have recently demonstrated efficacy in MM.

Methods: Tissue microarrays (TMAs) were created from formalin-fixed, paraffin-embedded tissue samples obtained from 326 patients with MM who were treated surgically. PDGF-CC, FGFR-1, VEGF and CD31 expression were analysed by immunohistochemical (IHC) staining. The H-score method assigned a score of 0-300 to each sample, based on the percentage of cells stained at different intensities. CD31 was evaluated via Chalkley's method to evaluate microvessel density. We evaluated the association between expression of the biomarkers, clinicopathological factors and outcomes, in patients with MM.

Results: CD31 high (≥5) was seen in only 31/302 (10.3%) irrespective of histology. PDGF-CC high (≥150) was seen in 203 /310 (65%) of all samples. VEGF high (≥80) was seen in 219/322 (68%) of all MM with 143/209 (68%) of epithelioid histology. FGFR-1 high (≥40) was seen in 127/310 (41%) of all MM. There was no association of VEGF and FGFR-1 IHC with survival nor differences between histological subtypes. There was a non-significant trend towards poorer survival in epithelioid tumours with increased PDGF-CC expression (OS 18.5 vs 13.2 months; HR 0.7928; 95% CI 0.5958 to 1.055, P = 0.1110). High CD31 score was associated with significantly poorer survival (OS 12 vs 8.6 months; HR 0.48; 95% CI 0.2873 to 0.7941, P = 0.0044). Of the 31 patients with high CD31 scores; 23/31 (74%) were also high for PDGF-CC and 20/31 (64%) with high VEGF scores. CD31 was found to be an independent prognostic factor in multivariate analysis (HR 1.540; 95% CI 1.018 to 2.330; p = 0.041).

Conclusions: High CD31 was an independent poor prognostic factor and high PDGF-CC expression was associated with poor survival in MM. Abrogating these pathways may have prognostic implications.
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http://dx.doi.org/10.1016/j.lungcan.2020.09.022DOI Listing
December 2020

Targeting and Efficacy of Novel mAb806-Antibody-Drug Conjugates in Malignant Mesothelioma.

Pharmaceuticals (Basel) 2020 Oct 2;13(10). Epub 2020 Oct 2.

Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Victoria 3084, Australia.

Epidermal growth factor receptor (EGFR) is highly overexpressed in malignant mesothelioma (MM). MAb806 is a novel anti-EGFR antibody that selectively targets a tumor-selective epitope. MAb806-derived antibody drug conjugates (ADCs), ABT-414, ABBV-221 and ABBV-322, may represent a novel therapeutic strategy in MM. EGFR and mAb806 epitope expressions in mesothelioma cell lines were evaluated using an array of binding assays, and the in vitro cell effects of ABT-414 and ABBV-322 were determined. In vivo therapy studies were conducted in mesothelioma xenograft and patient-derived xenograft (PDX) tumor models. We also performed biodistribution and imaging studies to allow the quantitative targeting of MM by mAb806 using a Zr-labeled immunoconjugate-ch806. A high EGFR expression was present in all mesothelioma cell lines evaluated and mAb806 binding present in all cell lines, except NCIH-2452. ABT-414 and ABBV-322 resulted in significant tumor growth inhibition in MM models with high EGFR and mAb806 epitope expressions. In contrast, in an EGFR-expressing PDX model that was negative for the mAb806 epitope, no growth inhibition was observed. We demonstrated the specific targeting of the mAb806 epitope expressing MM tumors using Zr-based PET imaging. Our data suggest that targeting EGFR in MM using specific ADCs is a valid therapeutic strategy and supports further investigation of the mAb806 epitope expression as a predictive biomarker.
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http://dx.doi.org/10.3390/ph13100289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601847PMC
October 2020

New insights into ErbB3 function and therapeutic targeting in cancer.

Expert Rev Anticancer Ther 2020 12 26;20(12):1057-1074. Epub 2020 Oct 26.

Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute , Melbourne, Australia.

Introduction: The importance of ErbB3 receptor tyrosine kinase in cancer progression, primary and acquired drug resistance, has become steadily evident since its discovery in 1989. ErbB3 overexpression in various solid organ malignancies is associated with shorter survival of patients. However, initial strategies to therapeutically target ErbB3 have not been rewarding.

Areas Covered: Here, we provide an overview of ErbB3 biology in carcinogenesis. We outline the role of ErbB3 as a critical pathway for resistance to other anti-cancer drugs. We focus on emerging clinical data, which will steer the potential future development of ErbB3 directed therapies.

Expert Opinion: Initial approaches to ErbB3 targeting have been challenging. However, the lack of success of anti-ErbB3 therapies in ongoing clinical trials may relate more to the complex biology of the receptor and challenges with the biomarkers used to date. Furthermore, it seems certain that the expression of the receptor is necessary but not sufficient for the response to ErbB3 therapies. Emerging data suggest that more sophisticated biomarkers are needed. Nonetheless, it is also likely that ErbB3 therapies may have the most efficacy in combination therapy, and their favorable toxicity profile makes this feasible.
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http://dx.doi.org/10.1080/14737140.2020.1829485DOI Listing
December 2020

Targeting Multiple EGFR-expressing Tumors with a Highly Potent Tumor-selective Antibody-Drug Conjugate.

Mol Cancer Ther 2020 10 26;19(10):2117-2125. Epub 2020 Aug 26.

AbbVie Inc., North Chicago, Illinois.

ABBV-321 (serclutamab talirine), a next-generation EGFR-targeted antibody-drug conjugate (ADC) incorporates a potent pyrrolobenzodiazepine (PBD) dimer toxin conjugated to the EGFR-targeting ABT-806 affinity-matured AM1 antibody. ABBV-321 follows the development of related EGFR-targeted ADCs including depatuxizumab mafodotin (depatux-m, ABT-414), ABT-806 conjugated to monomethyl auristatin F (MMAF), and ABBV-221 (losatuxizumab vedotin), AM1 antibody conjugated to monomethyl auristatin E (MMAE). The distinct tumor selectivity of ABBV-321 differentiates it from many previous highly active antibody PBD conjugates that lack a therapeutic window. Potency of the PBD dimer, combined with increased binding of AM1 to EGFR-positive tumor cells, opens the possibility to target a wide array of tumors beyond those with high levels of EGFR overexpression or amplification, including those insensitive to auristatin-based ADCs. ABBV-321 exhibits potent antitumor activity in cellular and studies including xenograft cell line and patient-derived xenograft glioblastoma, colorectal, lung, head and neck, and malignant mesothelioma tumor models that are less sensitive to depatux-m or ABBV-221. Combination studies with ABBV-321 and depatux-m suggest a promising treatment option permitting suboptimal, and potentially better tolerated, doses of both ADCs while providing improved potency. Collectively, these data suggest that ABBV-321 may offer an extended breadth of efficacy relative to other EGFR ADCs while extending utility to multiple EGFR-expressing tumor indications. Despite its highly potent PBD dimer payload, the tumor selectivity of ABBV-321, coupled with its pharmacology, toxicology, and pharmacokinetic profiles, support continuation of ongoing phase I clinical trials in patients with advanced EGFR-expressing malignancies.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0149DOI Listing
October 2020

The role and contribution of treatment and imaging modalities in global cervical cancer management: survival estimates from a simulation-based analysis.

Lancet Oncol 2020 08;21(8):1089-1098

Department of Global Health and Population, Harvard T H Chan School of Public Health, Harvard University, Boston, MA, USA.

Background: Cervical cancer is the fourth most common cancer among women worldwide, causing more than 300 000 deaths globally each year. In addition to screening and prevention, effective cancer treatment is needed to reduce cervical cancer mortality. We discuss the role of imaging in cervical cancer management and estimate the potential survival effect of scaling up imaging in several different contexts.

Methods: Using a previously developed microsimulation model of global cancer survival, we estimated stage-specific cervical cancer 5-year net survival in 200 countries and territories. We evaluated the potential survival effect of scaling up treatment (chemotherapy, surgery, radiotherapy, and targeted therapy), and imaging modalities (ultrasound, x-ray, CT, MRI, PET, and single photon emission CT [SPECT]) to the mean level of high-income countries, both individually and in combination.

Findings: We estimate global cervical cancer 5-year net survival as 42·1% (95% uncertainty interval [UI] 33·8-48·5). Among individual imaging modalities, expanding MRI would yield the largest 5-year survival gains globally (data are absolute percentage point increase in survival 0·6, 95% UI 0·1-2·1), scaling up ultrasound would yield the largest gains in low-income countries (0·5, 0·0-3·7), expanding CT and x-ray would have the greatest effect in Latin America (0·8, 0·0-3·4) and Oceania (0·4, 0·0-3·2), and expanding PET would yield the largest gains in high-income countries (0·2, 0·0-0·8). Scaling up SPECT did not show major changes in any region. Among individual treatment modalities, scaling up radiotherapy would yield the largest absolute percentage point gains in low-income countries (5·2, 0·3-13·5), and expanding surgery would have the largest effect in lower-middle-income countries (7·4, 0·3-21·1) and upper-middle-income countries (0·8, 0·0-2·9). Estimated survival gains in high-income countries were very modest. However, the gains from expanding any single treatment or imaging modality individually were small across all income levels and geographical settings. Scaling up all treatment modalities could improve global 5-year net survival to 52·4% (95% UI 44·6-62·0). In addition to expanding treatment, improving quality of care could raise survival to 57·5% (51·2-63·5), and the cumulative effect of scaling up all imaging modalities together with expanded treatment and quality of care could improve 5-year net survival for cervical cancer to 62·5% (57·7-67·8).

Interpretation: Comprehensive scale-up of treatment, imaging, and quality of care could substantially improve global cervical cancer 5-year net survival, with quality of care and imaging improvements each contributing about 25% of the total potential gains. These findings suggest that a narrow focus on the availability of treatment modalities could forgo substantial survival gains. Investments in imaging equipment, personnel, and quality of care efforts will also be needed to successfully scale up cervical cancer treatment worldwide.

Funding: Harvard T H Chan School of Public Health and National Cancer Institute.
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http://dx.doi.org/10.1016/S1470-2045(20)30316-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574952PMC
August 2020

Estimating the impact of treatment and imaging modalities on 5-year net survival of 11 cancers in 200 countries: a simulation-based analysis.

Lancet Oncol 2020 08;21(8):1077-1088

Department of Global Health and Population, Harvard T H Chan School of Public Health, Harvard University, Boston, MA, USA; Department of Global Health and Social Medicine, Harvard Medical School, Harvard University, Boston, MA, USA.

Background: Accurate survival estimates are important for cancer control planning. Although observed survival estimates are unavailable for many countries, where they are available, wide variations are reported. Understanding the impact of specific treatment and imaging modalities can help decision makers to effectively allocate resources to improve cancer survival in their local context.

Methods: We developed a microsimulation model of stage-specific cancer survival in 200 countries and territories for 11 cancers (oesophagus, stomach, colon, rectum, anus, liver, pancreas, lung, breast, cervix uteri, and prostate) comprising 60% of global diagnosed cancer cases. The model accounts for country-specific availability of treatment (chemotherapy, surgery, radiotherapy, and targeted therapy) and imaging modalities (ultrasound, x-ray, CT, MRI, PET, single-photon emission CT), as well as quality of care. We calibrated the model to reported survival estimates from CONCORD-3 (which reports global trends in cancer survival in 2000-14). We estimated 5-year net survival for diagnosed cancers in each country or territory and estimated potential survival gains from increasing the availability of individual treatment and imaging modalities, and more comprehensive packages of scale-up of these interventions. We report the mean and 95% uncertainty intervals (UIs) for all outcomes, calculated as the 2·5 and 97·5 percentiles of the simulation results.

Findings: The estimated global 5-year net survival for all 11 cancers combined is 42·6% (95% uncertainty interval 40·3-44·3), with survival in high-income countries being an average of 12 times (range 4-17) higher than that in low-income countries. Expanding availability of surgery or radiotherapy or improving quality of care would yield the largest survival gains in low-income (2·5-3·4 percentage point increase in survival) and lower-middle-income countries (2·4-6·1 percentage point increase), whereas upper-middle-income and high-income countries are more likely to benefit from improved availability of targeted therapy (0·7 percentage point increase for upper-middle income and 0·4 percentage point increase for high income). Investing in medical imaging will also be necessary to achieve substantial survival gains, with traditional modalities estimated to provide the largest gains in low-income settings, while MRI and PET would yield the largest gains in higher-income countries. Simultaneous expansion of treatment, imaging, and quality of care could improve 5-year net survival by more than ten times in low-income countries (3·8% [95% UI 0·5-9·2] to 45·2% [40·2-52·1]) and could more than double 5-year net survival in lower-middle-income countries (20·1% [7·2-31·7] to 47·1% [42·8-50·8]).

Interpretation: Scaling up both treatment and imaging availability could yield synergistic survival gains for patients with cancer. Expanding traditional modalities in lower-income settings might be a feasible pathway to improve survival before scaling up more modern technologies.

Funding: Harvard T H Chan School of Public Health.
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http://dx.doi.org/10.1016/S1470-2045(20)30317-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020599PMC
August 2020
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