Publications

Abstract LF11-322 (PFWRIRIRR-NH 2 ) (PFR peptide), a nine amino acid-residue peptide fragment derived from human lactoferricin, possesses potent cytotoxicity against bacteria. We report here the discovery and characterization of its antitumor activity in leukemia cells. PFR peptide inhibited the proliferation of MEL and HL-60 leukemia cells by inducing cell death in the absence of the classical features of apoptosis, including chromatin condensation, Annexin V staining, Caspase activation and increase of abundance of pro-apoptotic proteins. Instead, necrotic cell death as evidenced by increasing intracellular PI staining and LDH release, inducing membrane disruption and up-regulating intracellular calcium level, was observed following PFR peptide treatment. In addition to necrotic cell death, PFR peptide also induced G 0 /G 1 cell cycle arrest. Moreover, PFR peptide exhibited favorable antitumor activity and tolerability in vivo . These findings thus provide a new clue of antimicrobial peptides as a potential novel therapy for leukemia.

<p>Western blot analysis of ERK and phosphorylated ERK in the MCC 14, MCC 13 and MCC26 Merkel cell carcinoma lines.</p>

151 Background: There are fewer preclinical models of prostate cancer compared to other common tumours. New models that represent the diverse features of castrate-sensitive and castration-resistant prostate cancer (CRPC) are required for thorough preclinical testing of novel treatments. Therefore, the goal of the Melbourne Urological Research Alliance (MURAL) is to develop patient-derived xenografts (PDXs) spanning the clinical trajectory of prostate cancer. Methods: We grafted >200 surgery, biopsy or rapid autopsy samples into testosterone-supplemented or castrated male NSG mice. Actively growing tumours were serially transplanted or grown as explants or organoids. PDXs were analysed using RNAseq, targeted genomic sequencing and histopathology review. Results: We previously reported 4 serially transplantable PDXs (Lawrence, et al., 2018, European Urology). Now we have established ~30 additional models spanning treatment naïve primary disease to CRPC. PDXs of CRPC were often from soft tissue metastases of patients who had failed docetaxel, cabazitaxel, enzalutamide, abiraterone and other contemporary treatments. Accordingly, they had diverse mechanisms of resistance, including AR mutations, genomic structural rearrangements, gene amplifications and expression of AR variants. In addition, several PDXs had AR-null phenotypes, including small cell prostate cancer. All PDXs closely reflected the genomic, transcriptomic and histopathological characteristics of the original patient tumours. As renewable sources of tissue, the PDXs could also be grown as ex vivo slice cultures and in vitro organoids, providing complementary models with different timescales and endpoints. Conclusions: We have developed a new collection of castrate-sensitive and castrate-resistant PDXs of prostate cancer, providing diverse tumours for preclinical testing of candidate treatments.

Abstract Introduction The Prostate Cancer Foundation (PCF) convened a PCF prostate‐specific membrane antigen (PSMA) Theranostics State of the Science Meeting on 18 November 2019, at Weill Cornell Medicine, New York, NY. Methods The meeting was attended by 22 basic, translational, and clinical researchers from around the globe, with expertise in PSMA biology, development and use of PSMA theranostics agents, and clinical trials. The goal of this meeting was to discuss the current state of knowledge, the most important biological and clinical questions, and critical next steps for the clinical development of PSMA positron emission tomography (PET) imaging agents and PSMA‐targeted radionuclide agents for patients with prostate cancer. Results Several major topic areas were discussed including the biology of PSMA, the role of PSMA‐targeted PET imaging in prostate cancer, the physics and performance of different PSMA‐targeted PET imaging agents, the current state of clinical development of PSMA‐targeted radionuclide therapy (RNT) agents, the role of dosimetry in PSMA RNT treatment planning, barriers and challenges in PSMA RNT clinical development, optimization of patient selection for PSMA RNT trials, and promising combination treatment approaches with PSMA RNT. Discussion This article summarizes the presentations from the meeting for the purpose of globally disseminating this knowledge to advance the use of PSMA‐targeted theranostic agents for imaging and treatment of patients with prostate cancer.

Abstract Background In recent years, immune checkpoint blockade has become a standard therapy for a wide range of cancers. Adverse events, including endocrinopathies, result from the induction of autoimmunity. Case report We report a case series of nine individuals who presented with immunotherapy‐induced Type 1 diabetes between 2015 and 2017. Onset of diabetes occurred within 12 weeks of commencing therapy. Anti‐glutamic acid decarboxylase antibodies were present in six people. Retrospective testing of islet antibodies in pre‐treatment samples was possible in two people and this revealed anti‐glutamic acid decarboxylase seroconversion in the first and high anti‐glutamic acid decarboxylase titres pre‐ and post‐treatment in the second person. Six people had high risk human leukocyte antigen haplotypes. Clinical and genetic factors are described and compared with previously published cases. Conclusion This rare form of iatrogenic diabetes is a result of an accelerated, fulminant islet autoimmunity induced by immune checkpoint inhibitors. High risk human leukocyte antigen haplotypes have been found in the majority of cases. The role of pre‐existing islet autoantibodies as a biomarker is not yet known.

277 Background: Pembrolizumab monotherapy, whilst not standard of care, has demonstrated efficacy in clear cell renal cell carcinoma (ccRCC). The first-line KEYNOTE-427 study demonstrated an overall response rate (ORR) of 34%, and a median progression-free survival (PFS) of 7.1 mo (McDermott D et al. J Clin Oncol 2020; 38:S15; 5069-5069). Stereotactic ablative body radiotherapy (SABR) is an option for oligometastatic ccRCC, but patients often develop distant progression or relapse within irradiated sites. The RAPPORT study (NCT02855203) was a multi-institutional single arm, phase I/II study evaluating safety and efficacy of SABR and pembrolizumab. Methods: Patients with up to 2 lines of prior systemic therapy with 1-5 oligometastases from ccRCC were eligible. A single fraction of 20Gy SABR to all metastatic sites was given (or 10 fractions of 3 Gy of conventional radiotherapy [CRT] if SABR was not feasible), followed by pembrolizumab 200mg administered Q3W for 8 cycles. The primary objective was safety (CTCAEv4.03), with secondary key objectives of efficacy (RECIST1.1) by disease control rate (DCR), defined as complete response (CR), partial response (PR) or stable disease for at least 6 months, ORR, PFS and overall survival (OS). Results: Thirty patients were enrolled and received protocol treatment. The median follow-up was was 2.3 years. The median age was 62 (range 47-80) years, 23 patients (77%) were male. Twenty-three patients (77%) were treatment naïve, 1 patient (3%) had a prior interleukin-2 therapy and 6 patients (20%) had a prior tyrosine kinase inhibitor. Nine patients (30%) had prior metastasectomy. Eighty-three oligometastases were treated (median of 3 per patient), of which 64 (77%) received SABR, and 19 (23%) received CRT. There were 8 adrenal, 11 bone, 43 lung, 12 lymph node and 9 soft tissue metastases irradiated. Four patients (13% [95%CI: 4-31%]) had one or more grade 3 treatment-related AE: Pneumonitis (n=2), dyspnoea (n=1) and elevated ALP/ALT (n=1). There were no grade 4 or 5 AEs. All eight cycles of pembrolizumab were completed by 24 (80%) patients. DCR was 83% (95%CI: 65-94%). ORRs are tabulated below. Median PFS was 15.6 mo. Estimated 1 and 2-year OS was 90% (95%CI: 72-97%) and 74% (95%CI: 53-87%), respectively, while PFS was 60% (95%CI: 40-75%) and 45% (95%CI: 27-62%), respectively. Freedom from local progression at 2-years was 92% (95%CI: 80-97%). Conclusions: The combination of SABR and pembrolizumab in oligometastatic renal cell carcinoma is well tolerated with excellent local control. Durable responses and encouraging PFS were observed with this approach, which warrants further investigation. Clinical trial information: NCT02855203 . [Table: see text]

Substance P (SP) regulates multiple biological processes through its high-affinity neurokinin-1 receptor (NK-1R). While the SP/NK-1R signaling axis is involved in the pathogenesis of solid cancer, the role of this signaling pathway in hematological malignancy remains unknown. Here, we demonstrate that NK-1R expression is markedly elevated in the white blood cells from acute myeloid leukemia patients and a panel of human leukemia cell lines. Blocking NK-1R induces apoptosis in vitro and in vivo via increase of mitochondrial reactive oxygen species. This oxidative stress was triggered by rapid calcium flux from the endoplasmic reticulum into mitochondria and, consequently, impairment of mitochondrial function, a mechanism underlying the cytotoxicity of NK-1R antagonists. Besides anticancer activity, blocking NK-1R produces a potent antinociceptive effect in myeloid leukemia-induced bone pain by alleviating inflammation and inducing apoptosis. These findings thus raise the exciting possibility that the NK-1R antagonists, drugs currently used in the clinic for preventing chemotherapy-induced nausea and vomiting, may provide a therapeutic option for treating human myeloid leukemia.

Introduction: Pts with r/r PTCL have limited treatment options and poor outcomes to standard of care therapy. CDK9 regulates transcription elongation through phosphorylation of RNA polymerase II. AZD4573 is a highly potent and selective CDK9 inhibitor that downregulates short-lived transcripts and labile proteins such as MCL1, BFL1, and MYC, which are overexpressed in haematologic tumours including T cell lymphoma. Preclinical studies demonstrate that AZD4573 induces apoptosis and inhibits tumour growth of PTCL cell lines and patient samples in vitro and in vivo (Cidado, CCR 2020;26:922–34). In a phase 1, first-in-human study in pts with haematologic cancers, the recommended phase 2 dose of AZD4573 monotherapy was 12 mg IV QW (Brümmendorf, ASH 2022, abs 1353). Here we report the efficacy and safety of AZD4573 monotherapy in a phase 2a study of pts with r/r PTCL (NCT05140382). Methods: Pts in this single-arm, open-label study were ≥18 years old, had ECOG PS ≤2, and ≥1 prior line of therapy including an alkylating agent and/or anthracycline. Primary cutaneous and primary leukemic PTCL subtypes were excluded. Each pt received an intra-pt ramp-up of AZD4573: 6 mg on day 1, 9 mg on day 8, then the target dose of 12 mg on day 15, continuing QW thereafter. The primary objective was efficacy by investigator-assessed ORR (Lugano 2014 criteria); secondary objectives included efficacy by complete response (CR) rate, duration of response, progression-free survival and overall survival; safety and tolerability; and pharmacokinetics (PK). Results: Eighteen pts received AZD4573; median age was 63.0 years (range 45–83), 66.7% were male and median number of prior regimens was 3.0 (range: 1–9). At the 1 Feb 2023 data cutoff, efficacy was evaluable in 12 pts who had received at least one 12 mg dose. The ORR was 3/12 (25.0%, all CRs) in the efficacy-evaluable set (Table). The CRs lasted 7.7 wks to 17.4+ wks. An additional complete metabolic response (CMR) was observed in a pt after initial progressive disease (PD). Safety was evaluable in 18 pts who received ≥1 dose. Treatment-emergent adverse events (TEAEs) occurred in 16 pts (88.9%), all of which were Grade ≥3. Key Grade ≥3 TEAEs were neutropenia (55.6%) and increased AST (22.2%). Two pts (11.2%) discontinued due to TEAEs (hospitalisation and septic shock, n = 1 each). Serious TEAEs were reported in 72.2% and were deemed treatment-related by investigators in 61.1%. Grade 5 treatment-related AEs were reported in 2 pts (11.1%, both septic shock). AZD4573 exhibited linear PK (half-life ∼6 hrs) with dose-dependent increases in Cmax and AUC. Conclusions: Preliminary results show encouraging clinical activity with AZD4573 monotherapy in pts with r/r PTCL, including 3 CRs and one CMR after initial PD. Safety and PK profiles are consistent with the phase 1 study with no unexpected findings, and the study continues to expand in the PTCL population. Previously submitted to EHA 2023. Encore Abstract - previously submitted to EHA 2023 The research was funded by: AstraZeneca Keywords: Aggressive T-cell non-Hodgkin lymphoma, Molecular Targeted Therapies Conflicts of interests pertinent to the abstract. P. L. Zinzani Consultant or advisory role: Takeda, BMS, MSD, Beigene, Roche, Incyte, Gilead Honoraria: Takeda, BMS, MSD, Beigene, Roche, Incyte, Gilead T. Feldman Consultant or advisory role: Kite, Seagen, ADCT, Gilead, AstraZeneca Other remuneration: Takeda, SecuraBio, Epizyme G. Collins Consultant or advisory role: Roche, Takeda, Beigene, AstraZeneca, Incyte, BMS Honoraria: Roche, Takeda, Incyte, Beigene, AstraZeneca, SecuraBio, Kite, Novartis Research funding: Pfizer, BMS, AstraZeneca, Amgen, Beigene J. Zain Consultant or advisory role: SecuraBio, Myeloid, Seattle Genetics Honoraria: Kyowa Kirin Research funding: SecuraBio, Myeloid, Seattle Genetics, CRSPR AstraZeneca A. Khot Honoraria: Janssen, Celgene/ BMS, Amgen, Mundipharma, Kyowa Kirin F. Morschhauser Consultant or advisory role: Genmab, Novartis, Gilead, Roche T. M. Kim Consultant or advisory role: Boryung, AstraZeneca/MedImmune, Takeda, Novartis, Janssen, Hanmi, and Regeneron Honoraria: Takeda, Janssen, Regeneron, Samsung Bioepis, and AstraZeneca Research funding: Boryung, Boehringer-Ingelheim, BMS, Bayer, AstraZeneca/MedImmune, Takeda, Roche/Genentech, Novartis, Janssen, Hanmi, Genmab, Merck Serono, Merck Sharp & Dohme, Regeneron, and Sanofi J. Roderick Employment or leadership position: AstraZeneca J. L. Yoon Employment or leadership position: AstraZeneca S. Sharma Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca J. Saeh Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca J. Dai Employment or leadership position: AstraZeneca R. Reyes Employment or leadership position: AstraZeneca R. F. Olsson Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca J. Shortt Consultant or advisory role: Otsuka, Novartis, Astellas, Pfizer, BMS, Mundipharma Honoraria: Mundipharma (speakers bureau) Research funding: Amgen, BMS, Astex