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Purpose: Radium-223 prolongs survival in a fraction of men with bone metastatic prostate cancer (PCa). However, there are no markers for monitoring response and resistance to Radium-223 treatment. Exosomes are mediators of intercellular communication and may reflect response of the bone microenvironment to Radium-223 treatment. We performed molecular profiling of exosomes and compared the molecular profile in patients with favorable and unfavorable overall survival. Experimental Design: We performed exosomal transcriptome analysis in plasma derived from our preclinical models (MDA-PCa 118b tumors, TRAMP-C2/BMP4 PCa) and from the plasma of 25 patients (paired baseline and end of treatment) treated with Radium-223. All samples were run in duplicate, and array data analyzed with fold changes +2 to −2 and P < 0.05. Results: We utilized the preclinical models to establish that genes derived from the tumor and the tumor-associated bone microenvironment (bTME) are differentially enriched in plasma exosomes upon Radium-223 treatment. The mouse transcriptome analysis revealed changes in bone-related and DNA damage repair–related pathways. Similar findings were observed in plasma-derived exosomes from patients treated with Radium-223 detected changes. In addition, exosomal transcripts detected immune-suppressors (e.g., PD-L1) that were associated with shorter survival to Radium-223. Treatment of the Myc-CaP mouse model with a combination of Radium-223 and immune checkpoint therapy (ICT) resulted in greater efficacy than monotherapy. Conclusions: These clinical and coclinical analyses showed that RNA profiling of plasma exosomes may be used for monitoring the bTME in response to treatment and that ICT may be used to increase the efficacy of Radium-223.

Purpose: 90Y-FF-21101 is an Yttrium-90–conjugated, chimeric mAb that is highly specific for binding to human placental (P)-cadherin, a cell-to-cell adhesion molecule overexpressed and associated with cancer invasion and metastatic dissemination in many cancer types. We report the clinical activity of 90Y-FF-21101 in a first-in-human phase I study in patients with advanced solid tumors. Patients and Methods: The safety and efficacy of 90Y-FF-21101 were evaluated in a phase I 3+3 dose-escalation study in patients with advanced solid tumors (n = 15) over a dose range of 5–25 mCi/m2. Dosimetry using 111In-FF-21101 was performed 1 week prior to assess radiation doses to critical organs. Patients who demonstrated clinical benefit received repeated 90Y-FF-21101 administration every 4 months. Results: 111In-FF-21101 uptake was observed primarily in the spleen, kidneys, testes, lungs, and liver, with tumor uptake observed in the majority of patients. Organ dose estimates for all patients were below applicable limits. P-cadherin expression H-scores ranged from 0 to 242 with 40% of samples exhibiting scores ≥100. FF-21101 protein pharmacokinetics were linear with increasing antibody dose, and the mean half-life was 69.7 (±12.1) hours. Radioactivity clearance paralleled antibody clearance. A complete clinical response was observed in a patient with clear cell ovarian carcinoma, correlating with a high tumor P-cadherin expression. Stable disease was observed in a variety of other tumor types, without dose-limiting toxicity. Conclusions: The favorable safety profile and initial antitumor activity observed for 90Y-FF-21101 warrant further evaluation of this radioimmunotherapeutic (RIT) approach and provide initial clinical data supporting P-cadherin as a potential target for cancer treatment.

Background Metastatic prostate cancer in bone is difficult to treat as the tumor cells are relatively resistant to hormonal or chemotherapies when compared to primary prostate cancer. Irreversible electroporation (IRE) is a minimally invasive ablation procedure that has potential applications in the management of prostate cancer in bone. However, a common limitation of IRE is tumor recurrence, which arises from incomplete ablation that allows remaining cancer cells to proliferate. In this study, we combined IRE with radium-223 (Ra-223), a bone-seeking radionuclide that emits short track length alpha particles and thus is associated with reduced damage to the bone marrow and evaluated the impact of the combination treatment on bone-forming prostate cancer tumors. Methods The antitumor activity of IRE and Ra-223 as single agents and in combination was tested in vitro against three bone morphogenetic protein 4 (BMP4)-expressing prostate cancer cell lines (C4-2B–BMP4, Myc-CaP–BMP4, and TRAMP-C2–BMP4). Similar evaluation was performed in vivo using a bone-forming C4-2B–BMP4 tumor model in nude mice. Results IRE and Ra-223 as monotherapy inhibited prostate cancer cell proliferation in vitro, and their combination resulted in significant reduction in cell viability compared to monotherapy. In vivo evaluation revealed that IRE with single-dose administration of Ra-233, compared to IRE alone, reduced the rate of tumor recurrence by 40% following initial apparent complete ablation and decreased the rate of proliferation of incompletely ablated tumor as quantified in Ki-67 staining (53.58 ± 16.0% for IRE vs. 20.12 ± 1.63%; for IRE plus Ra-223; p = 0.004). Histological analysis qualitatively showed the enhanced killing of tumor cells adjacent to bone by Ra-223 compared to those treated with IRE alone. Conclusion IRE in combination with Ra-223, which enhanced the destruction of cancer cells that are adjacent to bone, resulted in reduction of tumor recurrence through improved clearance of proliferative cells in the tumor region.

Although 3′-deoxy-3′[(18)F]-fluorothymidine (FLT)-positron emission tomography (PET) has been utilized for tumor response assessment to neoadjuvant chemotherapy in soft tissue sarcomas, it has not been exploited for the assessment of early response to systematically targeted therapies. Herein, we investigated the 18F-FLT PET/CT kinetics in patients with sarcoma who received targeted therapies. Among 15 patients with sarcoma who underwent 18F-FLT PET/CT, 5 patients (33%) patients were imaged at three time points: At baseline and at 1−15 weeks (MDM2-inhibitor treatment), and 10 patients (67%) were imaged twice: At baseline and at 1−4 weeks (MDM2 inhibitor, n = 5; c-met inhibitor n = 5). The patients with sarcoma had a total of 18 identifiable tumors. Twelve of 15 patients (80%) demonstrated 18F-FLT concentrations changes early, i.e., at 1−4 weeks. Eight patients responded (53.3%), four patients progressed (26.7%) based on FLT change of more than 10% increase, and three patients (20%) demonstrated no change. 18F-FLT PET/CT may be used for early response imaging to molecularly targeted therapies in patients with sarcoma. Further larger studies in specific sarcoma sub-types are warranted.

Prostate-specific antigen (PSA) flare is a well-known phenomenon in patients with prostate cancer, but its impact during radium-223 dichloride (223RaCl2) therapy is still unclear. This radioisotope has shown to improve overall survival in metastatic castration-resistant prostate cancer (mCRPC). We sought to evaluate the impact of PSA flare on survival and its relation with metabolic parameters on 18F-labeled sodium fluoride PET/CT. We conducted a retrospective study of 168 patients with mCRPC (median age 69; median PSA 29.7) receiving 223RaCl2. Overall survival (OS) and progression-free survival (PFS), estimated by the Kaplan–Meier method and compared using a log-rank test, were evaluated for patient groups corresponding to different definitions of PSA flare. Metabolic 18F-fluoride PET/CT data were analyzed as well. Immediate PSA decline was observed in 49 patients (29.2%), whereas no PSA response was observed in 59 patients (35.1%). PSA flare (defined as rise after the first cycle followed by decrease below the baseline) was observed in 20 patients (11.9%) and PSA flare followed by a decrease from peak but not below baseline was observed in 40 (23.8%). The first flare subgroup had a median PFS and OS of 20.8 and 23.9 months, respectively. These outcomes were not significantly different from patients with immediate PSA decrease, but were significantly better than in patients with persistent PSA elevation (3.1 months for PFS and 11.5 months for OS, p

Although 2-deoxy-2-[18F]-fluoro-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) is a sensitive nuclear medicine modality, specificity for characterizing lung cancer is limited. Tumor proliferation and early response to molecularly targeted therapy could be visualized using 3′-deoxy-3′[(18)F]-fluorothymidine (18F-FLT) PET/CT. The superiority of 18F-FLT PET/CT over 18F-FDG PET/CT in early therapeutic monitoring has been well described in patients after chemotherapy, radiotherapy, and/or chemo/radiotherapy. In thispilot study, we explorethe use of 18F-FLT PET/CT as an early response evaluation modality in patients with lung cancerand provide specific case studies of patients with small cell lung cancer and non-small cell lung cancer who received novel targeted therapies. Early response for c-MET inhibitor was observed in four weeks and for MDM2 inhibitor in nine days.

Background: CDH3 gene overexpression of P-cadherin correlates with increased tumor cell invasiveness and is observed in breast, colon, lung, and pancreatic tumors. FF-21101 is a human-mouse chimeric monoclonal antibody directed against P-cadherin, conjugated with 111In for dosimetry and 90Y for therapy. This first-in-human study assesses dosimetry (biodistribution) and therapeutic outcome of FF-21101(90Y). Methods: For dosimetry, patients (pts) received 5 mCi/5mg FF-21101(111In) 1 week before the FF-21101(90Y) therapeutic dose to assess biodistribution and ensure 90Y radiation dose estimates did not exceed the recommended allowable limit for each organ. Single therapeutic dose cohorts were planned for FF-21101(90Y) (8 mCi/mg) at 5, 10, 15, 20 or 25 mCi/m2 (3+3 dose escalation schema), with repeat doses allowed every 4 cycles. Disease assessments were based on RECIST V1.1. Pre-treatment tumor samples were assessed for P-cadherin expression by immunohistochemistry (IHC). Pharmacokinetics (PK) of FF-21101 also were assessed. Results: Seven pts (3M, 4F) with advanced primary solid tumors and loco-regional metastases were treated with FF-21101(90Y) in the first 3 dose cohorts. Median (range) values: age 55 years (31 – 69), number of prior treatments, including surgery, radiation and/or chemotherapy 5 (2 – 8); tumor types: ovarian carcinoma (CA) (2 pts), vaginal CA, pancreatic neuroendocrine tumor (PNET), desmoplastic small round cell (DSRC) tumor, colorectal CA (CRC), recurrent liposarcoma (1 pt each). Primary and/or metastatic tumors from 4 of 7 pts (57.1%) demonstrated positive uptake of FF-21101(111In). Highest uptake was seen in epithelial tumors, consistent with P-cadherin targeting. Median (range) time on study following the FF-21101(90Y) dose was 8 (4 – 40) weeks. The vaginal CA pt demonstrated an 18.5% decrease as best response through 16 weeks following a single therapeutic dose. A viable pre-study tumor sample was not available for IHC staining. Pre-treatment tumor samples available from 6 of 7 patients demonstrated high H scores (≥ 100) in 3 pts (50%); 2 ovarian and 1 PNET; all remain on study through 4, 12 and 40 weeks, respectively, thus demonstrating the potential predictive utility of pre-treatment tumor P-cadherin expression. FF-21101(90Y) has been well-tolerated. Drug-related adverse events (AEs) include Gr 1 rash (1 pt) and increased AST (Gr 1/2, 2 pts) at 5 mCi/m2, and lymphopenia (1 Gr 3 in 3 pts at 10 mCi/m2), all reversible. There have been no drug-related serious AEs. Mean FF-21101 Cmax and AUC0-t increased with dose, suggesting linear PK. Conclusions: Tumor P-cadherin overexpression provides an attractive target for radioimmunotherapy. FF-21101(111In/90Y) exhibits favorable dosimetry, good tolerability and preliminary evidence of reduction in tumor burden. Pre-treatment tumor P-cadherin expression may be an important biomarker for patient selection. Citation Format: Vivek Subbiah, William Erwin, Osama Mawlawi, Carlos Gonzalez Lepera, Masahiko Tokura, Masayuki Kawakami, Holly Liu, Shubham Pant, Michele Rosner, Mary Johansen, Louis De Palatis, Thomas Myers, Linda Paradiso, Elmer Santos, Gregory Ravizzini. Phase 1 study of FF-21101(90Y), a radioimmunotherapeutic targeting P-cadherin, in advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT097. doi:10.1158/1538-7445.AM2017-CT097

Protection against viral challenge with canine oral papillomavirus (COPV) was achieved by immunisation via particle-mediated DNA delivery (PMDD) of a plasmid encoding the COPV L1 gene to cutaneous and oral mucosal sites in beagle dogs. The initial dose of approximately 9 microg of DNA was followed by two booster doses at 6 week intervals. A similar approach was used to vaccinate a control group of animals with plasmid DNA encoding the Hepatitis B virus S gene. Following challenge at the oral mucosa with COPV all animals vaccinated with the COPV L1 gene were protected against disease. However five of six animals in the control group developed COPV induced papillomas at the oral mucosa. Both cell-mediated lymphoproliferative and humoral antibody responses to the DNA vaccine were observed. Our data indicate that PMDD of plasmid DNA can protect against mucosal challenge with papillomavirus.