Reolysin (pelareorep)

P1, N=12, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed | Trial completion date: Nov 2024 --> May 2024

P2, N=25, Recruiting, Mridula George, MD | Trial primary completion date: Jan 2024 --> Jun 2024

P1, N=12, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Nov 2023 --> Nov 2024

We previously performed a phase II trial of P with carboplatin (C) and paclitaxel (Pxl) vs C and Pxl alone in metastatic PDAC (NCT01280058). High CEACAM6 and IFITM3 play a role in P viral infectivity across multiple pancreatic cell lines, confirming results obtained in translational datasets. Further analysis is ongoing to elucidate mechanism and identify pathways to alter expression of CEACAM6 and IFITM3 and enhance P infectivity in future trials.

P1, N=15, Completed, Adlai Nortye Biopharma Co., Ltd. | Active, not recruiting --> Completed

P2, N=25, Recruiting, Mridula George, MD | Trial completion date: Sep 2023 --> Sep 2024 | Trial primary completion date: Jun 2023 --> Jan 2024

P1/2, N=42, Recruiting, University of Southern California | Phase classification: P1b/2 --> P1/2

PELA/BZ/Dex is well-tolerated and associated with anti-MM activity in a subset of responding patients, characterized by immune reprogramming and TiME changes, warranting further investigation of PELA as an immunomodulator.

P1, N=23, Completed, Emory University | Active, not recruiting --> Completed | Trial completion date: May 2024 --> Oct 2022 | Trial primary completion date: May 2024 --> Oct 2022

Methods Newly diagnosed HR+/HER2- eBC patients were enrolled into two cohorts: Cohort 1: pela + letrozole (n=10); and Cohort 2: pela + letrozole + atezolizumab (n=10). Conclusions In accordance with the prior AWARE-1 results, IMC demonstrated an enhanced immune state of the tumors after treatment. IMC allows us to analyze the potent immune response and cellular interactions in the TME and characterization of these complex interactions provides a better understanding of the key mechanisms of action of these treatments in order to plan future clinical trials.

We reviewed seven virus types that have been investigated in past or ongoing pediatric tumor clinical trials: adenovirus (AdV-tk, Celyvir, DNX-2401, VCN-01, Ad-TD-nsIL-12), herpes simplex virus (G207, HSV-1716), vaccinia (JX-594), reovirus (pelareorep), poliovirus (PVSRIPO), measles virus (MV-NIS), and Senecavirus A (SVV-001). However, the antitumor effects of OVT remain variable depending on tumor type and viral agent used. Although the widespread adoption of OVT faces many challenges, we are optimistic that OVT will play an important role alongside standard chemotherapy and radiotherapy for the treatment of malignant pediatric solid tumors in the future.

Pelareorep and pembrolizumab showed modest efficacy in unselected patients, although potential immune and metabolic biomarkers were identified to warrant further evaluation.

Patients receive pela, atezo and trifluridine/tipiracil. Given pela's immunologic mechanism of action and the significant changes seen in the T cell repertoire by C2D1, we hypothesize that potentially protective immune responses may have been initiated. However, these heavily pretreated patients may have been too immunocompromised or have insufficient time before progressing to benefit fully from the immunotherapy.

P1, N=23, Active, not recruiting, Emory University | Trial completion date: Oct 2024 --> May 2024 | Trial primary completion date: May 2023 --> May 2024

In our studies we compared several laboratory MRV strains (T1L, R2) to the strain most similar to Reolysin, which is being tested in clinical trials (i.e. T3D)...We propose to generate a novel MRV strain with enhanced BCSC-targeting capacity using forward genetic approaches by serially passaging MRV strains in BCSC enriched 3D tumorsphere cultures of MCF-7 Paclitaxel resistant (TaxR) cells to generate a selective oncolytic virus...Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*

Six pts (12%) previously received everolimus, and 3 alpelisib. The addition of pelareorep to PTX is an active regimen with a high 6-month PFS rate worthy of further study. One third of patients discontinued either pelareorep or avelumab due to toxicity, highlighting the need for attentive supportive care. Survival data is maturing.

IMPORTANCE The use of Pelareorep (mammalian orthoreovirus) as a therapy for metastatic breast cancer has shown promising results in recent clinical trials...Using a panel of breast cancer cell lines, we found that the expression levels of the MAPK11 (p38β) isoform are a strong determinant of reovirus uncoating and infection establishment. Our findings suggest that selecting prognostic markers that target key steps in reovirus replication may improve patient stratification during oncolytic reovirus therapy.

P2, N=25, Recruiting, Rutgers, The State University of New Jersey | Trial completion date: Dec 2022 --> Sep 2023 | Trial primary completion date: Dec 2022 --> Jun 2023

Methods Newly diagnosed HR+/HER2- early BC patients were enrolled into two cohorts: Cohort 1 (C1): pela + letrozole (n=10); and Cohort 2 (C2): pela + letrozole + atezolizumab (n=10). Conclusions These results demonstrate that treatment with pela alters the TME to induce and enhance anti-tumor immunity. This enhancement of anti-tumor immunity may potentiate the TME for CPI therapy.

To date, intravenous administration of AN1004 plus PTX is safe and well-tolerated in Chinese patients with advanced/metastatic breast cancer, and demonstrates anti-tumor activity.

P2, N=25, Recruiting, Rutgers, The State University of New Jersey | Trial completion date: Jun 2022 --> Dec 2022 | Trial primary completion date: Jun 2022 --> Dec 2022

15 patients with newly diagnosed GBM were treated with GM-CSF 50μg subcutaneously on days 1-3 and intravenous pelareorep on days 4-5 in weeks 1 and 4 of chemoradiotherapy, and subsequently in week 1 of each adjuvant temozolomide course: 7 patients received 1x10 10 TCID 50 (dose level 1); 8 received 3x10 10 TCID 50 (dose level 2). Although based on small numbers, these long-term follow up data suggest this may be an active combination in a subset of GBM patients. Translational data confirm that pelareorep potentially activates tumour-targeting immune pathways in GBM, with consequential immune checkpoint modulation. These data support a combination clinical trial of pelareorep, radiotherapy and immune checkpoint blockade in GBM.

P1, N=15, Active, not recruiting, Adlai Nortye Biopharma Co., Ltd. | Recruiting --> Active, not recruiting

P1, N=15, Recruiting, Adlai Nortye Biopharma Co., Ltd.

P1, N=26, Terminated, Oncolytics Biotech | Recruiting --> Terminated; Enrollment into AWARE cohorts1-4 have concluded and the primary objective and core goals for the study were met.

P2, N=48, Active, not recruiting, Oncolytics Biotech | Recruiting --> Active, not recruiting | Trial completion date: Jan 2024 --> Jul 2024

Sargramostim/pelareorep was administered to pediatric patients with recurrent or refractory high-grade brain tumors. Hyponatremia was the only dose limiting toxicity (DLT), though maximum tolerated dose (MTD) was not determined.

Previous data from the AWARE-1 study demonstrated that addition of atezolizumab (atezo) to pela increased the CelTIL score (study 's primary endpoint) by more than 30% in 60% of HR+/HER2- early breast cancer (BC) patients...Here we report additional translational research results from AWARE-1.Methods HR+/HER2- early BC patients were enrolled in two cohorts: Cohort 1 (C1)– pela + letrozole (n=10); and Cohort 2 (C2)– pela + letrozole + atezo (n=10)...DSP showed an increase in activated T cells but not exhausted T cells in both cohorts.Conclusions These data show that pela induces an inflamed tumor phenotype and demonstrate its synergy with atezo. Moreover, these data support pela's immune-based mechanism of action and suggest that combining pela with atezo may improve outcomes in BC.

IMC allows us to analyze the potent immune response and cellular interactions in the tumor microenvironment in multiple myeloma treated with Pelareorep and Bortezomib. Characterization of these complex interactions allows for a deeper understanding of the key mechanisms of action of these treatments and planning of future combination studies.

We previously reported that intravenous delivery of pelareorep with standard chemoradiotherapy is tolerable in newly diagnosed GBM. Although based on small numbers, these long-term follow up data suggest that this may be an active combination in a subset of GBM patients and further randomized studies are warranted.

The therapeutic potential of reovirus (Reolysin, pelareorep, Oncolytic Inc., Calgary, Canada), which induces its oncolysis with RAS activation through multimodal immune mechanisms, has been demonstrated in preclinical and clinical studies. In this review, we outline the specific immune mechanisms of reovirus induced oncolysis and provide both preclinical and clinical data on its applications in metastatic colorectal cancer patients.

P1, N=29, Recruiting, Oncolytics Biotech | Trial completion date: Dec 2020 --> May 2022 | Trial primary completion date: Oct 2020 --> Feb 2022

Our collective data demonstrate that Reolysin is a safe and well tolerated agent with potent immunomodulatory effects that synergistically augments the anti-AML effects of azacitidine. A phase I investigator-initiated clinical trial further investigating the safety and preliminary efficacy of this combination in patients with AML is currently being planned.

A phase 2 study is currently underway studying the combination with the rationale that the administration of pelareorep will prime the tumor microenvironment for enhanced tumor response to PD-1 inhibitor retifanlimab. Accrual: The study is currently enrolling patients at Rutgers Cancer Institute of New Jersey and Ohio State University Comprehensive Cancer Center. There are no safety signals with the combination in patients who have received both drugs to date.

P2, N=48, Recruiting, Oncolytics Biotech | Trial completion date: Jun 2021 --> Jan 2024 | Trial primary completion date: May 2021 --> Jun 2022

Background: A previous phase 2 study in metastatic breast cancer demonstrated a statistically significant improvement in overall survival (OS) in patients treated with pelareorep (pela), an intravenously delivered immuno-oncolytic reovirus, given in combination with paclitaxel (PTX) versus PTX alone [1]...Five patient cohorts are being examined: Cohort 1: HR+/HER2-neg (10 patients) receiving pelareorep + letrozole (without atezolizumab); Cohort 2: HR+/HER2-neg (10 patients) receiving pelareorep + letrozole + atezolizumab; Cohort 3: TNBC (6 patients) receiving pelareorep + atezolizumab; Cohort 4: HR+/HER2+ (6 patients) receiving pelareorep + trastuzumab + atezolizumab; Cohort 5: HR-neg/HER+ (6 patients) receiving pelareorep + trastuzumab + atezolizumab... Changes in the TME by IHC demonstrate that treatment with pela in the presence of atezolizumab increases the CD8/Treg ratio, a predictor of greater therapeutic efficacy, similar to preclinical breast cancer mouse models [3, 4]. Detailed TCR-seq, Ventana PD-L1 assay results, and IHC analysis will be presented, focusing on differences between patients receiving pela in the absence or presence of atezolizumab (Cohorts 1 and 2, respectively), and between CelTIL scores of responders and non-responders. Overall, these data demonstrate that pela can promote an inflamed tumor phenotype that allows for synergy with checkpoint blockade therapy in breast cancer.

N=30 --> 17

This was the first reported study where transcriptome assay was performed on KRAS mutated CRC patients receiving reovirus (pelareorep) therapy...Using PBMC we also performed flow cytometry, cytokine ELISA, immunohistochemistry, and determination of the expression level of CRC specific microRNA miR-29a-3p. Our data supports the therapeutic competence of reovirus and identifies the four major ways by which it exerts its antitumor effects.

We also map the enhanced oncolytic properties of r2Reovirus in TNBC to interactions between a Type 3 M2 gene segment and Type 1 genes. Our data show that understanding the interplay between the host cell environment and the genetic composition of oncolytic viruses is crucial for the development of efficacious viral oncolytics.

Pelareorep hijacks host autophagic machinery in KRAS-Mutant conditions to augment its propagation and preferential oncolysis of the cancer cells.

Belinostat-resistant cells displayed significant cross-resistance to other HDAC inhibitors including romidepsin, panobinostat, and vorinostat. Importantly, Reolysin also significantly increased the antilymphoma activity of belinostat in HDAC inhibitor-resistant cells. Our data demonstrate that Reolysin alone or in combination with belinostat is a novel therapeutic strategy to treat TCL patients who develop resistance to HDAC inhibitors.

We present the first clinical data using intravenous pelareorep with GM-CSF alongside standard chemoradiotherapy in patients with GBM, suggesting that the combination is tolerable. Further analysis is underway and efficacy results will be ready for presentation at the conference. This work was supported by CRUK, The Brain Tumour Charity, Yorkshire Cancer Research and Oncolytics Biotech Inc.