Trialing reovirus in combination for I–O applications

Immuno-Oncology Insights 2023; 4(4), 137–141

DOI: 10.18609/ioi.2023.018

Published: 4 May 2023
Interview
Houra Loghmani


Roisin McGuigan, Editor, Immuno-Oncology Insights, speaks to (pictured) Houra Loghmani, Senior Scientist, Oncolytics Biotech, about her role in the development of pelareorep, an intravenously-administered oncolytic virus currently in clinical trials.



What are you currently working on?

HL: I am a Senior Translational Research Scientist at Oncolytics Biotech. We are developing an oncolytic respiratory enteric orphan virus (reovirus) – pelareorep – via several ongoing clinical Phase 2 trials. As a senior scientist, I help with developing protocols ranging from preclinical studies for new drug combination testing, to planning different exploratory experiments on the clinical samples we receive to look for biomarkers of response. We want to identify what kinds of biomarkers we can correlate with the responses that we are seeing in our clinical trials.

I also support the company’s business development efforts, including evaluating new collaborators. We are constantly looking for collaborators to work with. In the checkpoint blockade field, we are currently working with Roche, Pfizer, Incyte, and we also have collaborators for our CAR-T program.

Can you tell me more about pelareorep?

HL: It is a naturally occurring reovirus that has demonstrated oncolytic properties thanks to the double-stranded RNA introduced into cancer cells and its ability to induce an inflamed phenotype in certain tumors. There are two main differentiating factors that this oncolytic virus has compared to the rest of the oncolytic viruses in the field: first, it is naturally occurring, and has not been genetically modified, therefore it is categorized under the biosafety level two and can be administered in a typical chemo suite. Second, it is given intravenously, which is important to note as most other oncolytic viruses must be given intratumorally, a complex means of administration not favored by most oncology practices.

In addition, the virus is very safe, with the most commonly observed adverse events being under the category of flu-like symptoms. We have administered pelareorep to more than 1,100 patients so far and have observed severe reactions at much lower rates than those of the chemotherapies and/or PD-1/L1 agents that pelareorep is co-administered with.

By its nature as an oncolytic virus, pelareorep selectively replicates in and kills tumor cells and not healthy cells. Part of that is via direct lysis. That said, as we’ve understood more about the mechanism of action for pelareorep, we’ve come to realize that its true value is in its ability to activate the innate and adaptive immune response to weaken tumor defense mechanisms and make them more susceptible to a broad range of oncology treatments.

We ran a window of opportunity study, AWARE-1, in which we were able to collect breast cancer tumor samples from newly diagnosed HR+/HER2- breast cancer patients. We looked at the tumor microenvironment to understand how the virus is activating the T cells and bringing them to the tumor. We observed that pelareorep can highly activate the interferon gamma signaling pathway, which has been shown to help traffic the T cells to the tumor and increase PD-L1 expression, and therefore prime the tumor for checkpoint blockade therapy. Plus these T cells have more of an active memory phenotype, rather than an exhaustive type [1]Loghmani H, Gavilá J, Mans L et al. SABCS 2022 Pelareorep primes the tumor for checkpoint inhibition therapy by activating the interferon-gamma signaling pathway and tumor inflammation signature in early breast cancer patients – results of the AWARE-1 trial. Cancer Res. March 1 2023; 83 (5_Supplement) [2]Gavila Gregori J, Loghmani H, Manso Sanchez LM et al. ESMO Breast Cancer 2022. The oncolytic virus pelareorep primes the tumor microenvironment for checkpoint blockade therapy in early breast cancer patients – results from AWARE-1 study. [3]González-Navarro EA et al. SITC 2022. The oncolytic virus pelareorep in combination with immune checkpoint inhibitor activates T cell functioning in early breast cancer patients – immunophenotype results from AWARE-1 study. [4]Manso L, Salvador F, Villagrasa P et al. A window-of-opportunity study with atezolizumab and the oncolytic virus pelareorep in early breast cancer (AWARE-1). .

Can you give an overview of the current clinical development strategy for pelareorep? What have been the most promising developments so far?

HL: We think of pelareorep as an enabling technology for both chemotherapies and I–O therapies, and we have published a number of papers demonstrating that the virus can turn a cold microenvironment into a hot one [5]Collienne M, Loghmani H, Heineman T, Arnold D. GOBLET: A phase 1/2 study of pelareorep and atezolizumab +/- chemo in advanced or metastatic gastrointestinal cancers. Future Oncol. 2022. [6]Evgin L, Kottke T, Tonne J et al. Oncolytic Virus-mediated Expansion of Dual Specific Dual-Purpose CAR T Cells with Improved Efficacy Against Solid Tumors. Sci. Transl. Med. 2022; 14(640), eabn2231.  [7]M Collienne, D Arnold, A Stein, E Goekkurt, U Martens, H Loghmani, T Heineman. ESMO GI 2022 GOBLET: A phase 1/2 multiple indication signal finding and biomarker study in advanced gastrointestinal cancers treated with pelareorep and atezolizumab – safety and preliminary response resultsBesides chemotherapy agents, we have observed pelareorep synergies with chimeric antigen receptors (CAR-Ts) and checkpoint inhibitors, as well as bispecific antibodies. For any treatment that needs an immune component to it, we think that pelareorep could enhance that. We have already proven this in our clinical trials with checkpoint inhibitors, and we hope we can do so with other combinations.

Our near-term focus is on metastatic breast and pancreatic cancer, as we have observed very promising responses across multiple Phase 2 trials. We have observed a near doubling of overall survival in HR+/HER2- metastatic breast cancer when we compared pelareorep plus paclitaxel to standard of care paclitaxel. In first-line pancreatic cancer, we have observed a near tripling of the response rate for the the pelareorep and atezolizumab plus chemotherapy arm compared to the standard-of-care chemotherapy control arm [8]Arnold, Dirk et al. SITC 2022. Pelareorep combined with atezolizumab and chemotherapy demonstrates encouraging results as first-line treatment in advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) patients – Interim results from the GOBLET study.. Pelareorep’s demonstrated potential to synergize with both chemotherapy and a range of immuno-oncology agents to treat a number of tumor targets has led to collaborations with Pfizer, Roche, Merck Serono, and Adlai Nortye.

What advantages can an oncolytic virus and CAR-T combination offer over other approaches in the solid tumor space?

HL: CAR-T therapy faces challenges in solid tumors. Firstly, it is difficult for CAR T cells to reach the tumor – and if they manage to get there, they encounter a harsh and suppressive microenvironment. With pelareorep, we are able to traffic the T cells to the tumor.

We also know that by loading pelareorep on CAR-T cells we are able to make CAR-Ts expand more, be more persistent, and have more of a memory phenotype. We call these dual-specific CAR-Ts because they are specific to both the CAR target and also to pelareorep epitopes. We have also observed that a subsequent, IV-delivered single pelareorep boosting dose can re-activate those CAR-T cells, which would otherwise become exhausted. This CAR-T work has been done at the Mayo Clinic by Professor Richard Vile’s group [6]Evgin L, Kottke T, Tonne J et al. Oncolytic Virus-mediated Expansion of Dual Specific Dual-Purpose CAR T Cells with Improved Efficacy Against Solid Tumors. Sci. Transl. Med. 2022; 14(640), eabn2231. .

What are your own, and your company’s, key goals and priorities looking at the next few years?

HL: My focus will be mainly on advancing our translational understanding of how pelareorep could be leveraged to treat multiple tumor targets, especially when combined with PD-1/PD-L1 inhibitors, CAR-Ts, chemotherapy, and bispecific antibodies. I want to deepen our understanding by looking at the translational data that we get from patients, as well as the preclinical models we are using.

Biography

Houra Loghmani received her doctorate degree in Molecular Medicine from Hanover Medical School (Germany) and then went on to complete two postdoctoral fellowships at University Hospital Tubingen (Germany) and the Center of Blood Research (CBR) at the University of British Columbia. Throughout her academic career, Houra’s research has focused on investigating the molecular mechanisms underlying hematopoiesis, blood diseases and malignancies, as well as small molecule drug testing and cell signaling, which the results of her work have been published in many peer-reviewed journals. Currently, Houra is a Senior Scientist at Oncolytics Biotech, where she is helping with the development of pelareorep, a proprietary isolate of the naturally occurring reovirus, a promising therapeutic oncolytic virus.

Affiliation 

Houra Loghmani
Senior Scientist,
Oncolytics Biotech

References

1. Loghmani H, Gavilá J, Mans L et al. SABCS 2022 Pelareorep primes the tumor for checkpoint inhibition therapy by activating the interferon-gamma signaling pathway and tumor inflammation signature in early breast cancer patients – results of the AWARE-1 trial. Cancer Res. March 1 2023; 83 (5_Supplement)  Crossref

2. Gavila Gregori J, Loghmani H, Manso Sanchez LM et al. ESMO Breast Cancer 2022. The oncolytic virus pelareorep primes the tumor microenvironment for checkpoint blockade therapy in early breast cancer patients – results from AWARE-1 study.  Crossref

3. González-Navarro EA et al. SITC 2022. The oncolytic virus pelareorep in combination with immune checkpoint inhibitor activates T cell functioning in early breast cancer patients – immunophenotype results from AWARE-1 study.  Crossref

4. Manso L, Salvador F, Villagrasa P et al. A window-of-opportunity study with atezolizumab and the oncolytic virus pelareorep in early breast cancer (AWARE-1).  Crossref

5. Collienne M, Loghmani H, Heineman T, Arnold D. GOBLET: A phase 1/2 study of pelareorep and atezolizumab +/- chemo in advanced or metastatic gastrointestinal cancers. Future Oncol. 2022.  Crossref

6. Evgin L, Kottke T, Tonne J et al. Oncolytic Virus-mediated Expansion of Dual Specific Dual-Purpose CAR T Cells with Improved Efficacy Against Solid Tumors. Sci. Transl. Med. 2022; 14(640), eabn2231.  Crossref

7. M Collienne, D Arnold, A Stein, E Goekkurt, U Martens, H Loghmani, T Heineman. ESMO GI 2022 GOBLET: A phase 1/2 multiple indication signal finding and biomarker study in advanced gastrointestinal cancers treated with pelareorep and atezolizumab – safety and preliminary response results  Crossref

8. Arnold, Dirk et al. SITC 2022. Pelareorep combined with atezolizumab and chemotherapy demonstrates encouraging results as first-line treatment in advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) patients – Interim results from the GOBLET study.  Crossref

Authorship & conflict of interest

Contributions: The named author takes responsibility for the integrity of the work as a whole, and has given her approval for this version to be published.

Acknowledgements: None. 

Disclosure and potential conflicts of interest: Loghmani H discloses she has royalities/licenses from Adlai Nortye.

Funding declaration: The author received financial support for the research, authorship and/or publication of this article from Pfizer (BRACELET trial financial support 50/50), Roche (Drug supply agreement supporting AWARE1 and GOBLET trial financial support) and Incyte (IRENE trial financial support 50/50).

Article & copyright information 

Copyright: Published by Immuno-Oncology Insights under Creative Commons License Deed CC BY NC ND 4.0 which allows anyone to copy, distribute, and transmit the article provided it is properly attributed in the manner specified below. No commercial use without permission.

Attribution: Copyright © 2023 Loghmani H. Published by Immuno-Oncology Insights under Creative Commons License Deed CC BY NC ND 4.0. 

Article source: This article is based on an invited interview with Houra Loghmani carried out on Feb 23 2023. 

Interview held: Feb 23 2023; Revised manuscript received: Apr 19 2023; Publication date:
May 5 2023


This article is part of the Combination therapy spotlight