Oncolytics Biotech Inc T.ONC

reo and t cell-based strategies

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Cancer Immunol Res

 

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. 2024 Jan 9.

 doi: 10.1158/2326-6066.CIR-23-0480. Online ahead of print.

Neutralizing antibodies impair the oncolytic efficacy of reovirus but permit effective combination with T cell-based immunotherapies

Christianne Groeneveldt 1, Priscilla Kinderman 1, Lisa Griffioen 1, Olivia Rensing 1, Camilla Labrie 2, Diana J M van den Wollenberg 1, Rob C Hoeben 1, Matthew Coffey 3, Houra Loghmani 4, Els M E Verdegaal 1, Marij J P Welters 1, Sjoerd H van der Burg 1, Thorbald van Hall 1, Nadine van Montfoort 1

Affiliations expand

• PMID: 38194598
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• DOI: 10.1158/2326-6066.CIR-23-0480

Abstract

Reovirus type 3 Dearing (Reo), manufactured for clinical application as Pelareorep, is an attractive anticancer agent under evaluation in multiple phase 2 clinical trials for the treatment of solid tumors. It elicits its anticancer efficacy by inducing both oncolysis and intratumoral T-cell influx. Since most people have been preexposed to Reo, neutralizing antibodies (NAbs) are prevalent in cancer patients and might present a barrier to effective Reo therapy. Here, we tested serum of cancer patients and healthy controls (n=100) and confirmed that Reo NAbs are present in >80% of individuals. To investigate the effect of NAbs on both the oncolytic and the immunostimulatory efficacy of Reo, we established an experimental mouse model with Reo preexposure. The presence of preexposure-induced NAbs reduced Reo tumor infection and prevented Reo-mediated control of tumor growth after intratumoral Reo administration. In B cell-deficient mice, the lack of NAbs provided enhanced tumor growth control after Reo monotherapy, indicating NAbs limit the oncolytic capacity of Reo. In immunocompetent mice, intratumoral T-cell influx was not affected by the presence of preexposure-induced NAbs and consequently, combinatorial immunotherapy strategies comprising Reo and T-cell engagers or checkpoint inhibitors remained effective in these settings, also after a clinically-applied regimen of multiple intravenous Pelareorep administrations. Altogether, our data indicate that NAbs hamper the oncolytic efficacy of Reo, but not its immunotherapeutic capacity. Given the high prevalence of seropositivity for Reo in cancer patients, our data strongly advocate for the application of Reo as part of T cell-based immunotherapeutic strategies.

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"  Altogether, our data indicate that NAbs hamper the oncolytic efficacy of Reo, but not its immunotherapeutic capacity. Given the high prevalence of seropositivity for Reo in cancer patients, our data strongly advocate for the application of Reo as part of T cell-based immunotherapeutic strategies. "

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April 2023 - "Besides virus-specific antibodies, preexisting OV-specific T cells can also be directly recruited for antitumor efficacy using CD3-bispecific molecules (also known as bispecific T-cell engagers (BiTEs)). For instance, intratumoral Reovirus administration to subcutaneous KPC3 pancreatic tumors expressing tumor antigen TRP1 led to a strong influx of virus-specific CD8+ T

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And now ONCY has demonstrated pelareorep's effectiveness in combination with bispecifics.

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One of the directions that is being taken is to combine bi- or tri- specific T-cell engagers (BiTE or TriTE) with OVs to directly stimulate T-cell immunity without antigen presentation by APCs. This notwithstanding , it has been demonstrated that the response to reovirus-based therapy can be an indication that reovirus oncolytic virus-based treatments can reshape the tumor microenvironment