Vicki Jennings

Introduction: Immune checkpoint inhibitors (ICI) have dramatically improved the outcome for cancer patients across multiple tumor types. However the response rates to ICI monotherapy remain relatively low, in part due to some tumors cultivating an inherently ‘cold’ immune microenvironment. Oncolytic viruses (OV) have the capability to promote a ‘hotter’ immune microenvironment which can improve the efficacy of ICI.Areas covered: In this article we conducted a literature search through Pubmed/Medline to identify relevant articles in both the pre-clinical and clinical settings for combining OVs with ICIs and discuss the impact of this approach on treatment as well as changes within the tumor microenvironment. We also explore the future directions of this novel combination strategy.Expert opinion: The imminent results of the Phase 3 study combining pembrolizumab with or without T-Vec injection are eagerly awaited. OV/ICI combinations remain one of the most promising avenues to explore in the success of cancer immunotherapy.

Abstract The treatment paradigm for patients with metastatic cancer has evolved rapidly with the approval of agents targeting CTLA-4 and the PD-1/L1 immune checkpoint axis. Despite the profound impact these agents have had, they are minimally effective in the majority of cancer patients. Rational combinations of complementary immune-modulating agents have thus far not led to clear patient benefit, and newer technologies that are better able to safely combine multiple modes of action could well prove to be vital. Oncolytic viruses (OVs) have the capacity to be the ideal therapeutic partner for immune checkpoint therapeutics in several ways. First, on their own OVs can “heat up” immunologically “cold” tumors by initiating a proinflammatory infection within the tumor microenvironment (TME). Second, some OVs can be engineered to strategically express one or more immune-modulating molecules. Finally, certain OVs have the capacity to be delivered systemically and thus enhance immune cell recruitment and activation in all metastatic sites. We have selected a novel vaccinia virus as our therapeutic OV platform and are using it to engineer multi-mechanistic cancer therapeutics. Previously it has been demonstrated that oncolytic vaccinia viruses can be delivered systemically and spread within metastatic lesions. These clinical candidates, however, contain multiple potent immune-suppressive genes. Furthermore, in clinical studies some of these therapeutics exhibited off-tumor infections (e.g., pox lesions), which may ultimately limit their ability to be used to deliver potent immune modulators. We used a combination of functional genomics and bio-selection strategies to generate a novel oncolytic vaccinia backbone (termed SKV) containing a large genome deletion that exhibited augmented oncolytic activity and improved tumor selectivity. Our new best-in-class vaccinia robustly stimulates anti-immune responses, rapidly spreads within and between tumors, and has a substantially improved preclinical safety profile when compared to other vaccinia clinical candidates. As predicted, SKV synergizes well with immune checkpoint inhibitor antibodies and potently activates human immune cells. Due to the exquisite tumor selectivity of SKV, we have been able to engineer and express three potent immune modulators that are safest and most effective when expressed within the TME: anti-CTLA4 antibody, membrane tethered IL-12, and the antigen-presenting cell-activating ligand FLT-3L. Tumor-selective transgene expression has been demonstrated in murine tumor models in which therapeutic payload concentrations (e.g., >1 ug/ml IL-12) were achieved within the TME without any detectable transgene product in the systemic circulation (serum). Expression of the therapeutic payloads increased survival versus the SKV backbone control in an immunocompetent, syngeneic tumor model. Ongoing toxicity and efficacy studies are being carried out prior to clinical evaluation of the novel virus construct. This abstract is also being presented as Poster A02. Citation Format: Adrian Pelin, Mike Huh, Matt Tang, Fabrice LeBouef, Brian Keller, Jessie Duong, Katherine Knowles, Julia Petryk, Vicki Jennings, Alan Melcher, Ragunath Singaravelu, Mathieu Crupi, Larissa Pikor, Caroline Breitbach, Steven Bernstein, Michael Burgess, John C. Bell. Utilizing novel oncolytic vaccinia virus for selective expression of immunotherapeutic payloads in metastatic tumors [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr PR19.

Abstract Cytoplasmic nucleic acid sensors for double-stranded (ds) RNA (RIG-I/MDA5) and DNA (cGAS-STING) are pattern recognition receptors (PRRs) key to intracellular anti-viral responses. Recent research has highlighted roles for PRR agonists, including oncolytic virotherapy agents, in anti-tumor immunotherapy. Reovirus type 3 Dearing (Rt3D) is an oncolytic dsRNA virus with limited single-agent activity in clinical studies, but potential for use in combination regimens. We sought synergistic drug-virotherapy combinations using an unbiased screening approach that highlighted the CDK4/6 inhibitor, palbociclib, as a leading hit. We found that, when combined with Rt3D, palbociclib augmented oncolytic virus-induced endoplasmic reticulum (ER) stress/unfolded protein response (UPR) signaling. Combined Rt3D-palbociclib treatment potently increased interferon signaling and endogenous retroviral transcripts. Knockdown (siRNA) studies indicated key UPR proteins and the RNA sensor, RIG-I, were essential to the phenotype observed. Mechanistically independent experiments, using canonical RIG-I agonists and the ER stress inducer (thapsigargin), confirmed cross-talk between RNA sensing and ER stress pathways that augment cancer cell death and interferon production. Combined Rt3D-palbociclib increased innate immune activation and effector function. Our findings demonstrate that UPR signaling and innate immune RNA sensor crosstalk can be exploited to enhance anti-cancer efficacy with pro-immunogenic consequences. This has implications for future clinical development of PRR agonists and oncolytic viruses, as well as broadening the therapeutic remit of CDK4/6 inhibitors to include their role as ER stress sensitizers. Citation Format: Victoria Roulstone, Joan Kyula, Richard Elliot, Christopher J. Lord, Nik Matthews, Vicki Jennings, Harriet Whittock, David Mansfield, Jyoti Choudhary, James Wright, Lu Yu, Alan Melcher, Richard Vile, Matt Coffey, Martin McLaughlin, Kevin Harrington. Mechanisms of therapeutic synergy between pattern recognition response agonists and cdk4 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1960.