Insights from veterinary models for advancing oncolytic virotherapy through comparative oncology

Cancer is a complex disease affecting both humans and animals. Comparative immuno-oncology explores immune responses across species to develop effective cancer therapies. Oncolytic viruses (OVs) serve as both direct tumor-lysing agents and immune stimulants, making them an attractive therapeutic option. This review highlights the role of naturally occurring tumors in animal models for OV-based cancer immunotherapy. We examine immune responses in different species, the latest advancements in OV therapy, and the role of precision medicine in veterinary oncology. Understanding these comparative aspects enhances OV translation from preclinical to clinical applications in both veterinary and human oncology

SARS-CoV-2 RBD protein enhances the oncolytic activity of the vesicular stomatitis virus

Despite recent advances in the research on oncolytic viruses (OVs), a better understanding of how to enhance their replication is key to improving their therapeutic index. Understanding viral replication is important to improve treatment outcomes based on enhanced viral spreading within the tumor milieu. The VSV-Δ51 oncolytic virus has been widely used as an anticancer agent with a high selectivity profile. In this study, we examined the role of the SARS-CoV-2 spike protein receptor-binding domain (RBD) in enhancing VSV-Δ51 viral production and oncolytic activity. To test this hypothesis, we first generated a novel VSV-Δ51 mutant that encoded the SARS-COV-2 RBD and compared viral spreading and viral yield between VSV-Δ51-RBD and VSV-Δ51 in vitro. Using the viral plaque assay, we demonstrated that the presence of the SARS-CoV-2 RBD in the VSV-Δ51 genome is associated with a significantly larger viral plaque surface area and significantly higher virus titers. Subsequently, using an ATP release-based assay, we demonstrated that the SARS-CoV-2 RBD could enhance VSV-Δ51 oncolytic activity in vitro. This observation was further supported using the B16F10 tumor model. These findings highlighted a novel use of the SARS-CoV-2 RBD as an anticancer agent.Instituto de BiotecnologíaFil: Alkayyal, Almohanad A. University of Tabuk. Faculty of Applied Medical Sciences. Department of Medical Laboratory Technology; Arabia SauditaFil: Alkayyal, Almohanad A. King Abdullah International Medical Research Center. Immunology Research Program; Arabia SauditaFil: Ajina, Reham. King Abdullah International Medical Research Center. Immunology Research Program; Arabia SauditaFil: Ajina, Reham. King Saud bin Abdulaziz University for Health Sciences. College of Applied Medical Sciences. Department of Clinical Laboratory Sciences; Arabia SauditaFil: Cacciabue, Marco Polo Domingo. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Agrobiotecnología y Biología Molecular; ArgentinaFil: Cacciabue, Marco Polo Domingo. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cacciabue, Marco Polo Domingo. Universidad Nacional de Luján. Departamento de Ciencias Básicas; ArgentinaFil: Alkayyal, Aaesha A. Taibah University. College of Medicine; Arabia SauditaFil: Saeedi, Nizar H. University of Tabuk. Faculty of Applied Medical Sciences. Department of Medical Laboratory Technology; Arabia SauditaFil: Hussain Alshehry, Taofik. Ministry of National Guard Health Affairs. King Saud University for Health Sciences. King Abdullah International Medical Research Centre; Arabia SauditaFil: Kaboha, Feras. Ministry of National Guard Health Affairs. King Saud University for Health Sciences. King Abdullah International Medical Research Centre; Arabia SauditaFil: Alotaibi, Mohammed A. University of Tabuk. Faculty of Applied Medical Sciences. Department of Medical Laboratory Technology; Arabia SauditaFil: Alotaibi, Mohammed A. Ministry of National Guard Health Affairs. King Saud University for Health Sciences. King Abdullah International Medical Research Centre; Arabia SauditaFil: Zaidan, Nada. King Abdulaziz City for Science and Technology. Joint Centers of Excellence Program. 8King Abdulaziz City for Science and Technology-Brigham and Women's Hospital (KACST-BWH) Centre of Excellence for Biomedicine; Arabia SauditaFil: Shah, Khalid. Harvard Medical School. Brigham and Women’s Hospital. Center for Stem Cell and Translational Immunotherapy (CSTI); Estados UnidosFil: Shah, Khalid. Harvard Medical School. Brigham and Women’s Hospital. Department of Neurosurgery; Estados UnidosFil: Shah, Khalid. Harvard University. Harvard Stem Cell Institute; Estados UnidosFil: Alroqi, Fayhan. King Abdullah International Medical Research Center. Immunology Research Program; Arabia SauditaFil: Alroqi, Fayhan. Ministry of the National Guard. Department of Immunology; Arabia SauditaFil: Alroqi, Fayhan. King Saud bin Abdulaziz University for Health Sciences. Faculty of Medicine; Arabia SauditaFil: Bakur Mahmoud, Ahmad. Taibah University. College of Applied Medical Sciences; Arabia SauditaFil: Bakur Mahmoud, Ahmad. Taibah University. Strategic Research and Innovation Laboratories; Arabia SauditaFil: Bakur Mahmoud, Ahmad. King Abdullah International Medical Research Center. Immunology Research Program; Arabia Saudit

Repurposing the oncolytic virus VSV∆51M as a COVID-19 vaccine

The coronavirus disease 2019 (COVID-19) pandemic imposes an urgent and continued need for the development of safe and cost-effective vaccines to induce preventive responses for limiting major outbreaks around the world. To combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we repurposed the VSV∆51M oncolytic virus platform to express the spike receptor-binding domain (RBD) antigen. In this study, we report the development and characterization of the VSV∆51M-RBD vaccine. Our findings demonstrate successful expression of the RBD gene by the VSV∆51M-RBD virus, inducing anti-RBD responses without attenuating the virus. Moreover, the VSV∆51M-RBD vaccine exhibited safety, immunogenicity, and the potential to serve as a safe and effective alternative or complementary platform to current COVID-19 vaccines

A 5-Year Update on the Clinical Development of Cancer Cell-Based Vaccines for Glioblastoma Multiforme

Glioblastoma multiforme (GBM) is considered one of the most aggressive forms of brain cancer with a 15-month median survival, despite advancements in surgery, radiotherapy, and chemotherapy. The immune-suppressed tumor microenvironment and the blood–brain barrier are major contributors to its poor prognosis and treatment resistance. In the last decade, significant progress has been made in developing cell-based vaccines to boost immune responses against GBM. This review provides an extensive update on recent clinical trials involving various cancer cell vaccines, including ICT-107, the α-type-1 DC vaccine, and others. Although these trials have demonstrated potential improvements in progression-free survival (PFS) and overall survival (OS), the diverse and immune-suppressed nature of GBM poses challenges for consistent therapeutic success. We discuss the details of these trials along with the potential mechanism of vaccine efficacy and immune activations. The findings of these trials highlight the significance of a personalized immunotherapy approach and suggest that patient stratification could significantly advance the clinical management of GBM

Interleukin-12-expressing oncolytic virus: A promising strategy for cancer immunotherapy

AbstractOncolytic viruses (OVs) are an emerging class of novel anti-cancer therapeutic agents that selectively infect and destroy cancerous tissues without damaging normal cells. With the recent US Food and Drug Administration (FDA) approval of Herpes Virus (T-VEC) for the treatment of advanced melanoma, oncolytic virotherapy has gained more attention for further development as a novel form of immunotherapy. A viable approach to maximize the efficacy of OVs involves arming them with immune-enhancing cytokines that are capable of boosting the host's immune response to effectively attack tumour cells. Interleukin-12 (IL-12) is a powerful cytokine with potent antitumour activities that activates both innate and adaptive anti-tumour responses. Several studies have demonstrated that IL-12-expressing OVs improve the therapeutic index in pre-clinical tumour models by activating and recruiting dendritic cells (DCs), cytotoxic natural killer (NK) cells and cytotoxic T cells, which subsequently improve tumour clearance. In this review, the immunological mechanisms of IL-12–expressing viruses are discussed

Remodeling the tumor immune microenvironment with oncolytic viruses expressing miRNAs

MiRNAs (miRNA, miR) play important functions in the tumor microenvironment (TME) by silencing gene expression through RNA interference. They are involved in regulating both tumor progression and tumor suppression. The pathways involved in miRNA processing and the miRNAs themselves are dysregulated in cancer. Consequently, they have become attractive therapeutic targets as underscored by the plethora of miRNA-based therapies currently in pre-clinical and clinical studies. It has been shown that miRNAs can be used to improve oncolytic viruses (OVs) and enable superior viral oncolysis, tumor suppression and immune modulation. In these cases, miRNAs are empirically selected to improve viral oncolysis, which translates into decreased tumor growth in multiple murine models. While this infectious process is critical to OV therapy, optimal immunomodulation is crucial for the establishment of a targeted and durable effect, resulting in cancer eradication. Through numerous mechanisms, OVs elicit a strong antitumor immune response that can also be further improved by miRNAs. They are known to regulate components of the immune TME and promote effector functions, antigen presentation, phenotypical polarization, and varying levels of immunosuppression. Reciprocally, OVs have the power to overcome the limitations encountered in canonical miRNA-based therapies. They deliver therapeutic payloads directly into the TME and facilitate their amplification through selective tumoral tropism and abundant viral replication. This way, off-target effects can be minimized. This review will explore the ways in which miRNAs can synergistically enhance OV immunotherapy to provide the basis for future therapeutics based on this versatile combination platform.</jats:p

Heterologous prime-boost cellular vaccination induces potent antitumor immunity against triple negative breast cancer

IntroductionTriple negative breast cancer (TNBC) is the most aggressive and hard-to-treat subtype of breast cancer, affecting 10-20% of all women diagnosed with breast cancer. Surgery, chemotherapy and hormone/Her2 targeted therapies are the cornerstones of treatment for breast cancer, but women with TNBC do not benefit from these treatments. Although the prognosis is dismal, immunotherapies hold significant promise in TNBC, even in wide spread disease because TNBC is infiltrated with more immune cells. This preclinical study is proposing to optimize an oncolytic virus-infected cell vaccine (ICV) based on a prime-boost vaccination strategy to address this unmet clinical need. MethodsWe used various classes of immunomodulators to improve the immunogenicity of whole tumor cells in the prime vaccine, followed by their infection with oncolytic Vesicular Stomatitis Virus (VSVd51) to deliver the boost vaccine. For in vivo studies, we compared the efficacy of a homologous prime-boost vaccination regimen to a heterologous strategy by treating 4T1 tumor bearing BALB/c mice and further by conducting re-challenge studies to evaluate immune memory responses in surviving mice. Due to the aggressive nature of 4T1 tumor spread (akin to stage IV TNBC in human patients), we also compared early surgical resection of primary tumors versus later surgical resection combined with vaccination.ResultsIn vitro results demonstrated that immunogenic cell death (ICD) markers and pro-inflammatory cytokines were released at the highest levels following treatment of mouse 4T1 TNBC cells with oxaliplatin chemotherapy and influenza vaccine. These ICD inducers also contributed towards higher dendritic cell recruitment and activation. With the top ICD inducers at hand, we observed that treatment of TNBC-bearing mice with the influenza virus-modified prime vaccine followed by VSVd51 infected boost vaccine resulted in the best survival. Furthermore, higher frequencies of both effector and central memory T cells along with a complete absence of recurrent tumors were observed in re-challenged mice. Importantly, early surgical resection combined with prime-boost vaccination led to improved overall survival in mice.ConclusionTaken together, this novel cancer vaccination strategy following early surgical resection could be a promising therapeutic avenue for TNBC patients.</jats:sec

SARS-CoV-2 RBD protein enhances the oncolytic activity of the vesicular stomatitis virus

Despite recent advances in the research on oncolytic viruses (OVs), a better understanding of how to enhance their replication is key to improving their therapeutic index. Understanding viral replication is important to improve treatment outcomes based on enhanced viral spreading within the tumor milieu. The VSV-Δ51 oncolytic virus has been widely used as an anticancer agent with a high selectivity profile. In this study, we examined the role of the SARS-CoV-2 spike protein receptor-binding domain (RBD) in enhancing VSV-Δ51 viral production and oncolytic activity. To test this hypothesis, we first generated a novel VSV-Δ51 mutant that encoded the SARS-COV-2 RBD and compared viral spreading and viral yield between VSV-Δ51-RBD and VSV-Δ51 in vitro. Using the viral plaque assay, we demonstrated that the presence of the SARS-CoV-2 RBD in the VSV-Δ51 genome is associated with a significantly larger viral plaque surface area and significantly higher virus titers. Subsequently, using an ATP release-based assay, we demonstrated that the SARS-CoV-2 RBD could enhance VSV-Δ51 oncolytic activity in vitro. This observation was further supported using the B16F10 tumor model. These findings highlighted a novel use of the SARS-CoV-2 RBD as an anticancer agent.</jats:p

Abstract A68: Phosphodiesterase-5 inhibition modulates surgery-induced myeloid-derived suppressor cells to reduce postoperative metastatic disease

Abstract Purpose: Cancer surgery while necessary for primary tumor removal, has been shown to induce immune suppression and promote metastases in preclinical models and human cancer surgery patients. Activating the immune system and reversing immunosuppression have emerged as promising ways to treat cancer and they can be safely employed in the perioperative period. In this study, we evaluated the immunotherapeutic potential of phosphodiesterase-5 (PDE-5) inhibitors to target surgery-induced myeloid-derived suppressor cells (MDSC) and restore natural killer (NK) cell function in the clinically relevant perioperative period. Experimental Design: Immunocompetent mice tumor models of major surgery were used to characterize the functional suppression of surgery-induced MDSC and to assess the in vivo efficacy of perioperative PDE5 inhibition. In cancer surgery patients with abdominal malignancies, we assessed NK cell function following co-culture with MDSC and PDE5 inhibition. Results: Perioperative PDE5 inhibition reverses surgery-induced immunosuppression. In particular, sildenafil reduces surgery-derived granulocytic-MDSC (gMDSC) function through downregulation of arginase 1 (ARG1), IL4Rα; and reactive oxygen species (ROS) expression, enabling NK cell antitumor cytotoxicity and reducing postoperative disease recurrence. By removing surgery-derived immunosuppressive mechanisms on MDSC, sildenafil synergizes with the administration of perioperative influenza vaccination to reduce postoperative metastasis. Importantly, sildenafil reverses MDSC suppression in cancer surgery patients. Conclusions: These findings demonstrate that PDE5 inhibitors reduce postoperative metastasis by their ability to inhibit surgery-induced MDSC. Further clinical studies are warranted to investigate the immunotherapeutic role of PDE5 inhibitors in combination with cancer surgery. Note: This abstract was not presented at the conference. Citation Format: Lee-Hwa Tai, Almohanad A. Alkayyal, Katherine E. Baxter, Leonard Angka, Mike Kennedy, Christiano Tanese de Souza, Rebecca C. Auer. Phosphodiesterase-5 inhibition modulates surgery-induced myeloid-derived suppressor cells to reduce postoperative metastatic disease. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A68.</jats:p