Researchers from Queen Mary University of London and Zhengzhou University have developed a powerful therapeutic platform that uses a modified virus for the treatment of pancreatic cancer. By using the virus in combination with other drugs, the treatment significantly extended survival in preclinical models of pancreatic cancer.
Viruses that can selectively infect and destroy cancer cells, known as oncolytic viruses, are a promising new class of therapeutics for cancer. Through various mechanisms, oncolytic viruses kill cancer cells and elicit strong anti-tumour immune responses.
However, current oncolytic virotherapy is unable to produce a long-term cure in patients, and the treatment has to be delivered directly into the tumour – a route that is not feasible for deeply embedded tumours, or tumours that have spread around the body.
The study, published today in the Journal for ImmunoTherapy of Cancer, describes a novel platform for the treatment of pancreatic cancer using an oncolytic Vaccinia virus that was modified to improve its safety, ability to spread within and between tumours and capacity to activate potent anti-tumour immune responses.
The research was supported by the Medical Research Council (MRC), Pancreatic Cancer Research Fund, Pancreatic Cancer UK, Nature Sciences Foundation of China and National Key R&D Program of China.
A re-engineered virus system
The study built upon previous work by the team (Ferguson et al, 2019; Ahmed et al, 2020), which developed a modified Vaccinia virus through the deletion of two viral genes. By combining treatment with the modified virus and a clinically available drug (PI3Kδ inhibitor) that prevented the destruction of the virus particles by the body’s immune cells, the team created an effective treatment platform that was systemic (i.e. could travel through the body), specifically targeted pancreatic tumours and activated the immune system against the tumours in preclinical models.
In this new study, to improve the efficacy of the treatment platform, the team re-engineered the virus by modifying its genetic code to contain an additional, altered copy of a protein that is crucial to the ability of the virus to spread within and between tumours.
The team also armed the virus with a protein called IL-21, which improved the virus’ ability to trigger an immune response against the cancer.
Professor Yaohe Wang, from Barts Cancer Institute, Queen Mary University of London, who led the study, said: “This platform provides a powerful therapeutic to target multiple aspects of pancreatic cancer simultaneously through a convenient administration approach (intravenous injection), significantly improving the prospects of disease eradication and prevention of recurrence in pancreatic cancer patients. This platform is also suitable for treatment of other human tumour types.”
Following administration of the novel oncolytic Vaccinia virus (named VVL-21) in preclinical models of pancreatic cancer, the virus successfully remodelled the suppressive tumour microenvironment to trigger potent anti-tumour immune responses. Importantly, treatment with VVL-21 also sensitised tumours to treatment with a type of immunotherapy known as an immune checkpoint inhibitor.
The combination of the three therapeutics—VVL-21, PI3Kδ inhibitor and the immune checkpoint inhibitor – created a powerful systemic therapeutic platform that significantly extended survival in a number of different, complex preclinical models of pancreatic cancer.
The deadliest of the common cancers
Pancreatic cancer is the 11th most common cancer in the UK; however, it has the lowest survival rate of all the common cancers, with less than 7% of patients surviving their cancer for five years or more. Pancreatic cancer is often diagnosed in the late stages of its development when the cancer is advanced or has spread to other parts of the body, making treatment difficult.
Chemotherapy and radiotherapy alone are relatively unsuccessful in treating pancreatic cancer and while surgery to remove the tumour offers the best chance of survival, more than 80% of patients ultimately die of the disease due to local recurrence and/or distant metastasis.
While immunotherapeutics such as immune checkpoint inhibition (ICI) have emerged as a promising new therapeutic approach, pancreatic cancer in particular is unresponsive to ICI monotherapy. The new virus developed in this study demonstrated a promising synergistic anti-tumour effect in combination with ICI immunotherapy.
Following additional funding from the MRC, the team are now hoping to conduct the necessary steps required to take the viral treatment system forward into phase I clinical trials to determine its potential within the clinic.
Dr. Louisa Chard Dunmall, senior postdoctoral researcher at Barts Cancer Institute, Queen Mary University of London and joint first author of the study, said: “The current prognosis for patients with pancreatic cancer has not improved for many decades and so we urgently require new treatments that can improve long-term survival.
Our platform provides an exciting new mechanism of attacking the tumour in these patients and we are grateful that we have received further funding from the MRC to support this project through pre-clinical toxicity testing and virus manufacture in the hope that we can take this platform forward into phase I clinical trials within the next 3 years.”
Pancreatic cancer has one of the poorest prognoses of all common cancers, with under a 10% five-year survival rate [1]. Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer, accounting for about 90% of all cases of pancreatic cancer [2,3,4].
By the year 2030, PDAC is expected to become the second leading cause of cancer-related deaths in the United States [5,6]. The primary reason for the low survival rate of PDAC is a lack of direct or indirect diagnostic biomarkers for the disease which leads to late-stage diagnosis [2].
Most patients have either locally advanced or metastatic disease by the time of detection and diagnosis, which prevents curative resection [3]. Since complete resection is currently the only potential cure for PDAC, early detection is critical in the pursuit of increasing the median survival length of PDAC patients. One method of achieving early diagnosis is to screen patients demonstrating risk factors associated with PDAC.
Genetic risk factors, or non-modifiable risk factors, are associated with causation in 5–10% of new cases of PDAC [7,8]. Lifestyle-related risk factors, or modifiable risk factors, which include smoking, obesity, alcohol abuse and diabetes have also been linked to PDAC [9]. In the United States, 16.9% of PDAC cases can be attributed to body weight/obesity, while 10.2% can be attributed to smoking [10].
The aforementioned lifestyle-related risk factors are highly correlated with the occurrence of PDAC. Life-style associated risk factors are inherently modifiable; many can be mitigated or eliminated through patients electively executing life-style modifications, such as improved diet, frequent exercise and elimination of smoking. Medical intervention can also be implemented by primary care physicians.
For example, statins show promise in their ability to potentially reduce the risk of developing PDAC associated with obesity or high cholesterol, especially in males [11]. Commitment to risk-mitigating lifestyle habits may reduce incidence of PDAC, especially in populations inherently vulnerable such as the elderly or those who have genetic risk factors [7,8,9]. Screening of vulnerable populations for precancerous lesions may also assist in the prevention of PDAC via potentially improving early detection and diagnosis.
Following patient diagnosis, it is important to obtain proper staging of the disease to determine the most effective treatment regimen. Preoperative evaluations for the potential surgical resection are primarily facilitated via diagnostic imaging using computed tomography (CT) and/or magnetic resonance imaging (MRI); CT being the most common due to greater accessibility in clinical centers. H
owever, due to spatial resolution and tissue density sensitivity limitations in CT (specifically related to difficulty in adequately resolving low density tissue borders such as those of the lymph node or blood vessels in close approximation to high density tissues), up to 20% of patients are staged incorrectly upon primary diagnosis [12].
The most commonly practiced contemporaneous treatment is, as previously noted, surgical resection with adjuvant chemotherapy. Currently, adjuvant therapy is recommended for all patients with R0 or R1 resected PDAC [13] which, since adoption as common practice in the 1990s, has demonstrated marked improvement in patient survival in combination therapy with gemcitabine and capecitabine [14].
It is possible, as well, that patients with borderline resectable PDAC upon diagnosis may become resectable if treated with neoadjuvant chemotherapy with the folinic acid, 5-fluorouracil, irinotecan and oxaliplatin (mFOLFIRINOX) regime [12]. Patients with non-resectable PDAC will most commonly undergo palliative therapy [15].
While these advancements in PDAC treatment regimens have improved patient survival rates, reoccurrence is found in 75% of patients within the first two years after resection [14]. Continued efforts must remain focused on continued improvement in patient outcome and potential inclusion of additional therapeutics or procedures to attain such.
Future strategies may include modified combination therapy approaches to include therapeutic agents such as immuno-oncolytic viruses (OVs) which have demonstrated potential against differing forms of cancer and are currently being evaluated as treatment options against pancreatic cancer.
Introduction to Oncolytic Viruses
This section will present the genesis of development and application of immune-oncolytic viruses in the treatment of various forms of cancer and focus on the current application of OVs in the treatment of pancreatic cancer.
Definiton of Oncolytic Virus
The term “oncolytic virus” (OV) originated following the discovery of potential use and subsequent application of differing naturally occurring or genetically modified viruses as therapeutic agents in the treatment of various forms of cancer. Typically, these are non-pathogenic viral strains that demonstrate differing modes of selectivity for replication in cancer cells over noncancerous cells [25,26,27,28].
As standard practice for development of novel therapeutics, OVs have been assessed and have demonstrated efficacy in regression of differing forms of cancer in preclinical models [29]. The mechanism of action (MOA) of OVs differ widely: such as direct malignant cell lysis, expression of cytotoxic or immunomodulatory genes and inherent susceptibility of differing forms of cancer to viral replication [25,26,30].
The approach of genetically modifying wild-type virus to express immunomodulatory genes resulting in stimulation or suppression of the patient’s immune system results in an immunogenically “hot” environment around the tumor, which promotes regression of the malignant cell population [31].
OV expression of immunomodulatory genes and resultant malignant cell regression may occur through differing mechanisms dependent on the gene(s) expressed, such as direct cell lysis, disruption of tumor microenvironment vasculature or other, ultimately leading to destruction of cancer cells [32].
A representation of how OVs can potentially eliminate tumors is shown in Figure 1. As previously noted, specific OVs can be either genetically modified to selectively target and replicate in cancer cells, or OV can be used to target known disruptions in normal cell anti-viral activity in malignant cells. For example, in various forms of cancer the interferon signaling pathway is disrupted which results in decreased protein kinase R (PKR) activity; PKR is an intracellular protein kinase which recognizes double-stranded RNA and other viral elements leading to cell death and clearance of the virus. In some cancerous cells, the PKR signaling cascade is disrupted, this allows for viral replication to proceed uninterrupted and lead to effective regression of cancer cell population [33].
Simplified pathways oncolytic viruses employ to potentially regress tumors.
History
The first recorded correlation of a naturally occurring viral infection and potential anticancer activity was discovered in 1904 when Dr. George Dock published a report about a patient with leukemia who experienced a decreased leukocyte count after a naturally occurring influenza virus infection [34]. In 1949, the Russian Far East Virus was observed to inhibit the growth of tumors transplanted into mice [35].
In 1960, opportunistic infection of the rat protoparvovirus, H-1PV, was shown in transplantable human tumors, subsequently H-1PV was directly assessed in preclinical models and demonstrated suppressive properties of tumors cell proliferation [32]. These and other such discoveries of the potential anticancer properties of virus and advancements in recombinant DNA technology led to the development of genetically modified forms of virus to leverage the natural properties of viral replication in host cells as a means to induce cancer cell death and/or other means of regressing tumor progression via deletion or insertion of specific genes of interest to recruit the patient’s antitumor immunity.
In 1991, a genetically modified form of herpes simplex virus (HSV) was developed with depleted thymidine kinase or infected cell protein 34.5 which demonstrated preferential replication of the virus in human glioma xenografts [36]. In 2006, H101, a genetically altered adenovirus serotype-5, was approved in China for the treatment of nasopharyngeal cancers [37].
Following approval of H101 in China, in 2015, T-Vec, a modified HSV, was approved in the United States for the treatment of advanced melanoma [38]. Since the approval of T-Vec by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA), the use of OV as an established immunotherapy has become more widely adopted with significantly increased clinical trial activity assessing OVs and their application as a monotherapy or combination therapy against differing forms of cancer. A selection of ongoing clinical trials is summarized in Table 1.
Table 1
A sample of completed clinical trials assessing immuno-oncolytic virus (OV) safety and efficacy.
| Virus | Phase | Title | Interventions Used (OVs Italicized) | Enrollment Status | ClinicalTrials.gov Identifier |
|---|---|---|---|---|---|
| Adenovirus | I | AdV-tk + Valacyclovir Therapy in Combination with Surgery and Chemoradiation for Pancreas Cancer | AdV-tkValacyclovir | Completed [39] | NCT00638612 |
| Adenovirus | I | Phase I Study Combining Replication-Competent Adenovirus-Mediated Suicide Gene Therapy with Chemoradiotherapy for the Treatment of Non-Metastatic Pancreatic Adenocarcinoma | Ad5-yCD/mutTKSR39rep-ADP | Terminated (Poor enrollment) | NCT00415454 |
| Adenovirus | I | A Phase I, Multicenter, Open-label, Dose Escalation Study of Intratumoral Injections of VCN-01 Oncolytic Adenovirus with Intravenous Gemcitabine and Abraxane® in Advanced Pancreatic Cancer | VCN-01GemcitabineAbraxane® | Completed | NCT02045589 |
| Herpes Simplex-1 (HSV-1) | I | A Phase I Study of Recombinant hGM-CSF Herpes Simplex Virus | Recombinant HSV-1 Injection | Completed | NCT01935453 |
| Herpes Simplex-1 (HSV-1) | I | A Phase I Study of Repeated Intratumoral Administration of TBI-1401(HF10), a Replication Competent HSV-1 Oncolytic Virus, in Patients with Solid Tumors with Superficial Lesions | TBI-1401(HF10) | Completed | NCT02428036 |
| Herpes Simplex-1 (HSV-1) | I | Targeted Delivery of OncoVEX^GM-CSF by Endoscopic Ultrasound (EUS)-Guided Fine Needle Injection (FNI) in Patients with Irresectable Pancreatic Cancer: A Pilot Multinational Experiment on Safety and Proof of Concept | Talimogene Laherparepvec | Completed [40] | NCT00402025 |
| Parvovirus | I/II | A Non-controlled, Single Arm, Open Label, Phase II Study of Intravenous and Intratumoral Administration of ParvOryx in Patients with Metastatic, Inoperable Pancreatic Cancer | Parvovirus H-1 | Completed | NCT02653313 |
| Reovirus | II | A 2-arm Randomized Phase II Study of Carboplatin, Paclitaxel Plus Reovirus Serotype-3 Dearing Strain (Reolysin) vs. Carboplatin and Paclitaxel in the First Line Treatment of Patients with Recurrent or Metastatic Pancreatic Cancer | CarboplatinPaclitaxelWild-type Reovirus | Completed [41] | NCT01280058 |
| Reovirus | II | A Phase 2 Study of REOLYSIN in Combination with Gemcitabine for Patients with Advanced Pancreatic Adenocarcinoma | REOLYSINGemcitabine | Completed | NCT00998322 |
| Reovirus | I | A Phase 1b Study of Pembrolizumab (KEYTRUDA®) in Combination With REOLYSIN® (Pelareorep) and Chemotherapy in Patients with Advanced Pancreatic Adenocarcinoma | REOLYSINGemcitabineIrinotecanLeucovorin5-fluorouracilPembrolizumab | Completed | NCT02620423 |
| Vaccinia Virus | I | A Phase I Study of an MVA Vaccine Targeting P53 in Cancer | Modified Vaccinia Virus ankara vaccine expressing p53 | Completed [42] | NCT01191684 |
Oncolytic Viruses as Pancreatice Cancer Therapeutic
As previously discussed, forms of pancreatic cancer, specifically PDAC, maintain several distinct characteristics that present challenges for most all therapeutic approaches. One such characteristics of PDAC is the composition of the tumor microenvironment presenting as dense fibrotic stroma and stellate cells which prevent or inhibit access of intended therapeutic agents to proliferating cells.
Furthermore, the PDAC microenvironment is known to express immunosuppressive factors such as transforming growth factor-beta (TGF-β), interleukin-10 (IL-10) and others [43]. PDAC tumors also do not express neoantigens, thus immune system response to the tumor is limited [44]. As a result of these characteristics, treatment strategies such as those previously described present unique challenges for therapeutic efficacy of OVs.
The density and impenetrability of the PDAC tumor microenvironment limit access to and prevent robust exposure of OVs to the proliferating PDAC cells. To overcome the specific challenges associated with the density of the PDAC microenvironment, the use of Vitamin D in conjunction with therapeutic agents or the use of hyaluronidase is currently being investigated for the potential to increase OV exposure to the tumor microenvironment and facilitate enhanced therapeutic efficacy [31,45]. One can also predict the challenges posed to other common strategies of immune system modulation through viral-induced transfection being limited due to PDAC microenvironment immunosuppression and lack of neoantigen expression.
Below, we present several approaches and the current status of PDAC treatment via differing families of OVs.
Adenovirus
A significant number of ongoing research programs assessing the potential for OV platforms as a treatment of PDAC are comprised of those using adenoviruses (AV). The focus on use of AVs is due to several factors including high endogenous presence in the human population, DNA as viral nucleic acid, high transfection efficiency, low probability of insertional mutagenesis and suitability for genetic-modification dependent cancer type specificity.
Of the 57 serotypes of AVs, AV5 was the first to be investigated [46] and as previously mentioned, the H101 platform was approved in 2006 for treatment of nasopharyngeal cancer in China [37]. As an AV-5 serotype, H101, as shared with other AV-5 AVs, demonstrates natural tropism to respiratory tissue, as such, have limited applicability in the potential treatment of PDAC or GI cancers.
Contemporaneous OV development programs focus to leverage the natural tropism of OVs for the intended type of malignancy, thus AV-12, AV-40, AV-41 and AV-52 serotypes stand out as natural candidates for investigation into their effects on GI malignancies due to known tropism for GI tissues [46].
ONYX-015, an AV-5 OV therapy, which replicates selectively in cells demonstrating p-53 mutations and dysfunction, failed to cause an objective response when used as a monotherapy [36]. Under Phase II clinical trial assessment ONYX-15, when used in combination with gemcitabine, a limited response was observed in early clinical trials, but issues associated with low viral replication and patient development of high titer neutralizing antibodies resulted in cessation of the trial [31,36].
Leveraging the results of and understating the challenges encountered through the ONYX-015 trials, current attempts to increase the effectiveness of potential adenovirus vectors for PDAC treatment focus on genetic engineering of the virus to develop variants specific to the disease characteristics with the hopes of improving efficacy.
Examples of such are the adenovirus AxE1AdB-UPRT which expresses uracil phosphoribosyltransferase (UPRT), which helps overcome 5-FU resistance [46]. The AV-5 vector AV-5-yCD/mutTkSR39rep-ADP carries AV cytosine deaminase and HSV thymidine kinase and it was shown to improve the efficacy of radiotherapy in preclinical models [47]. VCN01, an AV modified to express hyaluronidase among other modifications, was tested in a preclinical model to adjust the tumor microenvironment to make PDAC more susceptible to OV therapy [46,48]. The VCN-01 and LOAd703 oncolytic adenoviruses have moved to Phase I trials as monotherapies or in combination with paclitaxel/gemcitabine. As can be seen in Table 2, there are many active clinical trials focusing on AV vectors in the treatment of PDAC. Researchers continue to explore the use of the adenovirus platform as a potential treatment of PDAC both for intratumoral and intravenous administration.
Table 2
A sampling of current clinical trials involving pancreatic cancer and oncolytic viruses.
| Virus | Phase | Title | Interventions Used (OVs italicized) | Enrollment Status | ClinicalTrials.gov Identifier |
|---|---|---|---|---|---|
| Adenovirus | I/IIa | Phase I/IIa Trial Evaluating Safety of LOAd703, an Armed Oncolytic Adenovirus for Pancreatic Cancer | LOAd703Gemcitabinenab-paclitaxel | Recruiting | NCT02705196 |
| Adenovirus | I/II | NANT Pancreatic Cancer Vaccine: Molecularly Informed Integrated Immunotherapy Combining Innate High-affinity Natural Killer (haNK) Cell Therapy with Adenoviral and Yeast-based Vaccines to Induce T-cell Responses in Subjects with Pancreatic Cancer Who Have Progressed on or After Standard-of-care Therapy | Aldoxorubicin HClALT-803ETBX-011GI-4000haNKavelumabbevacizumabCapecitabineCyclophosphamideFluorouracilLeucovorinnab-PaclitaxellovazaOxaliplatinStereotactic Body Radiation Therapy | Active, not recruiting | NCT03387098 |
| Adenovirus | I/II | Phase I/II Trial Investigating an Immunostimulatory Oncolytic Adenovirus for Cancer | LOAd703Standard of care chemotherapy | Recruiting | NCT03225989 |
| Adenovirus | I | VISTA (Virus Specific T Cells and Adenovirus): A First in Human Phase I Trial of Binary Oncolytic Adenovirus in Combination with HER2-Specific CAR VST Cells in Patients With Advanced HER2 Positive Solid Tumors | CAdVEC | Not yet recruiting | NCT03740256 |
| Adenovirus | I | A Phase I, Multicenter, Open-label, Dose Escalation Study of Intravenous Administration of VCN-01 Oncolytic Adenovirus with or Without Gemcitabine and Abraxane® in Patients with Advanced Solid Tumors | VCN-01GemcitabineAbraxane® | Active, not recruiting | NCT02045602 |
| Herpes Simplex-1 (HSV-1) | I | Phase I Study of Combination With TBI-1401(HF10), a Replication-competent HSV-1 Oncolytic Virus, and Chemotherapy in Japanese Patients with Stage III or IV Unresectable Pancreatic Cancer. | TBI-1401(HF10)GemcitabineNab-paclitaxelTS-1 | Active, not recruiting | NCT03252808 |
| Reovirus | II | Pembrolizumab and Pelareorep in Treating Patients with Advanced Pancreatic Cancer | PembrolizumabWild-type Reovirus | Recruiting | NCT03723915 |
| Vaccinia Virus & Fowlpox Virus | I | Immunotherapy for Unresectable Pancreas Cancer: A Phase 1 Study of Intratumoral Recombinant Fowlpox PANVAC (PANVAC-F) Plus Subcutaneous Recombinant Vaccinia PANVAC (PANVAC-V), PANVAC-F and Recombinant Granulocyte-Macrophage Colony Stimulating Factor (rH-GM-CSF) | FalimarevInalimarevSargramostim | Active, not recruiting | NCT00669734 |
| Vaccinia Virus | I | A Phase I Study of a p53MVA Vaccine in Combination with Pembrolizumab | Modified Vaccinia Virus Ankara Vaccine Expressing p53Pembrolizumab | Active, not recruiting | NCT02432963 |
| Vaccinia Virus | I | An Open Label, Non-randomized Phase 1b Study to Investigate the Safety and Effect of the Oncolytic Virus GL-ONC1 Administered Intravenously Prior to Surgery to Patients with Solid Organ Cancers Undergoing Surgery for Curative-Intent or Palliative Resection | GL-ONC1 | Active, not recruiting | NCT02714374 |
Herpes Simplex Virus
With the success of T-Vec and its approval for treatment of nasopharyngeal cancer, HSVs seem like a promising OV platform for further development and refinement. T-Vec is currently being assessed for potential efficacy in the treatment of melanoma, Merkel cell carcinoma and other forms of solid-state tumors in a Phase I clinical trial as monotherapy or in combination with radiotherapy (NCT02819843) [38].
T-Vec has also been assessed directly as a monotherapy against PDAC in a phase I trial, results demonstrated no objective response was found in 17 patients enrolled [40]. Myb34.5, a genetically altered, replication-conditional recombinant HSV which leverages the known overexpression of the cellular B-myb promoter in PDAC cells has been assessed in preclinical models. The Myb34.5 HSV variant, intratumorally injected and as a monotherapy it inhibited the growth of PDAC tumors and induced apoptosis. This result was also found to the enhanced in a dose-dependent manner in combination therapy with gemcitabine [49].
Unlike the human-engineered genomic variations of the T-Vec and Myb34.5 oncolytic HSVs, HF10 is a natural, spontaneously mutated HSV variant; the well-characterized mutations of HF10 and assumed resultant, potentially favorable, oncolytic activity have been assessed against many differing forms of cancer with positive results in preclinical models with and without combination therapy with chemotherapeutic agents [30].
A phase I clinical trial was conducted in eight, male Japanese PDAC patients who were HSV seropositive to assess efficacy and safety of HF10. Results showed no adverse effects across all patients with 3 of 8 (37%) of patients demonstrating reduced levels of the PDAC tumor marker CA19-9. Furthermore, HF10 envelop proteins were detected in autopsy specimens, as were macrophages, CD4+ and CD8+ cells and markers of natural killer (NK) cell activation. These results suggest that higher doses of HF10 can be used in clinical trials moving forward and HF10 may enhance antitumor immune system activity [30]. A current study combines HF10 with chemotherapeutic agents and is summarized in Table 2 (NCT03252808).
Protoparvovirus
H-1PV is a rodent protoparvovirus originally isolated from transplantable human tumors and found to be an opportunistic virus with natural tropism for human cancer cells. H-1PV has also been shown to mitigate spontaneous tumor formation in preclinical models [50,51]. While H-1PV has been observed in human tumors, it does not naturally occur in humans, thus allowing for primary treatments to be less negatively impacted by the patient’s immune system clearance of the virus.
This increases the duration of the therapeutic window for application as an OV as compared to other OVs endogenous in the human population [32]. As with other OVs, H-1PV, when used as combination therapy with gemcitabine, increased median length of survival in preclinical models [52]. ParvOryx02 was a phase I/IIa clinical study using H-1PV in PDAC patients to test for tolerability and safety (NCT02653313).
While the study has been completed, results have yet to be formally published. The Principal Investigator (PI) of the ParvOnyx02 trial- Guy Ungerechts; recently reported positive results of the trial have been reported at the Oncolytic Virus Immunotherapy Summit and International Oncolytic Virus Conference in 2019 indicating H-1PV was well tolerated in all patients and 2 of 7 patients experienced prolonged survival times which were associated with favorable immunological signatures.
Reovirus
Reoviruses are double stranded RNA viruses which replicate only in cells with an activated retrovirus-associated DNA sequences (RAS) pathway. A hallmark isoform mutation of PDAC is the mutation of Kirsten-RAS (KRAS), as such reovirus has a natural tropism for PDAC cells [53]. Due to reovirus tropism for PDAC, this family of virus has been assessed for potential as PDAC therapeutic, preclinical assessments demonstrated induction of apoptosis in PDAC tumors due to endoplasmic reticulum stress; clinically, Pelareorep, an isolate of a strain of reovirus, failed to increase progression-free survival either as monotherapy or in combination with paclitaxel and carboplatin [36,41].
In a separate phase II clinical study, Pelareorep was assessed as combination therapy with gemcitabine, results showed efficient viral replication within tumor cells with the combination therapy being was well-tolerated. Unfortunately, though, there was no significant benefit to the combination versus gemcitabine alone [54]. The potential of reovirus, specifically Pelareorep, continues ongoing clinical assessment as summarized in Table 2. Results recently published in 2020 from a phase Ib single-arm study comprised of patients with PDAC who progressed after first-line treatment demonstrated Pelareorep and pembrolizumab added to chemotherapy did not add significant toxicity and showed encouraging efficacy [55].
Vaccinia Virus
Vaccinia virus (VV) is a double-stranded DNA virus which is commonly used as a vaccine, most notedly as smallpox vaccine, and others due to suitability for genetic modification [56]. Amenability of VV for genetic modification and other favorable characteristics enabling potential use as an OV have led to assessment of VV variants against various forms of cancer. For example, JX-594 is a genetically engineered VV assessed for efficacy against hepatocellular carcinoma demonstrating well tolerated treatment and appreciable transgene expression and systemic dissemination in human patients [57].
As with previously described OVs, observed oncolytic activity against one form of cancer inevitably leads researchers to investigate the potential use of the specific OV against various forms of cancer. As such, the replication-competent VV variants GLV-1h68 and GLV-1h151 were assessed against pancreatic cancer cells maintained in in vitro and in vivo environments. Results demonstrated GLV-1h68 was effective as monotherapy and enhanced in combination treatment with gemcitabine and cisplatin [58]. GLV-1h151 also demonstrated efficacy as monotherapy, efficacy being enhanced when applied in combination with radiotherapy [59].
Multiple variants of VV have also been assessed against pancreatic cancer in preclinical studies leveraging the virus as an immunomodulatory agent and vaccine, results vary, but all provide greater insight as to the potential for VV as a treatment platform against human PDAC [60].
Clinical assessment of VV efficacy against PDAC has been limited. A Phase I study of VVDD in eleven patients presenting with various types of cancers, including PDAC, showed no dose-limiting adverse events related to treatment [61]. Currently, there are three ongoing clinical trials, represented in Table 2, involving VV as a vaccine in combination treatment with sargramostim in nonresectable PDAC patients (NCT00669734), as vaccine in combination therapy with pembrolizumab in PDAC patients failing previous treatments (NTC02432963) and as neoadjunctive treatment with variant GL-ONC1 prior to surgery (NTC02714374). All three trials are currently active, not recruiting as of last available updated through the U.S. National Library of Medicine.
reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698570/
More information: Giulia Marelli et al, A systemically deliverable Vaccinia virus with increased capacity for intertumoral and intratumoral spread effectively treats pancreatic cancer, Journal for ImmunoTherapy of Cancer (2021). DOI: 10.1136/jitc-2020-001624
