Anna Baran, MD 

Oncolytic virus (OV) immunotherapy is an innovative biological therapeutic approach to cancer treatment that deploys native or genetically modified viruses as therapeutic agents and transgenic delivery platforms that can selectively replicate within tumors, but not in cells of normal tissues. In 2015, the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) approved the first-in-class OV therapy, talimogene laherparepvec (T-VEC, or Imlygic) from Amgen for the management of unresectable metastatic melanoma.

 This opened a new venue of cancer treatment utilizing live virus’ to specifically target malignant tumor cells for killing through direct lysis, and simultaneously stimulating the host’s innate immunity through mechanically designed features such as transgenes.

Oncolytic virus immunotherapy also brings some unique challenges for drug deployment programs and regulations. In this article, we provide a brief overview of the status of OV immunotherapy and offer some thoughts based on our experience planning for and carrying out early phase clinical studies in anticipation of registration.

Oncolytic viruses are either DNA or RNA viruses. In general, they can be categorized as natural (not genetically manipulated) and genetically modified strains in therapeutic development.

 There are more than 20 OVs are currently in various stages of clinical development for cancer treatments including coxsackie virus, paramyxovirus, reovirus, and seneca valley virus, measles virus (MV; paramyxovirus), parvovirus, poliovirus (PV; picornavirus), vaccinia virus (VV; poxvirus), adenovirus (Ad), herpes simplex virus (HSV), and vesicular stomatitis virus (VSV; rhabdovirus), etc. Among these, HSV and Ad are probably the two most commonly delivery platforms for the OVs immunotherapy (Tab 1).

 In fact, T-VEC is an HSV-based OV immunotherapeutic agent. Its viral vector is constructed to contain a granulocyte-macrophage colony-stimulating factor transgene (GM-CSF) for releasing the recombinant cytokine in cancer cells.

Table 1. Common Herpes Simplex Virus and Adenovirus in Clinical Development for Cancer Treatment

Annotations: 4-1BBL, (CD137L) tumor necrosis factor ligand superfamily member 9; CCL4, C-C Motif Chemokine Ligand 4; CTLA-4, Cytotoxic T-lymphocyte antigen-4; CYP-2B1, cytochrome P450, family 2, subfamily b, polypeptide 1; CXCL, C-X-C motif chemokine ligand; FLT3LG, fms Related Receptor Tyrosine Kinase 3 Ligand; GALV-GP R, envelope glycoprotein of gibbon ape leukemia virus. GM-CSF, granulocyte-macrophage colony-stimulating factor; HSV-tk, herpes simplex virus-thymidine kinase (HSV-tk) gene; hTERT, human telomerase reverse transcriptase; HSV1, human simplex virus Type 1; IFNα, Interferon α; IL, interleukin; MAGE-A3, melanoma-associated antigen 3; NAT, noradrenaline transporter gene OX40L, ligand for OX40 on antigen-presenting cells; PH20, hyaluronidase; TNF, tumor necrosis factor.

Oncolytic viruses are a versatile biological platform for cancer cell killing and biological drug delivery. The design features can be further improved. 

 The anti-tumor effects of the engineered OVs are mediated by direct lysis of malignant cells and boost human immunity against cancer cells. OVs can selectively infect and replicate inside cancer cells, reducing the tumor burden of the target malignancy through virus-mediated cell lysis. The infection of OV to cancer is selective, and the killing is, therefore, specific for malignant cells and not to the normal cells.

The OV can be modified by genetic engineering on the viral genome with intentional deletions by designs for efficacy improvements and/or attenuation in off-target infectivity and transmutability in addition to insertions of transgenes to strengthen desirable biological effects on human immunity, such as antigen presentation, local delivery of cytokine and chemokine.

The direct consequence of oncolytic action is the release of tumor-specific or associated antigens leading to the activation of immune effector cells, such as T killer cells, and their infiltration inside the tumor tissue.

 Therefore, the genetically engineered OVs could boost in vivo the human innate immunity, which consists of dendritic cells, macrophages, and natural killer (NK) cells, and recruit the adaptive immunity to fight cancer cells in stimulation by the recombinant biological modifiers delivered as the transgenic payloads of the oncolytic platform.

Furthermore, an OV can also modulate the tumor microenvironment (TME) either by nature or by designs such as the inserted GM-CSF transgene which can promote the maturation and differentiation of immune cells, such as dendritic cells, monocyte, and macrophages, towards improvements in innate immunity. The other biological effects are the TME becoming lesser immunosuppressive, thereby leading to enhanced anti-tumor effects through reducing immune evasion.

HSV-1 virus can infect endothelial cells causing disruption of tumor vessels and potentially facilitating immune cell migration into the TME.

Special considerations in clinical study designs for oncolytic virus immunotherapy

Oncolytic viruses are a new class of biologic drugs for cancer treatment. They are live viruses which could replicate naturally inside human systems, although they are altered structurally for specifically targeting malignant cells. Their unique modes of action and cross talks with the host immune systems post significant and unique challenges in clinical developments.

There are a series of specific issues for planning a clinical trial with an OV for cancer treatment. First and foremost, it should be kept in mind that the therapeutic effects of OVs are dependent on the viral biological characteristics and its interactions with the immunity in humans. Therefore, we should consider the clinical study designs and executions in the context of viral biology and human immune response. The pharmacokinetics and pharmacodynamics for traditional drugs of either small or large molecules are largely becoming irrelevant to OVs. The OV is viable and replicable in humans and may not be completely cleared from the body systems if infected, such as in the case of HSV-1 infection. Furthermore, it is the local and systemic immune response of humans that we need to consider carefully when we plan and design a clinical study with genetically engineered OVs for registration and therapeutic use.

Biosafety and infection control are critically important at the individual level, as well as perhaps their potential ecological impact. The regulatory guidelines in Europe and the US stipulate the principles and advise practical approaches for handling OV in early and late-stage clinical developments.

 Individual training for infection control and biosafety precaution is needed which should include, but is not limited to, didactic lecture on policies for the safe-handling and storage of the agent; on protocol of accidental exposure using viral-specific training materials to study personnel who prepare the and administer the viral agent. The study and safety protocol as part of the regulatory requirements for a facility to carry out an OV clinical trial in every aspect of executing a clinical protocol involved OV biologics drugs should be meticulously reviewed and approved by Institutional Biosafety Committee (IBC) and Institutional Review Committee (IRB). The facility’s biosafety level of handling the OV biologics should be compatible and certified.

OVs are evaluated for safety and efficacy in clinical trials to determine clinical utilities and usefulness in combination regimens. The recent trend in cancer clinical trials, especially for advanced solid tumors, is to add immune check point inhibitors (ICI) in combinations with the OV-based therapeutics. The structurally modified OV could alleviate resistance and synergistically enhance the anti-tumor effects from its immunosuppressive releasing effects in TME. However, the individual biological responses to specific viral challenges are immunologic reactions. Finding a maximum tolerated dose based on toxicology reactions could take a longer time than expected, since the dose limiting toxicity (DLT) is an immunologic response which could be dose independent. It may be necessary to carry out the first-in-human (FIH) study in an integrated and stepwise approach with single ascending dosing and multiple ascending dosing for patient safety reasons.

The pharmacokinetic and biodynamic studies should focus on biodistribution, viral shedding, monitoring transgene expression, immune effector cell reactions and other systemic cytokine and/or chemokine changes. Careful follow-up with imaging modalities for tumor size alterations in conjunction with biopsy after OV administration is recommended and required. In this case, the clinical criteria, and the approach for assessing the immune response and outcome with itRESIST are different from that in evaluation of chemotherapy.

OV’s are immunotherapeutic drugs which can also act as a platform for virotherapy and/or potential gene therapy. OV is theoretically appealing since it can be modified genetically according to our knowledge and understanding of tumor biology by design. The transporting transgenes as molecular entities for therapeutic purpose cab be further improved overtime. The transgenes can be made highly effective according to tumor’s pathophysiological characteristics and to viral biology for local delivery by injections. The intertumoral injections guided by imaging either with or without contrast-enhanced Ultrasound (US) or Computed Tomography (CT) can increase the therapeutic index by ensuring effective local drug concentration gradient, and likely reduce systemic exposure with less toxicities. However, the procedures are of high technical complexities which introduce some technical uncertainties for repetitive use if a protocol required in follow-up treatments or multiple applications. Under such circumstances, the personal and collective skill sets of study personnel, such as imaging, endoscopy, and deep biopsy, are required for successfully executing the clinical trial protocol

Oncolytic viruses are a special class of drug biologics. Successful clinical development requires a focus on viral biology and host immune response. There are unique features in clinical trial designs and executions associated with the structural variations of OV which are different from other drug classes used in the past. Since pharmacokinetics and pharmacodynamics in traditional senses are likely not applicable to OV drugs, the clinical trials should be planned carefully and adaptively in the context of viral biology and host immune response.

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Successful oncolytic virus immunotherapy clinical development requires unique features that focus on viral biology and host immune response.

Anna Baran, MD

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Oncolytic Virus Immunotherapy: A Brief Overview and Considerations for Clinical Trial Planning