Oncolytic Viruses: A New Class of Cancer Immunotherapy
Naturally occurring or modified viruses are a potent new weapon against cancer
Since the late 1800s, doctors have observed that some patients with cancer go into remission, if only temporarily, after a viral infection. Although the notion of using viruses in cancer therapy is old, the science only began to move forward in the 1990s with advances in genetic engineering technology with another shift around 2005, as people began to realize the true value of viruses in cancer therapy is in immunotherapy.
When an oncolytic virus infects a tumor cell, it makes copies of itself until the cell bursts. The dying cancer cell releases tumor antigens and/or danger signals, which can change the tumor microenvironment to change an immunologically “cold” tumor (lacking T cells) into a “hot” tumor (influx of a multitude of immune cells and cytokines). Oncolytic viruses are alerting the immune system that something is wrong. This can lead to an immune response against nearby tumor cells (a local response) or tumor cells in other parts of the body (a systemic response).
Oncolytic viruses are naturally occurring or genetically modified to target specific types of cancer cells. They selectively replicate within the cancer cell via a tumor-specific promoter element that is incorporated into the viral genome or in deletions in key portions of the viral genome. The oncolytic viruses must be genetically stable and be incapable of reverting back to its wild-type form while replicating inside cancer cells. In addition, transgenes encoding interferon alpha, granulocyte macrophage colony stimulating factor (GM-CSF), and multiple cytokines have been inserted into oncolytic viruses to achieve a variety of immunomodulatory effect. The size of the oncolytic viral genome affects the transgene capacity, which makes certain oncolytic virus with larger genome more desirable.
The development of oncolytic viruses as cancer weapons is moving rapidly. A wide array of viruses are being developed for some of the toughest cancers, and there is even one on the market.
First Oncolytic Drug Attacks Melanoma
The first oncolytic virus to receive FDA approval was a treatment for melanoma known as talimogene laherparepvec (Imlygic®), or T-Vec. It has a herpes simplex virus type 1 (HSV-1) backbone that is modified with deletions in ICP34.5 to augment the tumor selective replication of the virus.
Tasadenoturev (DNX-2401) is a replication competent oncolytic adenovirus with enhancements to confer increased infectivity as well as tumor selectivity and was tested in a Phase I trial with recurrent malignant glioma. A 24-base pair deletion in the E1A region of the adenoviral genome allows DNX-2401 to selectively replicate in cancer cells that lack a functional Rb pathway.
Vaccinia viruses do not have a specific cell-surface receptor required for entry into the host, which contributes to the natural tropism for a variety of cancer cells and makes it an attractive candidate
for oncolytic virus. In addition, the potential for immune system stimulation by vaccinia virus and its
safety profile have been well documented based on its role in smallpox vaccination program. Pexa-Vec (JX-594) is an oncolytic vaccinia virus that expresses the human GM-CSF and beta-galactosidase transgene, along with an inactivated thymidine kinase gene in order to provide selective replication in cancer cells, which commonly have high level of thymine production. JX-594 has been tested in multiple clinical trials and has been shown to be well tolerated with antitumor activity across a range of solid malignancies.
The oncolytic properties of reovirus appear to be dependent, in part, on activated Ras signaling. In addition, reovirus replicates in the cytoplasm and produces viral RNAs that activate the PKR (protein kinase R) pathway. In cancer cells with activated Ras mutations, the PKR pathway is inhibited which results in the release of translational inhibition and serves to augment the replication and oncolysis of reoviruses. Aside from viral translation, Ras-transformation has been shown to promote oncolysis by affecting other steps of reovirus infectious life cycle including viral disassembly or uncoating, production of viral progeny with boosted infectivity, progeny release through increased apoptosis, and spread of virus in later cycles of infection. Preclinical and clinical studies have demonstrated the broad anticancer activity of wild-type unmodified type 3 Dearing strain reovirus (Reolysin®) across a spectrum of malignancies.
Through genetic manipulation, one recombinant poliovirus—rhinovirus chimera (PVSRIPO)—has shown promise for glioblastoma treatment in clinical studies. To attenuate PVSRIPO, the Internal Ribosomal Entry Site (IRES) from Human Rhinovirus type 2 (HRV2), which is an enterovirus specific to the respiratory system, was used. Changing the IRES, which is the feature paramount to viral protein synthesis, allows PVSRIPO to replicate in transformed cancer cells. However, HRV2 IRES precludes replication of PVSRIPO in normal neurons. In addition, PVSRIPO has a natural affinity for CD155 antigens, which are specific surface markers abundant on glioblastoma cells. Interestingly, CD155 is also expressed on antigen-presenting cells such as dendritic cells and macrophages capable of engaging T cells after exposed to PVSRIPO.
Maraba virus was first isolated from Amazonian phlebotomine sand flies in Brazil and has not been detected outside South America to date. Two single mutations have been introduced in the sequence of the M and G proteins of wild type Maraba virus, respectively, to create a mutant strain named MG1, which demonstrated a faster replication, a larger burst size, and an increased killing potency in tumor cells. Inversely, MG1 was strongly attenuated in normal primary cells, mostly due to the inability of MG1 to block type 1 interferon (IFN)-mediated antiviral immunity, thus restraining its productive cycle to cells deficient or defective in the IFN signaling pathway, which is an abnormality frequently acquired during oncogenesis. On top of its potent oncolytic activity, MG1 therapeutic efficacy also relies on its intrinsic ability to induce both innate and adaptive antitumor immunity. To further expand tumor-specific T-cell effector and long-lasting memory compartments, a replication-deficient adenoviral vector together with MG1 both expressing a same tumor antigen as transgene have been used in a prime-boost strategy during clinical studies to treat solid tumors.
A potent combo
Immune checkpoint inhibitors (ICIs) have helped revolutionize cancer treatment with solid tumors, but oftentimes, even the best response rates to these agents do not exceed 35% to 40%. Improved infection efficiency, highly-selective replication, and transgene expression make modern-day oncolytic viruses a robust cancer immunotherapy that are readily adaptable to combination therapy with ICIs. The goal of combining oncolytic viruses and ICIs is to use the viral infection to primer the tumor by altering the local immune microenvironment to one that is more immunogenic, with the understanding that ICIs work best in these “hot” environments. Along with oncolytic viruses, the administration of ICIs (either systematically or by viral transgene expression) has demonstrated great success in multiple preclinical models. As a result, there are multiple ongoing combination therapy clinical trials, such as DNX-2401 combined with pembrolizumab (anti-PD1) for glioblastoma and advanced melanoma; T-VEC combined with ipilimumab (anti-CTLA4) and pembrolizumab for advanced melanoma; MG1 combined with pembrolizumab for non-small cell lung cancer, metastatic melanoma, and cutaneous squamous cell carcinoma. The outcomes of these clinical studies are highly anticipated, as they will provide insight into optimal virus structure and transgene payload, timing and method of antibody delivery, and potential side effects of these combination therapies.