Viroimmunotherapy for Colorectal Cancer: Clinical Studies

Colorectal cancer is a leading cause of cancer incidence and death. Therapies for those with unresectable or recurrent disease are not considered curative at present. More effective and less toxic therapies are desperately needed. Historically, the immune system was thought to be an enemy to oncolytic viral therapy. Thinking that oncolysis would be the only mechanism for cell death, oncolytic virologists theorized that immune clearance was a detriment to oncolysis. Recent advances in our understanding of the tumor microenvironment, and the interplay of tumor survival and a patient’s immune system have called into question our understanding of both arenas. It remains unclear what combination of restrictions or enhancements of innate and/or cell-mediated immunity can yield the highest likelihood of viral efficacy. This article reviews the variety of mechanisms explored for viruses such as immunotherapy for colorectal cancer

Viroimmunotherapy for breast cancer: promises, problems and future directions

Virotherapy, a strategy to use live viruses as therapeutics, is a relatively novel field in the treatment of cancer. With the advancements in molecular biology and virology, there has been a huge increase in research on cancer virotherapy. For the treatment of cancer, viruses could be used either as vectors in gene therapy or as oncolytic agents. A variety of viruses have been studied for their potential usage in gene therapy or oncolytic therapy. In this review, we discuss virotherapy with a special focus on breast cancer. Breast cancer is the most common cancer and the leading cause of cancer-related deaths in women worldwide. Current treatments are insufficient to cure metastatic breast cancer and are often associated with severe side effects that further deteriorates patients' quality of life. Therefore, novel therapeutic approaches such as virotherapy need to be developed for the treatment of breast cancer. Here we summarize the current treatments for breast cancer and the potential use of virotherapy in the treatment of the disease. Furthermore, we discuss the use of oncolytic viruses as immunotherapeutics and the rational combination of oncolytic viruses with other therapeutics for optimal treatment of breast cancer. Finally, we outline the progress made in virotherapy for breast cancer and the shortcomings that need to be addressed for this novel therapy to move to the clinic for better treatment of breast cancer

Viroimmunotherapy for Colorectal Cancer: Clinical Studies

Colorectal cancer is a leading cause of cancer incidence and death. Therapies for those with unresectable or recurrent disease are not considered curative at present. More effective and less toxic therapies are desperately needed. Historically, the immune system was thought to be an enemy to oncolytic viral therapy. Thinking that oncolysis would be the only mechanism for cell death, oncolytic virologists theorized that immune clearance was a detriment to oncolysis. Recent advances in our understanding of the tumor microenvironment, and the interplay of tumor survival and a patient’s immune system have called into question our understanding of both arenas. It remains unclear what combination of restrictions or enhancements of innate and/or cell-mediated immunity can yield the highest likelihood of viral efficacy. This article reviews the variety of mechanisms explored for viruses such as immunotherapy for colorectal cancer

Oncolytic Virotherapy for Cancer: Clinical Experience

Oncolytic viruses are a new class of therapeutics which are largely in the experimental stage, with just one virus approved by the FDA thus far. While the concept of oncolytic virotherapy is not new, advancements in the fields of molecular biology and virology have renewed the interest in using viruses as oncolytic agents. Backed by robust preclinical data, many oncolytic viruses have entered clinical trials. Oncolytic viruses that have completed some levels of clinical trials or are currently undergoing clinical trials are mostly genetically engineered viruses, with the exception of some RNA viruses. Reolysin, an unmodified RNA virus is clinically the most advanced oncolytic RNA virus that has completed different phases of clinical trials. Other oncolytic viruses that have been studied in clinical trials are mostly DNA viruses that belong to one of the three families: herpesviridae, poxviridae or adenoviridae. In this review work we discuss recent clinical studies with oncolytic viruses, especially herpesvirus, poxvirus, adenovirus and reovirus. In summary, the oncolytic viruses tested so far are well tolerated, even in immune-suppressed patients. For most oncolytic viruses, mild and acceptable toxicities are seen at the currently defined highest feasible doses. However, anti-tumor efficacies of oncolytic viruses have been modest, especially when used as monotherapy. Therefore, the potency of oncolytic viruses needs to be enhanced for more oncolytic viruses to hit the clinic. Aiming to achieve higher therapeutic benefits, oncolytic viruses are currently being studied in combination with other therapies. Here we discuss the currently available clinical data on oncolytic viruses, either as monotherapy or in combination with other treatments

Optimizing Oncolytic Viral Design to Enhance Antitumor Efficacy: Progress and Challenges

The field of oncolytic virotherapy has seen remarkable advancements in last two decades, leading to approval of the first oncolytic immuno-virotherapy, Talimogene Laherparepvec, for the treatment of melanoma. A plethora of preclinical and clinical studies have demonstrated excellent safety profiles of other oncolytic viruses. While oncolytic viruses show clinical promise in already immunogenic malignancies, response rates are inconsistent. Response rates are even less consistent in immunosuppressed tumor microenvironments like those found in liver, pancreas, and MSI-stable colon cancers. Therefore, the efficacy of oncolytic viruses needs to be improved for more oncolytic viruses to enter mainstream cancer therapy. One approach to increase the therapeutic efficacy of oncolytic viruses is to use them as primers for other immunotherapeutics. The amenability of oncolytic viruses to transgene-arming provides an immense opportunity for investigators to explore different ways of improving the outcome of oncolytic therapy. In this regard, genes encoding immunomodulatory proteins are the most commonly studied genes for arming oncolytic viruses. Other transgenes used to arm oncolytic viruses include those with the potential to favorably modulate tumor stroma, making it possible to image the virus distribution and increase its suitability for combination with other therapeutics. This review will detail the progress made in arming oncolytic viruses with a focus on immune-modulatory transgenes, and will discuss the challenges that need to be addressed for more armed oncolytic viruses to find widespread clinical use

Oncolytic Virotherapy versus Cancer Stem Cells: A Review of Approaches and Mechanisms

A growing body of evidence suggests that a subset of cells within tumors are resistant to conventional treatment modalities and may be responsible for disease recurrence. These cells are called cancer stem cells (CSC), which share properties with normal stem cells including self-renewal, pluripotency, drug resistance, and the ability to maintain quiescence. While most conventional therapies can efficiently destroy rapidly dividing cancer cells comprising the bulk of a tumor, they often fail to kill the less abundant and quiescent CSCs. Furthermore, killing of only differentiated cells in the tumor may actually allow for enrichment of CSCs and thereby portend a bad prognosis. Therefore, targeting of CSCs is important to achieve long-term success in cancer therapy. Oncolytic viruses represent a completely different class of therapeutics that can kill cancer cells in a variety of ways, which differ from those of conventional therapies. Hence, CSCs that are inherently resistant to conventional therapies may be susceptible to oncolytic virus-mediated killing. Recent studies have shown that oncolytic viruses can efficiently kill CSCs in many types of cancer. Here, we discuss the mechanism through which CSCs can escape conventional therapies and how they may still be susceptible to different classes of oncolytic viruses. Furthermore, we provide a summary of recent studies that have tested oncolytic viruses on CSCs of different origins and discuss possible future directions for this fascinating subset of oncolytic virus research

Anti-Tumor Immunogenicity of the Oncolytic Virus CF33-hNIS-antiPDL1 against Ex Vivo Peritoneal Cells from Gastric Cancer Patients

We studied the immunotherapeutic potential of CF33-hNIS-antiPDL1 oncolytic virus (OV) against gastric cancer with peritoneal metastasis (GCPM). We collected fresh malignant ascites (MA) or peritoneal washings (PW) during routine paracenteses and diagnostic laparoscopies from GC patients (n = 27). Cells were analyzed for cancer cell markers and T cells, or treated with PBS, CF33-GFP, or CF33-hNIS-antiPDL1 (MOI = 3). We analyzed infectivity, replication, cytotoxicity, CD107α upregulation of CD8+ and CD4+ T cells, CD274 (PD-L1) blockade of cancer cells by virus-encoded anti-PD-L1 scFv, and the release of growth factors and cytokines. We observed higher CD45−/large-size cells and lower CD8+ T cell percentages in MA than PW. CD45−/large-size cells were morphologically malignant and expressed CD274 (PD-L1), CD252 (OX40L), and EGFR. CD4+ and CD8+ T cells did not express cell surface exhaustion markers. Virus infection and replication increased cancer cell death at 15 h and 48 h. CF33-hNIS-antiPDL1 treatment produced functional anti-PD-L1 scFv, which blocked surface PD-L1 binding of live cancer cells and increased CD8+CD107α+ and CD4+CD107α+ T cell percentages while decreasing EGF, PDGF, soluble anti-PD-L1, and IL-10. CF33-OVs infect, replicate in, express functional proteins, and kill ex vivo GCPM cells with immune-activating effects. CF33-hNIS-antiPDL1 displays real potential for intraperitoneal GCPM therapy