Oncolytic Viral Therapy: A Unique Approach to Explore in GI Cancers

Manish A. Shah, MD

Oncolytic viral therapy has been heavily investigated across oncology, but plenty of work still lies ahead to determine how this treatment approach can be applied in gastrointestinal malignancies.

“Oncolytic viral therapy is still in its infancy, though there is a lot we expect can be done with our next-generation techniques, if we’re able to modify the virus and how better to target it, evade the immune system, have better tropism for cancer, and perhaps even better modulation of the immune microenvironment to augment an antitumor response,” said Manish A. Shah, MD, chief of the Solid Tumor Service and the Bartlett Family Professor of Medicine at Weill Cornell Medical College of Cornell University, and an associate attending physician at NewYork-Presbyterian Hospital.

In a presentation during the 2020 Ruesch Center Symposium, Shah discussed the history of viral anticancer therapy, the different types of oncolytic viruses and their ideal characteristics, and preliminary data with some of these novel treatments.¹

The types of oncolytic viral platforms are broken down first DNA—which can be adenoviridae, herpesviridae, or poxviridae—or RNA, under which falls reoviridae, picornaviridae, rhabdoviridae, and paramyxoviridae.

Viral infections have been documented since 1904, when the first viral infection was found to induce tumor regression in leukemia.² That followed with the rabies and adenovirus utilized to treat patients with cervical cancer, measles for leukemia, and mumps in solid tumors, among others. Viruses were later able to be engineered, as seen in 1997 in head and neck cancer and pancreatic cancer in 1997. In 2015, the FDA approved the first-in-class oncolytic immunotherapy talimogene laherparepvec (T-VEC; Imlygic) for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery.

One of the intentions of oncolytic viral therapy is to not only locally kill cancer cells, but it may induce immunity against the tumor by creating an antiviral abscopal effect against the tumor as well—turning “cold” tumors into “hot” ones. Antitumor activity is mediated by selective replication and lysis within infected cancer cells, and by induction of host antitumor immunity.

“This is something we’re really looking forward to over the next several years in terms of developing new treatments using this platform to harness not only locally treat it but also the immune system to try to treat the cancers,” Shah said.

To date, oncolytic viral therapy is only indicated to treat patients with melanoma when the lesion is accessible, and given the requirement for intratumoral administration, clinical indications where lesions are at, or just under the skin, are preferred. While safety precautions must be observed, however, oncolytic viruses are generally well tolerated with low-grade fever, fatigue, and injection site pain. No deaths have been reported in studies of oncolytic viral therapies to date.

Building an Optimal Oncolytic Viral Therapy

The desired attributes of an oncolytic viral treatment are tumor specificity, high replication, immunomodulation, low pre-existing immunity, malleable genome, and the ability to be tracked.

For oncolytic attributes of a vesicular stomatitis virus, it should be a negative strand RNA virus, be a small malleable genome (~11 kb), have broad tropism for most mammalian cells, a high replication rate (10-100,000 copies/24 hours), low seroprevalence, and exquisite sensitivity to type I interferon response.

Telomelysin (OBP-301)

Shah spoke to telomelysin (OBP-301) as a type of virus that has been at the center of investigation. Telomelysin is a type 5 adenovirus-based replicable virus, in which the early gene promoter is replaced by the hTERT promoter. Telomerase, which is a ribonucleoprotein complex that is responsible for adding TTAGGG repeats onto the ends of chromosomes, activates the hTERT promoter.

The majority of tumors, Shah said, express telomerase activity, including esophageal (87%), hepatocellular (86%), gastric (85%), pancreatic (95%), and colorectal (89%) cancers. Additionally, telomerase is strongly repressed in most normal somatic tissues; therefore, it may be a reasonable target for cancer diagnosis and treatment.

Prior studies evaluated telomelysin for a number of solid tumors, which showed that local injection of it is safe,³ and that telomerase-dependent oncolytic adenovirus sensitizes human cancer cells to ionizing radiation via inhibition of DNA repair machinery, thereby showing that it sensitizes radiation.⁴

“The proposed mechanism of action is direct cell lysis by the virus with activation of local immunity, which then they activate the immune system and create a systemic response, which can lead to abscopal treatment effect,” said Shah

Telomelysin was evaluated in a phase 1 dose-escalation study across various solid tumors.⁵ Results showed that the treatment elected a local response in injected cancers, which included a patient with gallbladder carcinoma. In a case report of a patient who experienced an immune response, investigators noted that after injection, the tumor cells were largely swollen, thereby indicating their degeneration, and the number of tumor-infiltrating APC and CD8+ T cells were increased—while Treg was decreased—which suggests immunological activation.

Overall, results showed that single and multiple doses of telomelysin were well tolerated up to 5 x 10¹² vp, and most adverse events were mild to moderate in severity and transient, with no liver toxicity. Transient lymphopenia was observed 24 hours following injection.

Regarding pharmacokinetics, investigators noted measurable levels in plasma after 1 to 3 hours, and at 7 and 14 days after treatment. There was a suggestion of reduction in the treated tumor area in some patients, but no patients showed any local progressive disease.

Currently ongoing is a phase 1b/2 single-arm study evaluating the efficacy and safety of telomelysin in combination with pembrolizumab (Keytruda) in patients with metastatic gastroesophageal cancers following 2 or more lines of therapy. The primary end pint is response rate; secondary end points are progression-free survival, overall survival, safety, and dose-limiting toxicities. Immune response is an exploratory outcome measure.

References

1. Shah MA. Oncolytic viruses. 2020 Ruesch Center Symposium; November 20-21, 2020; virtual.

2. Hamid O, Hoffner B, Gasal E, et al. Oncolytic immunotherapy: unlocking the potential of viruses to help target cancer. Cancer Immunol Immunother. 2017;66(10):1249-1264. doi:10.1007/s00262-017-2025-8

3. Nemunaitis J, Tong AW, Nemunaitis M, et al. A phase I study of telomerase-specific replication competent oncolytic adenovirus (telomelysin) for various solid tumors. Mol Ther. 2010;18(2):429-434. doi:10.1038/mt.2009.262

4. Kuroda S, Fujiwara T, Shirakawa Y, et al. Telomerase-dependent oncolytic adenovirus sensitizes human cancer cells to ionizing radiation via inhibition of DNA repair machinery.Cancer Res. 2010;70(22):9339-9348. doi:10.1158/0008-5472.CAN-10-2333

5. Nemunaitis J, Crowley M, Burke J. A phase 1 dose-escalation study of intratumoral injection with telomerase-specific replication-competent oncolytic adenovirus, telomelysin (OBP-301) for various solid tumors. Mol Ther. 2010;18(2):429-434. doi:10.1038/mt.2009.262