The Rationale for Investigating Oncolytic Viruses in Melanoma

Dr Chmielowski on the Rationale for Investigating Oncolytic Viruses in Melanoma

“The story of oncolytic viruses is not completely new. For years, people knew herpes-based viruses could proliferate in the tumor environment. [Through this], they can destroy a local tumor, which leads to local inflammation, cytokine release, and possible release of tumor antigens. This will lead to enhanced immune responses.”

Bartosz Chmielowski, MD, PhD, health sciences clinical professor, medicine, Division of Hematology-Oncology, Sarcoma and Connective Tissue Medical Oncology, UCLA Health, discusses the rationale for investigating oncolytic viruses in melanoma.

Although the concept of oncolytic viruses is not entirely new, it represents an evolving approach in cancer therapy, Chmielowski begins. One oncolytic virus, 

 for the treatment of patients with advanced melanoma since 2015. T-VEC is administered via direct intratumoral injection, making it most suitable for patients with accessible lesions, such as those on the skin, in subcutaneous nodules, or within local lymph nodes, Chmielowski explains.

T-VEC is based on a modified herpes simplex virus designed to replicate selectively within the tumor microenvironment, Chmielowski details. Viral proliferation in tumor cells leads to localized tumor destruction, which in turn stimulates an inflammatory response, he says. This inflammation is characterized by cytokine release and, potentially, the release of tumor-associated antigens, which can enhance systemic antitumor immune responses, according to Chmielowski.

A common question arises regarding the efficacy of such oncolytic virus treatments in addressing uninjected lesions, which reflects the core challenge of achieving a systemic therapeutic effect from localized injections, Chmielowski continues. The therapeutic goal is to induce an immune-mediated response that extends beyond the injected sites, enabling control of distant metastases, he notes.

The potential of oncolytic viruses lies in their ability to combine direct oncolysis with immune activation, Chmielowski states. However, achieving consistent systemic efficacy remains a critical focus of ongoing research, he says. Investigators are exploring combinations with immune checkpoint inhibitors and other modalities to enhance systemic responses and broaden the applicability of oncolytic virus therapy in oncology, Chmielowski concludes.

Videos

Bartosz Chmielowski, MD, PhD, discusses the rationale for investigating oncolytic viruses in melanoma.

Bartosz Chmielowski, MD, health sciences clinical professor of medicine, the Division of Hematology-Oncology, Sarcoma and Connective Tissue Medical Oncology, the University of California, Los Angeles (UCLA) Health, discusses the current treatment landscape of metastatic melanoma.

The treatment landscape for patients with melanoma has shifted within recent years, according to Chmielowski, particularly in regard to anti–PD-1–based therapies that have emerged as optimal first-line treatment for the majority of patients diagnosed with melanoma. However, patients can still experience disease progression or never respond to this treatment, Chmielowski says.

The up-front treatment landscape in melanoma became complicated with the emergence of different therapies and combinations. Clinicians must decide if they will treat patients with a single-agent PD-1 checkpoint blockade or with combination therapy, Chmielowski continues. These combination therapies include the use of a anti–PD-1 agent and an anti–CTLA-4 agent with nivolumab (Opdivo) plus ipilimumab (Yervoy), or nivolumab with LAG-3–blocking antibody relatlimab-rmbw (Opdualag). These treatment decisions can already be difficult, and they can become increasingly complicated for patients with 

 mutations, who can also receive treatment with targeted therapy combinations, Chmielowski adds.

If a patient begins treatment with single-agent nivolumab, subsequent therapies can involve the combination of nivolumab plus ipilimumab or relatlimab, or combination therapy with the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) for patients harboring 

 mutations. If a patient begins treatment with a combination, they could also switch to another of the aforementioned combinations that have not been used yet, Chmielowski notes.

Although there are several treatment options for patients with metastatic melanoma, there remains an unmet need in the space due to the number of patients who will experience progressive disease, emphasizing the need for new drug development, Chmielowski concludes.

Bartosz Chmielowski, MD, discusses the current treatment landscape of metastatic melanoma.

Dr. Chmielowski on the Current Treatment Landscape of Metastatic Melanoma

Bartosz Chmielowski, MD, health sciences clinical professor of medicine, the Division of Hematology-Oncology, Sarcoma and Connective Tissue Medical Oncology, the University of California, Los Angeles (UCLA) Health, discusses the potential role of vusolimogene oderparepvec (RP1) in the treatment of patients with melanoma who failed prior treatment with an anti–PD-1 therapy.

RP1 is an oncolytic vaccine based on a proprietary new strain of herpes simplex virus (HSV), and it is being investigated in combination with nivolumab (Opdivo) in the ongoing phase 2 IGNYTE trial (NCT03767348) in 3 tumor-specific cohorts, including 1 featuring patients with anti–PD-1–failed cutaneous melanoma. Among the first 75 patients enrolled in this cohort, the overall response rate was 36%, including a complete response rate of 20%.

Additionally, data from the trial demonstrated systemic activity with the combination of RP1 and nivolumab in both injected and un-injected lesions, including in un-injected visceral disease. Notably, responses were observed in patients who did not achieve a response to prior anti–PD-1 therapy.

Although RP1 is a newer therapy being investigated in the treatment of melanoma and other malignancies, it is similar to the oncolytic viral intratumoral therapy talimogene laherparepvec (T-VEC; Imlygic). The backbone of RP1 is an HSV type 1 strain that is selected to kill a broad panel of human cancer cells, Chmielowski says. RP1 is modified to enhance the agent’s specificity and selectivity with the goal of increased proliferation in the tumor cells without affecting normal cells, Chmielowski says. By proliferating tumor cells, RP1 can led to the release of antigens and activation of the immune system within the tumor, Chmielowski emphasizes.

Similar to T-VEC, RP1 is armed with granulocyte-macrophage colony-stimulating factor; however, the structure of RP1 is unique. This altered structure is hoped to increase the activity of RP1 compared with T-VEC, although head-to-head trials have not been conducted between the agents, Chmielowski concludes.

Bartosz Chmielowski, MD, discusses the potential role of vusolimogene oderparepvec in the treatment of patients with melanoma who failed prior treatment with an anti–PD-1 therapy.

Bartosz Chmielowski, MD

Articles

Dr Chmielowski on the Rationale for Investigating Oncolytic Viruses in Melanoma

Dr. Chmielowski on the Current Treatment Landscape of Metastatic Melanoma

Dr. Chmielowski on the Potential Role of RP1 in Melanoma after Anti–PD-1 Failure