Sigrid Eckardt, PhD

Ongoing clinical trials are evaluating a new immunotherapeutic approach for the treatment of malignant melanomathe combination of an oncolytic virus with checkpoint inhibition. This regimen could offer a new therapeutic strategy for patients with metastatic melanoma.

Advanced melanoma with metastasis to deeper parts of the skin or other organs remains difficult to treat with poor response to standard chemotherapeutic regimens, and patients with distant disease face 5-year survival rates of less than 20%.

Preliminary outcomes from a phase Ib study

indicate the safety and efficacy of a combination regimen of talimogene laherparepvec (T-VEC) with systemic ipilimumab in advanced melanoma.

No dose-limiting toxicities were observed, and 6 of 18 treated patients (33%) experienced a complete response. The overall response rate was 56%, and the disease control rate 72%.

Based on these outcomes, the ongoing study is now recruiting for its phase II component, in which patients will be randomized to ipilimumab alone or combined with T-VEC, explains author Robert HI Andtbacka, MD, CM, a surgeon and investigator with Intermountain Healthcare and Huntsman Cancer Institute, &ldquo;We are very encouraged by the results and look forward to more details over the next few years.&rdquo; The study plans to enroll 149 patients, and efficacy outcomes from phase II of the study, with overall survival as the primary measure, are expected in 2016 (NCT01740297).

The combination regimen exploits the synergy between 2 immune therapeutic strategies that are active in advanced melanoma as monotherapy. However, according to John Bell, PhD, cancer researcher at the Ottawa Hospital Research Institute, &ldquo;Given the heterogeneity of cancers, it seems unlikely that either platform (immune-checkpoint inhibitor or oncolytic virus) alone will suffice to effect cures in the majority of patients, but their combination just might.&rdquo;

Oncolytic viral agents such as T-VEC, a modified herpes simplex virus, have been engineered to selectively infect and replicate in tumor cells. This not only causes tumor cell lysis but also triggers immune responses following the release of proinflammatory cytokines and tumor-derived antigens.

However, malignant cells evade the immune system by creating an immunosuppressive microenvironment through expression of inhibitory checkpoint receptors such as cytotoxic T-lymphocyte associated antigen 4 (CTL4-A) or programmed death (PD) that normally prevent uncontrolled T-cell responses.

Combining oncolytic agents with immune-checkpoint inhibitor therapeutics is therefore expected to enhance the activity of either regimen. &ldquo;T-VEC can unleash multiple antigens from the lysing tumor regardless of the tumor genotype. These antigens will then be presented to the dendritic cells, which are driven to the event by the granulocyte-macrophage colony-stimulating factor (GM-CSF) expressed by T-VEC,&rdquo; explains Igor Puzanov, MD, lead author and medical oncologist at the Vanderbilt-Ingram Cancer Center. &ldquo;These dendritic cells will educate T cells to start killing the tumor locally, regionally, and hopefully throughout the body. In order to augment the global response throughout the body, we use ipilimumab.&rdquo;

The combination regimen is also expected to accelerate responses. &ldquo;Although ipilimumab helps 25% of patients live longer and have long durable responses, however, sometimes these responses are slow. Adding T-VEC may help speed up the responses in a safe manner,&rdquo; Puzanov said.

Potential synergistic activity of T-VEC with other checkpoint inhibitors is also anticipated. &ldquo;Now there are some interesting drugs, and T-VEC is one of them,&rdquo; said Jeffrey Weber, MD, PhD, director of the Donald A. Adam Comprehensive Melanoma Research Center, Moffit Cancer Center. &ldquo;I see this as a niche drug that would be best used to prime the immune system and follow up with a drug such as pembrolizumab, nivolumab, ipilimumab, or a combination of those.&rdquo;

&ldquo;To explore the idea that maybe a programmed cell death protein-1 (PD-1) inhibitor will be a better partner for T-VEC than ipilimumab,&rdquo; explains Puzanov, &ldquo;A phase Ib/2 trial evaluating the combination of T-VEC with pembrolizumab (MK3475) was recently initiated.&rdquo;

Pembrolizumab targets PD-1, suppressing inhibitory signals in the tumor microenvironment during the effector phase. The agent received accelerated approval from the US Food and Drug Administration (FDA) for the treatment of advanced melanoma with disease progression following treatment with ipilimumab, based on trial outcomes demonstrating substantial (28%) and durable responses (88% at 1 year).

The combination trial (NCT02263508)6 with a planned enrolment of 110 patients with previously untreated, unresected, stage 3B to 4M1c melanoma will investigate the safety and tolerability of the combination regimen, followed by an efficacy comparison of pembrolizumab with or without T-VEC. Outcomes are expected early in 2017.

&ldquo;Having both these trials will allow us to glean what is the better partner for T-VEC. And maybe, we may be surprised,&rdquo; Puzanov said.

American Cancer Society: Cancer Facts and Figures 2014. Atlanta, Ga: American Cancer Society, 2014. http://www.cancer.org/acs/groups/content/@research/documents/webcontent/acspc-042151.pdf. Accessed November 15, 2014.

Amgen. Ipilimumab With or Without Talimogene Laherparepvec in Unresected Melanoma. Available from: http://clinicaltrials.gov/show/NCT01740297. NLM identifier: NCT01740297. Accessed November 15, 2014.

Puzanov I, Milhem MM, Andtbacka RHI, et al. Primary analysis of a phase 1b multicenter trial to evaluate safety and efficacy of talimogene laherparepvec (T-VEC) and ipilimumab (ipi) in previously untreated, unresected stage IIIB-IV melanoma.

Lichty BD, Breitbach CJ, Stojdl DF, Bell JC. Going viral with cancer immunotherapy.

Duraiswamy J, Kaluza KM, Freeman GJ, Coukos G. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors.

Amgen: MK-3475 With or Without Talimogene Laherparepvec in Unresected Melanoma. Available from: http://clinicaltrials.gov/show/NCT02263508. NLM identifier: NCT02263508. Accessed November 15, 2014.

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Ongoing clinical trials are evaluating a new immunotherapeutic approach for the treatment of malignant melanomaâ€“the combination of an oncolytic virus with checkpoint inhibition.

Sigrid Eckardt, PhD | Authors

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Combining Oncolytic Immunotherapy With Checkpoint Inhibitors Could Affect Cure