Combination Strategies Harness the Power of the Oncolytic Virus Talimogene Laherparepvec


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The injectable oncolytic immunotherapy talimogene laherparepvec (also known as T-VEC, Imlygic) may become a valuable component of combination immunotherapy approaches in melanoma, a strategy believed to help overcome resistance of tumors to single-agent immunotherapies.


The next wave in immuno-oncology will be combination approaches, and we have early data suggesting that combinations of [talimogene laherparepvec] with checkpoint inhibitors will be of interest.
— David M. Reese, MD

“[Talimogene laherparepvec] is a first-in-class oncolytic virus that is on the leading edge of an explosion of these oncolytic viruses. Depending on how you define them, there are 60 to 80 platforms in development,” according to David M. Reese, MD, Senior Vice President of Translational Sciences for Amgen. “The next wave in immuno-oncology will be combination approaches, and we have early data suggesting that combinations of [talimogene laherparepvec] with checkpoint inhibitors will be of interest.”

At the 2nd International Cancer Immunotherapy Conference, Dr. Reese described encouraging results from experiments of talimogene laherparepvec in combination with the anti–CTLA-4 (cytotoxic T-lymphocyte–associated protein 4) agent ipilimumab (Yervoy) and antibodies against programmed cell death protein 1 and its ligand (PD-1/PD-L1).1

In a presentation at the 2016 European Society for Medical Oncology (ESMO) Congress, encouraging results with talimogene laherparepvec were also discussed by Jeffrey Weber, MD, PhD, Deputy Director of the Laura and Isaac Perlmutter Cancer Center at New York University Langone Medical Center and a pioneer in checkpoint inhibitor therapy.2 “The beauty of [talimogene laherparepvec] is not that it appears that promising a drug by itself, but as a directly injected agent, it can cause an inflammatory tumor microenvironment to arise. If you can inject enough tumors with enough volume, I think you will begin to make ‘cold’ [immunologically nonresponsive] tumors into ‘hot’ tumors. That would be a very good thing to subsequently follow up with checkpoint inhibition,” he said.

Jeffrey Weber, MD, PhD

Jeffrey Weber, MD, PhD

Study Behind FDA Approval

Talimogene laherparepvec is an oncolytic virus that selectively replicates within tumors and produces granulocyte macrophage colony-stimulating factor (GM-CSF) to enhance systemic antitumor immune responses. Directly administered into accessible lesions, it is designed to have a dual mechanism of action, namely tumor lysis of injected lesions and induction of a systemic antitumor immune response.

Talimogene laherparepvec was approved by the U.S. Food and Drug Administration for the treatment of advanced melanoma, based on the international OPTiM study of 436 patients with unresected stage IIIB/C and IV melanoma, who were randomized to talimogene laherparepvec or subcutaneous GM-CSF.3 The durable response rate (objective response lasting at least 6 months) was 16.3% with talimogene laherparepvec and 2.1% with GM-CSF, an almost ninefold improvement (P < .0001). Overall response rates were 26.4% and 5.7%, respectively (P < .001). Median overall survival was 23.2 months vs 18.9 months, a 21% reduction in risk (P = .051).

“In an exploratory analysis of overall survival, there was a suggestion that patients with earlier-stage disease derived a survival benefit, but the curves looked relatively similar in later-stage disease, raising the question of whether tumor burden correlates with outcome,” Dr. Reese said. “We will explore this in subsequent trials.”

Generating Systemic Immune Response

The mechanism by which talimogene laherparepvec may induce responses in uninjected, distant lesions has not been fully elucidated. To investigate this question, Dr. Reese’s team conducted preclinical experiments using various syngeneic models in which both injected and uninjected tumors in a single mouse could be evaluated. As anticipated, the studies indicated that a high proportion of lesions directly injected with talimogene laherparepvec underwent complete regression. A proportion of distant, uninjected tumors also regressed and demonstrated significant immune cell infiltrates; efficacy was dependent on the generation of systemic antitumor CD8-positive T cells.

“Additionally, we wanted to rule out that we are getting viral spreading and infection of the distant lesions, and the experiments all conclusively demonstrated we are not,” he said. “This leads us to believe this is, indeed, an immune response.”

The investigators also conducted another experiment in which T cells were taken from mice “cured” of their cancer and injected into naive mice. The animals were then challenged with tumor, which they rejected. “This strongly implies we are transplanting immunity to that tumor,” he added.

“Putting all these experiments together within the confines of this model, we have very strong presumptive evidence that we are generating a systemic immune response,” Dr. Reese explained.

Combinations With Checkpoint Inhibitors

Preclinical experiments, focusing on both the CTLA-4 and PD-1/PD-L1 axes, showed that following talimogene laherparepvec injection, the expression of CTLA-4 was increased in tumor-draining lymph nodes, whereas PD-L1 expression was increased in the tumor. “This suggests that combinations with both these agents might be of interest,” revealed Dr. Reese.

These experiments were done after previous preclinical studies in the mouse model showed a modest effect with anti–CTLA-4 therapy alone, but in combination with talimogene laherparepvec, approximately 90% of local and distant tumors were eradicated. The median overall survival was not reached; nine of ten mice survived for the duration of the experiment, “which for a mouse, appears to be a cure,” he noted. “We saw a potent interaction between [talimogene laherparepvec] and anti–CTLA-4.”

In a phase IB study of talimogene laherparepvec plus ipilimumab in 18 patients with advanced melanoma, the objective response rate was 50%, and 22% were complete responses.4 “Some patients had substantial changes in tumor burden over time, and some remain in complete response, with relatively prolonged follow-up,” he said. On the basis of these findings, a large randomized controlled phase II trial is evaluating this combination therapy.

Talimogene Laherparepvec in Melanoma

  • The oncolytic virus talimogene laherparepvec (also known as T-VEC) yielded a ninefold improvement in the durable response rate in patients with advanced melanoma in the OPTiM trial and received FDA approval.
  • The injectable immunotherapy may, however, be most beneficial when used in combination with other systemic immunotherapy approaches.
  • Studies of talimogene laherparepvec plus ipilimumab or pembrolizumab indicate response rates are much higher with these combinations than with either checkpoint inhibitor alone.

In his presentation, Dr. Weber commented on this combination, noting the response rate is at least double that of ipilimumab alone, and responses were observed even in patients with locoregionally advanced and visceral disease. “You see that a significant number of lesions completely or almost completely disappear, and we also see significant responses in visceral lesions that were not even injected…. This looks very promising,” he said, and may represent “a major advance.”

Talimogene laherparepvec has also been evaluated in combination with pembrolizumab (Keytruda) in the phase IB MASTERKEY-265 trial of 21 patients.5 No dose-limiting toxicities were observed, and preliminary responses were observed in 12 of 21 evaluable patients.

According to Dr. Weber, “What’s interesting is that with pembrolizumab alone, the complete response rate is less than 10%, but here we see complete responses in 6 of 21 patients, and a response rate of 66% in eligible patients. That’s pretty darn good.”

The study will be expanded to a phase III trial of approximately 660 patients with unresectable stage IIIB/IV melanoma who are naive to systemic treatment. The co-primary endpoints are progression-free and overall survival. “This will be one of the largest immunotherapy trials and will help us understand these sorts of combinations, going forward,” Dr. Reese said.

Discussions are also under way regarding a study that will evaluate [talimogene laherparepvec] in combination with both an anti–CTLA-4 and anti–PD-1/PD-L1 agent, he added.

Future Directions

The use of talimogene laherparepvec is expected to move into the larger immunotherapeutic landscape, Dr. Reese told The ASCO Post. His team is taking a number of new approaches, one of which is optimizing systemic immune response. “Because the herpes genome is large, we are looking at modifications. For example, rather than just using GM-CSF, should we put in other cytokines to enhance the systemic response?” he asked.

Another investigative avenue for talimogene laherparepvec is injection to help render “cold” tumors more sensitive. The researchers will evaluate this strategy by injecting hepatic metastases from a variety of solid tumors. After establishing a safe dosing paradigm for talimogene laherparepvec in the liver, they will explore using this approach in combination with other immunotherapies. “These are examples of where this whole field is heading,” Dr. Reese concluded. ■

Disclosure: Dr. Weber reported no potential conflicts of interest. Dr. Reese is an employee of and holds stock in Amgen.

References

1. Reese DM: New frontiers in oncolytic virus Therapy. 2nd International Cancer Immunotherapy Conference. Abstract IA24. Presented September 27, 2016.

2. Weber J: Melanoma: Does the run of success continue? New checkpoints. 2016 ESMO Congress. Presented October 9, 2016.

3. Andtbacka RH, Kaufman HL, Collichio F, et al: Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol 33:2780-2788, 2015.

4. Puzanov I, Milhem MM, Minor D, et al: Talimogene laherparepvec in combination with ipilimumab in previously untreated, unresectable stage IIIB-IV melanoma. J Clin Oncol 34:2619-2626, 2016.

5. Long GV, Dummer R, Ribas A, et al: A phase 1/3 multicenter trial of talimogene laherparepvec in combination with pembrolizumab for unresected, stage IIIB-IV melanoma (MASTERKEY-265). 2016 ASCO Annual Meeting. Abstract TPS9598.



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