Novel Agents, T-VEC Combos Mark Next Phase of Oncolytic Immunotherapy Era in Melanoma

Robert Andtbacka, MD

With the FDA approval of the first oncolytic immunotherapy—talimogene laherparepvec (T-VEC; Imlygic)—in October, the stage has been set for increased research into these agents, according to Robert Andtbacka, MD, associate professor in the division of Surgical Oncology at the Utah School of Medicine and a research investigator with the Huntsman Cancer Institute.

Oncolytic immunotherapies, such as T-VEC, are genetically modified viruses or plasmids that can invade tumors and replicate—killing cancer cells and spurring an overall immune response as well, Andtbacka said in a presentation at the 2015 Society for Melanoma Research Congress. In research on patients treated with T-VEC and other oncolytic immunotherapies, melanoma patients showed responses in injected and non-injected tumorous lesions, as well as responses at sites of distant metastases, such as the lung and liver.

“Most of us believe these responses are immune-mediated and not virus-mediated,” Andtbacka said. Analyses of lesions treated with oncolytic immunotherapies show that these treatments induce antigen-specific immunity with increased levels of CD4 regulatory T cells, CD8 suppressor T cells, and myeloid-derived suppressive T cells. New phase I/II trials also show that oncolytic immunotherapies may enhance the effect of other immunomodulatory agents, such as the checkpoint inhibitor therapy, ipilimumab, Andtbacka noted.

In the phase III OPTiM clinical trial, which led to the approval of T-VEC, durable responses (≥6 months) and objective overall responses in T-VEC—treated stage IIIB-IV melanoma patients were compared to results after treatment with GM-CSF. In the study, 295 patients were treated with intralesional injections of T-VEC and 141 received subcutaneous injections of GM-CSF.

Results revealed that the durable response rate was 16.3% in T-VEC patients vs. 2.1% in GM-CSF patients. The objective response rate was also superior among T-VEC patients—26.4% compared with 5.7% for GM-CSF.

T-VEC also appeared to prompt a global immune response, since 10.8% of patients treated with the agent had a complete response. Although tissue samples from the study were not analyzed, later studies have shed light on the mechanisms through which oncolytic immunotherapies incite a global immune response.

“Treatments such as T-VEC increase the exposure of tumor cell antigens to the immune system—which explains the complete responses seen in the OPTiM clinical trial,” Andtbacka said.

Other oncolytic therapies now being investigated include other viruses, as well as plasmids. The phase II CALM trial of CVA21, an oncolytic therapy that utilizes the Coxsackie virus, has also shown promising results in stage IIIC and IV melanoma patients. Among 54 evaluable patients, 38.6% experienced a complete or partial response or stable disease after 24 weeks of treatment. The 1-year survival was 75.4% with no grade 3/4 events. Among patients with lung and liver lesions, the partial response rate was notable—37.5%, Andtbacka said.

The investigators in the CALM trial analyzed the biology of the tumors injected with CVA21, and found that after just 3 injections, the number of lymphocytes within the tumors had significantly increased. Subsequent biopsies also revealed that the tumors showed increased infiltration of T cells. “As a result, these agents are being investigated in combination with checkpoint inhibitor treatments such as ipilimumab [Yervoy] as a means of improving response and survival,” Andtbacka said.

Limited data sets in combination trials of T-VEC with ipilimumab or pembrolizumab [Keytruda]—such as the initial results from the MASTERKEY-265 phase 1b study—indicate that these combined regimens improve tumor response. The improved tumor response rates have also been achieved without undue toxicity, Andtbacka said.

In an effort to understand the systemic immunity conferred by oncolytic agents such as T-VEC and CVA21, investigators initiated the phase I STORM study. In the study, patients with advanced non­—small cell lung cancer, bladder cancer, prostate cancer, and melanoma were treated with intravenous CVA21—rather than local injections of the oncolytic immunotherapy agent. CVA21 was well tolerated in the study, and most adverse events were grade 1, Andtbacka said. Although it is too soon to assess efficacy, patient tumor and blood samples did shed light on the local and systemic immune effects of CVA21.

The investigators of the STORM study first documented an increase in viral RNAs within tumors. Their results also showed an increased viral load among prostate cancer and melanoma patients in the study, which may indicate that the genetically modified viruses in the bloodstream were able to recognize, hone in, and kill tumor cells, Andtbacka said.

“Agents such as CVA21 have the potential to induce responses in injected and non-injected lesions and to induce an overall immune response that could affect even metastatic lesions,” Andtbacka noted. “Since they can increase T-cell infiltration into tumors, oncolytic immunotherapies could be used as a rescue strategy to reconstitute the tumor microenvironment in patients resistant to checkpoint inhibitor therapies,” he added.

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