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Best Practices in Immunotherapy – June/July 2017 Vol 8
T-VEC Boosts Immunotherapy in Phase 1 Trials
A genetically modified herpesvirus appears to enhance response to immunotherapy in melanoma patients.
According to preliminary data presented at the 2017 ASCO-SITC Clinical Immuno-Oncology Symposium, when used in combination with either ipilimumab or pembrolizumab, talimogene laherparepvec (T-VEC) demonstrated promising efficacy with minimal added toxicity. The phase 1b studies suggest that T-VEC, which selectively replicates in melanoma cells, sensitizes tumors to immune checkpoint blockade and improves the therapy’s effects.
“Combination of locoregional therapy with systemic immunotherapy seems to be safe with several agents and combinations in development,” said Igor Puzanov, MD, MSCI, FACP, Director, Early Phase Clinical Trials Program and Chief of Melanoma at Roswell Park Cancer Institute, Buffalo, NY. “Expanding the definition of ‘injectable lesion’ to liver, deep lymph nodes, and other locations would increase and multiply the potential of such therapies.”
As Dr Puzanov reported, T-VEC, which is delivered by direct injection into tumor cells, causes lysis release of tumor-associated antigens and subsequent activation of dendritic cells, which then present the antigens to CD8+ T cells. When combined with a checkpoint inhibitor, the systemic effects are potentially amplified: more T-cell recognition and more T-cell–mediated tumor cell death, and release of additional tumor-derived antigens.
T-VEC is now approved by the FDA for unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery.
T-VEC and Ipilimumab Combo Activates T-Cell Response
For the first phase 1b study, patients with metastatic melanoma were injected with T-VEC for the first 6 weeks and then received an anti–CTLA-4 antibody, ipilimumab, at standard dose (3 mg/kg IV every 3 weeks for 4 cycles). The primary end point was incidence of dose-limiting toxicities, and key secondary end points were safety and overall response rate.
According to Dr Puzanov, complete responses were observed in 22% of patients, and 27% had partial responses. These responses were durable, lasting months from treatment initiation. The disease control rate was 72%.
Moreover, total and activated CD8+ T cells in the peripheral blood increased from baseline following monotherapy with T-VEC at weeks 4 and 6 and further increased at weeks 9 and 15 after combination T-VEC and ipilimumab therapy.
At week 6, after receiving 2 doses of T-VEC, 10 of 12 patients with disease control had a greater than 1.4 times increase in activated CD8 T-cell count, whereas 4 of 5 patients with tumor growth did not.
“This pattern was no longer evident after ipilimumab was given, which suggests that there were 2 different mechanisms in play,” said Dr Puzanov.
Investigators also observed changes in gene expression in peripheral blood mononuclear cells (PBMCs) after both T-VEC monotherapy and combination therapy. Many more genes were upregulated at week 9 and week 15 following administration of ipilimumab, Dr Puzanov reported.
“With this study, we have seen that T-VEC alone can have effects on differential gene expression in PBMCs,” said Dr Puzanov, who noted that 185 genes had signs of a T-VEC effect in the monotherapy phase.
These genes were known to control the lymphoid tissue differentiation activation as well as proliferative burst of virus-specific natural killer cells responding to infection. The combination effects were enriched for genes involved in lymphoid tissue structure and development and immune cell trafficking, Dr Puzanov reported. Further studies will be performed to correlate with changes in individual tumor gene levels.
T-VEC plus Pembrolizumab Shows Minimal Toxicity
MASTERKEY-265, a phase 1b study of T-VEC and pembrolizumab for unresectable stage IIIB-IV melanoma, also demonstrated promising results.
The study design mirrored the previous combination study, with patients starting on 2 rounds of T-VEC injections. Instead of ipilimumab, however, patients continued on pembrolizumab (200 mg IV every 2 weeks) until progression or intolerable side effects.
The primary end point in this study was also incidence of dose-limiting toxicities. Secondary end points included incidence of adverse events, overall response rate, duration of response, and progression-free survival.
As Dr Puzanov reported, safety results showed no dose-limiting toxicities. No patients permanently discontinued therapy because of adverse events related to T-VEC, and only 2 patients (10%) permanently discontinued therapy because of adverse events related to pembrolizumab (autoimmune hepatitis and pneumonitis).
At 57%, the overall response rate was relatively high, said Dr Puzanov, and 23% of patients had complete responses. In addition, responses induced by this combination were “mostly durable.” At the time of analysis, median progression-free survival had not been reached.
Circulating T-Cell Subsets
The absolute numbers of CD3+ cells were increased by initial T-VEC injections, and PD-L1 expression increased as well. Researchers also observed an increase in absolute numbers and proliferation of CD4+ cells.
“Interestingly,” said Dr Puzanov, “there was increase in TIM-3+ cells, which may lead us to speculate about some further combinations and their benefit.”
The phase 3 trial is currently enrolling and will be testing the T-VEC plus pembrolizumab combination in frontline patients where BRAF treatment is allowed.
Although other agents are undergoing similar development, the optimal selection of both patients and agents is unlikely to be answered in randomized trials, Dr Puzanov said.
“Development of biomarkers for selection is of extreme importance,” he concluded. “Ordering biopsies of 1 or 2 doses of anti–PD-1 or T-VEC may be a better selection marker than trying to develop selection markers de novo in naive patients.”
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