Phase II trial of Modified Vaccinia Ankara (MVA) virus expressing 5T4 and high dose Interleukin-2 (IL-2) in patients with metastatic renal cell carcinoma

Howard L Kaufman, Bret Taback, William Sherman, Dae Won Kim, William H Shingler, Dorota Moroziewicz, Gail DeRaffele, Josephine Mitcham, Miles W Carroll, Richard Harrop, Stuart Naylor, Seunghee Kim-Schulze, Howard L Kaufman, Bret Taback, William Sherman, Dae Won Kim, William H Shingler, Dorota Moroziewicz, Gail DeRaffele, Josephine Mitcham, Miles W Carroll, Richard Harrop, Stuart Naylor, Seunghee Kim-Schulze

Abstract

Background: Interleukin-2 (IL-2) induces durable objective responses in a small cohort of patients with metastatic renal cell carcinoma (RCC) but the antigen(s) responsible for tumor rejection are not known. 5T4 is a non-secreted membrane glycoprotein expressed on clear cell and papillary RCCs. A modified vaccinia virus Ankara (MVA) encoding 5T4 was tested in combination with high-dose IL-2 to determine the safety, objective response rate and effect on humoral and cell-mediated immunity.

Methods: 25 patients with metastatic RCC who qualified for IL-2 were eligible and received three immunizations every three weeks followed by IL-2 (600,000 IU/kg) after the second and third vaccinations. Blood was collected for analysis of humoral, effector and regulatory T cell responses.

Results: There were no serious vaccine-related adverse events. While no objective responses were observed, three patients (12%) were rendered disease-free after nephrectomy or resection of residual metastatic disease. Twelve patients (48%) had stable disease which was associated with improved median overall survival compared to patients with progressive disease (not reached vs. 28 months, p = 0.0261). All patients developed 5T4-specific antibody responses and 13 patients had an increase in 5T4-specific T cell responses. Although the baseline frequency of Tregs was elevated in all patients, those with stable disease showed a trend toward increased effector CD8+ T cells and a decrease in Tregs.

Conclusion: Vaccination with MVA-5T4 did not improve objective response rates of IL-2 therapy but did result in stable disease associated with an increase in the ratio of 5T4-specific effector to regulatory T cells in selected patients.

Trial registration number: ISRCTN83977250.

Figures

Figure 1
Figure 1
5T4-specific T cell responses in patients with (A) progressive disease and (B) stable disease.
Figure 2
Figure 2
Characterization of T cell responses. (A) CD8+CD107a+ effector cells, (B) CD8+perforin+ effector cells, (C) PD-1+ T cells, (D) CD4+CD25+FoxP3+ Tregs before and after treatment.
Figure 3
Figure 3
Representative effector CD8+ T cell and Treg responses in 3 patients (A-C). effector/regulatory T cell ratio in all patients (D). SD, stable disease (open square), PD, progressive disease (closed square).
Figure 4
Figure 4
Kaplan-Meier analysis of (A) overall (solid line) and progression-free (dashed line) survival of per-protocol patients treated with MVA-5T4 and IL-2. (B) Overall survival of stable (solid line) and progressive (dashed line) disease patients. Numbers of patients at risk at 8, 20 and 28 months are shown below the graph.

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