Immunologic response to the survivin-derived multi-epitope vaccine EMD640744 in patients with advanced solid tumors

Abstract

Purpose: Survivin is a member of the inhibitor-of-apoptosis family. Essential for tumor cell survival and overexpressed in most cancers, survivin is a promising target for anti-cancer immunotherapy. Immunogenicity has been demonstrated in multiple cancers. Nonetheless, few clinical trials have demonstrated survivin-vaccine-induced immune responses.

Experimental design: This phase I trial was conducted to test whether vaccine EMD640744, a cocktail of five HLA class I-binding survivin peptides in Montanide(®) ISA 51 VG, promotes anti-survivin T-cell responses in patients with solid cancers. The primary objective was to compare immunologic efficacy of EMD640744 at doses of 30, 100, and 300 μg. Secondary objectives included safety, tolerability, and clinical efficacy.

Results: In total, 49 patients who received ≥2 EMD640744 injections with available baseline- and ≥1 post-vaccination samples [immunologic-diagnostic (ID)-intention-to-treat] were analyzed by ELISpot- and peptide/MHC-multimer staining, revealing vaccine-activated peptide-specific T-cell responses in 31 patients (63 %). This cohort included the per study protocol relevant ID population for the primary objective, i.e., T-cell responses by ELISpot in 17 weeks following first vaccination, as well as subjects who discontinued the study before week 17 but showed responses to the treatment. No dose-dependent effects were observed. In the majority of patients (61 %), anti-survivin responses were detected only after vaccination, providing evidence for de novo induction. Best overall tumor response was stable disease (28 %). EMD640744 was well tolerated; local injection-site reactions constituted the most frequent adverse event.

Conclusions: Vaccination with EMD640744 elicited T-cell responses against survivin peptides in the majority of patients, demonstrating the immunologic efficacy of EMD640744.

Fig. 1

Vaccination and immunomonitoring schedule. Strength of arrows indicates priorities of analyses. EOS, end-of-study sample; ID-ITT, immunologic-diagnostic intent-to-treat population; ID population, immunologic diagnostic population

Fig. 2

a Frequencies of spot-forming cells (SFC) per 10⁵ CD8⁺ T cells as determined by ex vivo ELISpot assays (evELISpots) and ELISpots after short-term in vitro stimulation (ivsELISpots) for all patients who showed responses to survivin peptides. b Frequencies of pHLA-multimer-stained cells (as  % of vital CD8-positive T cells) analyzed ex vivo (evMultimer) or after in vitro stimulation (ivsMultimer) for all patients with available PBMC samples

Fig. 3

Summary of all T-cell responses detected by ELISpot and pMHC-multimer staining

Fig. 4

a Response course of patient 0005-0011 determined by ex vivo ELISpot analysis. The HLA-A24-positive patient showed responses to the vaccine cocktail (EMD640744) and to the HLA-A24-restricted peptide Sur20-28. b Response course of patient 0004–0015 to the HLA-A2-binding peptide Sur96-104/M2 by pHLA-multimer staining after in vitro stimulation with the corresponding peptide

Fig. 5

a ELISpot in patient 0004–0015. Responses to the HLA-A2-associated peptides Sur96-104 (native epitope) and Sur96-104/M2 (modified epitope) were detected by evELISpots in weeks 16, 24, and 60 but not at time points in between (not shown). b ivsELISpots on week 36- and end-of-study samples in the same patient (0004–0015) confirmed these responses by showing specific T cells at frequencies below the evELISpot detection limit. c Patient 0001–0007 showed a response to the A3-modified peptide with concurrent reactivity to the native peptide. (Counts were set to >500 when a significant proportion of spots were confluent, and the reader system was unable to count them as separate spots. **p < 0.001; SFC, spot-forming cells)