EBMT 2018 | Galinpepimut-S (GPS) vaccine in high-risk MM

The 44^th Annual Meeting of the European Society for Blood and Marrow Transplantation was held in Lisbon, Portugal, from 18–21 March 2018 and attended by the MM Hub. On Monday 19 March 2018, the oral abstract session 4 was held. The session was moderated by Catarina Geraldes, from the University of Coimbra, Portugal and Tamás Masszi, from Semmelweis University, Budapest, Hungary. The sixth talk in this session was presented by Guenther Koehne, from the Miami Cancer Institute, Bone Marrow Transplantation and Hematologic Oncology, Miami, FL, US, who presented a talk entitled: Clinical benefit after Galinpepimut-S (GPS), a WT-1 immunotherapeutic, correlates with antigen-specific immune responses in high-risk Multiple Myeloma: a complete analysis of the phase II GPS maintenance study.

Wilms tumor-1 (WT-1) zinc finger transcription factor has been shown to have diverse roles in cell proliferation, differentiation, apoptosis and organ development. WT-1 peptides overexpressed in MM cells are effectively presented to the TCR via the MHC, leading to activation of CTLs and killing of cancer cells expressing WT-1. A synthetic vaccine, Galinpepimut-S (GPS), consists of two native and two synthetic WT-1 peptides (WT1A-1*; 427L [long]; 331L, and 122A1L*). The mutated peptides (*) are also termed heteroclitic and are designed to have a higher affinity for HLA, can break immune tolerance, and generate a response to the native peptide sequence of the cognate target antigen expressed by cancer cells. Expression of native WT-1 peptides has been found on cancer cells of MM patients following donor-lymphocyte infusions. Therefore, GPS is a first in-class WT-1 peptide vaccine, which stimulates both CD4⁺ and CD8⁺ T-cell responses.

A phase II study was conducted in which MM patients with high-risk cytogenetic profiles were immunized with GPS following a first-line autologous stem cell transplant (ASCT). A median progression-free survival (PFS) of 23.6 months was reported, along with an 88% overall survival (OS) of 18 months. This was an impressive 11-month increase when compared to data from the PETHEMA/GEM05 trial, which assessed thalidomide plus bortezomib maintenance in a subset of patients with high-risk cytogenetics.

The study presented by Guenther Koehne set out to assess the correlation between clinical benefit (CB), as assessed by complete response (CR)/very good partial response (VGPR), and antigen-specific immune-responses (IR), using data from the phase II trial.

Key Findings:

• Patients (pts) = 19 evaluable; median age = 61.6 years (range 46–72)
• GPS administered with low-dose GM-CSF (70 µg) 2 weeks post-ASCT and every 2 weeks after (x 6 doses) followed by boosters every 4 weeks
• All pts received lenalidomide maintenance (10 mg daily), starting 3 months post-ASCT
• IR was assessed using intracellular IFN-γ analysis to measure WT1-specific responses (at baseline, then after 6 and 12 GPS doses), using PBMC's pulsed with each of the 4 peptides, the 2 native counterparts for the mutated peptides, or a pool of 113 partially overlapping peptides (15mers) derived from full-length WT1 (as a marker for cross-epitope reactivity)
• Responses were detected across all HLA types
• Absolute numbers of CD8/CD4 cells:

*Only 2/6 had reactive CD8⁺; all 6 had reactive CD4⁺; **All 4 pts had only reactive CD4+ cells; ^#Equal frequency of CD4/CD8 cells

• Rate of IR positivity:
  • For 4 peptides in GPS: CD4 or CD8 = 72–91%
  • For all pool peptides: CD4 or CD8 = 75%
  • Up to 64% of pts demonstrated IR⁺ (CD4/CD8) against >1 WT-1 peptide
• Rate of IR positivity in pts with complete response (CR)/very good partial response (VGPR):
  • Prior CD8 IR+ = 81.8% (N = 9)
  • Prior CD4 IR+ = 100% (N = 11)
• Rate of achievement of CR/VGPR in patients who maintained IR positivity:
  • If CD4 IR⁺ was maintained to any of the 4 native GPS peptides (N = 11) = 54.6%
  • If CD8 IR⁺ was maintained to any of the 4 native GPS peptides (N = 9) = 44.0%
  • If CD4 IR⁺ was maintained to ‘all pool’ peptides (N = 8) = 62.5%
  • If CD8 IR⁺ was maintained to ‘all pool’ peptides (N = 7) = 57.1%
• MM pts maintaining multivalent IRs (CD4/CD8) were more likely to achieve clinical response (CR/VGPR) on completion of GPS therapy

This study demonstrates an immune basis for both the prolonged PFS observed in MM patients immunized with GPS as well as the sustained clinical benefit. This is the first time such a link has been made for an MM-specific peptide vaccine and holds promise for future expanded trials.

Dr Koehne was asked about the overall expression of WT-1 and said they have observed that the more aggressive the disease the higher the expression of WT-1, and that the patients in this study were selected for high baseline WT-1 expression.