Peptide Vaccination Against PD-L1 With IO103 a Novel Immune Modulatory Vaccine in Multiple Myeloma: A Phase I First-in-Human Trial

Abstract

Background: Immune checkpoint blockade with monoclonal antibodies targeting programmed death 1 (PD-1) and its ligand PD-L1 has played a major role in the rise of cancer immune therapy. We have identified naturally occurring self-reactive T cells specific to PD-L1 in both healthy donors and cancer patients. Stimulation with a PD-L1 peptide (IO103), activates these cells to exhibit inflammatory and anti-regulatory functions that include cytotoxicity against PD-L1-expressing target cells. This prompted the initiation of the present first-in-human study of vaccination with IO103, registered at clinicaltrials.org (NCT03042793).

Methods: Ten patients with multiple myeloma who were up to 6 months after high dose chemotherapy with autologous stem cell support, were enrolled. Subcutaneous vaccinations with IO103 with the adjuvant Montanide ISA 51 was given up to fifteen times during 1 year. Safety was assessed by the common toxicity criteria for adverse events (CTCAE). Immunogenicity of the vaccine was evaluated using IFNγ enzyme linked immunospot and intracellular cytokine staining on blood and skin infiltrating lymphocytes from sites of delayed-type hypersensitivity. The clinical course was described.

Results: All adverse reactions to the PD-L1 vaccine were below CTCAE grade 3, and most were grade 1-2 injection site reactions. The total rate of adverse events was as expected for the population. All patients exhibited peptide specific immune responses in peripheral blood mononuclear cells and in skin-infiltrating lymphocytes after a delayed-type hypersensitivity test. The clinical course was as expected for the population. Three of 10 patients had improvements of responses which coincided with the vaccinations.

Conclusion: Vaccination against PD-L1 was associated with low toxicity and high immunogenicity. This study has prompted the initiation of later phase trials to assess the vaccines efficacy.

Clinical trial registration: clinicaltrials.org, identifier NCT03042793.

Keywords: PD-L1; first-in-human; myeloma; peptide; vaccination.

Copyright © 2020 Jørgensen, Klausen, Grauslund, Helleberg, Aagaard, Do, Ahmad, Olsen, Klausen, Breinholt, Hansen, Martinenaite, Met, Svane, Knudsen and Andersen.

Figures

Figure 1

IFNγ-ELISPOT immune responses against IO103. (A) responses in PBMCs in vaccinated patients (bars represent median); (B) Heatmap of responses in PBMCs per vaccinated per time point. (*DFRx1; **DFRx2); (C) representative example of ELISPOT-wells with response; (D) best response in PBMCs in vaccinated patients; (E) responses in unvaccinated reference cohort including time point before HDT (All p-values: Wilcoxon matched-pairs signed rank test); (F) IFNγ-ELISPOT responses against IO103 in bone marrow samples from patient 4.

Figure 2

Immune responses to the vaccine in the skin. (A) IFNγ-ELISPOT responses against the PD-L1 peptide IO103 of skin infiltrating lymphocytes after delayed type hypersensitivity reaction performed after 6 vaccines. 300,000 cells per well. Samples were run in triplicate or quadruplicate. **DFRx2; (B) intracellular cytokine staining (ICS) of SKILs. Almost all cells were CD4+ (not shown). Two out of six evaluable patients had TNFα- and INFγ-double positive SKILs; (C) example of a double positive ICS (patient 7).

Figure 3

Flow cytometric analyses of levels of Tregs. (A) FoxP3+ Treg. (B) CD25highCD127neg Treg; (C) CCR4 + Primed Tregs; (D) CD15s Effector Tregs. % of CD4+ PBMCs. Bars represent median (Mann-Whitney).

Figure 4

Clinical course. Swimmer’s plot. Colors of bars symbolize depth of response at start of vaccinations, after HDT and during the vaccination course. †patient 8 had a rapid relapse after having received 11 vaccinations and died shortly thereafter despite initiation of daratumumab-lenalidomide-dexamethasone.