Phase I/II Trial Of Immucin a Pan HLA, Anti-MUC1 Signal Peptide Vaccine, In Multiple Myeloma Patients With Residual Disease Or Progression Following Autologous Stem Cell Transplantation

Anti-multiple myeloma (MM) vaccinations have recently emerged as a strategy to eradicate MM cells in patients with residual tumor mass. However, most vaccination studies reported transient immune responses, involving CD8+ T-cells or antibodies responses in patients with predefined MHC repertoire.

Signal peptide (SP) domains, a 13-50 amino acid long peptides, have been demonstrated to present an exceptionally high number of antigen specific MHC class I, class II and B-cell epitopes per sequence length. Therefore, they are suitable to induce a robust immune response combining CD8+, CD4+ T-cells and antibodies across HLA barrier. Following this rationale we developed ImMucin, A 21-mer therapeutic vaccine encoding the entire SP domain of the MUC1 tumor-associated antigen (TAA), which is over expressed by most carcinomas and hematological tumors including MM.

A phase I/II study to assess the safety (primary endpoint) and efficacy (secondary endpoint) of ImMucin was conducted in MM subjects with stable or progressive residual asymptomatic MUC1+ disease who have already had upfront auto-SCT. Patients recruited into the study initially received 6 bi-weekly vaccination of intra-dermal 100ug ImMucin plus 250ug hGM-CSF. Based on immune and clinical response eligible patient could receive additional 6 bi-weekly vaccination of 100ug or 250ug ImMucin plus 250ug hGM-CSF.

Immunomonitoring analysis included; ImMucin-specific IFN-g production in CD4+ and CD8+ T-cells, HLA-A2.1 tetramer binding in CD8+ T-cells, proliferation and antibodies production. Positive response in these assays vs. pre vaccination levels were; x2 increase in IFN-g and >0.5%+ T-cells, any increase in tetramer binding levels, x2 increase and stimulation index (SI)>2 and any increase in anti-ImMucin titer respectively.

15 patients, median age 58 years participated in the study. The median number of prior therapies was 2. Median time from diagnosis and from auto-SCT to vaccination were 25 months (12-143) and 15 months (3-134) respectively. 9 patients had post auto-SCT residual MM and 6 had an evidence for biochemical progression. 11 patients completed the vaccination program while 4 discontinued the program due to PD. ImMucin was shown to be safe with no vaccine related grade ≥3 adverse events (AEs). Patients had temporary, grade 1,2 AEs, including injection related rash (n=8), fatigue (n=6), weakness, self-resolving fever and muscle pain (n=5).

IFN-g production response to ImMucin was highly positive in all patients with 4-80 folds increase for CD4+ and 18-80 folds increase for CD8+. Mean baseline and peak post vaccination levels for ImMucin-specific CD4+ T-cells were 0.21% and 4.07%, respectively (P<0.001, t-test) and of CD8+ T-cells 0.21% and 11.76%, respectively (P<0.0001, t-test).

All 4 HLA-A2.1 positive patients demonstrated < x2 increase in tetramer-positive cells after vaccination, with mean levels of 0.33% and 2.11% at baseline and peak post vaccination, respectively. Proliferative response to ImMucin increased signifcantly in all patients with mean baseline and peak of 3.24 and 15.92, respectively (P<0.024, t-test). An increased ImMucin humoral response of up to 40 folds from baseline levels was detected in 10 of 15 patients (66.6%). The vaccination efficacy was further confirmed by CD8+ T-cells and antibody mediated cytotoxicity against autologous BM cells. In these assays MUC1 control epitope didn’t show positive activation.

Since ImMucin target MUC1’s SP domain which is not part of soluble MUC1 (sMUC1), a reduction in sMUC1 following vaccination can reflect a specific tumor destruction. A reduction of up to 17 folds, 5129.44 pg/ml as a mean levels at baseline vs. 792.33 pg/ml at maximal response (P<0.002, t-test) was detected in 9 of 10 patients, initially presenting abnormally elevated sMUC1 levels.

Response assessment revealed disease stabilization in the majority of the patients, lasting for up to 29 months post study completion (ongoing follow up), including in patients entering study with PD.

The ImMucin therapeutic vaccine is directed to the less studied SP domain of MUC1 TAA. The current phase I/II results confirmed its high safety profile. ImMucin induced a robust CD8+ and CD4+ specific T-cell response in all patients and a marked anti-tumor humoral response. Further studies exploring ImMucin’s efficacy in patients with residual myeloma are under development.

Carmon:Vaxil BioTherapeutics Ltd. : Employment, Equity Ownership, Patents & Royalties. Avivi:Vaxil BioTherapeutics Ltd. : Consultancy. Riva:Vaxil BioTherapeutics Ltd. : Employment. Shapira:Vaxil BioTherapeutics Ltd. : Consultancy.