Phase I/II study exploring ImMucin, a pan‐major histocompatibility complex, anti‐MUC1 signal peptide vaccine, in multiple myeloma patients

Abstract

Summary ImMucin, a 21‐mer cancer vaccine encoding the signal peptide domain of the MUC1 tumour‐associated antigen, possesses a high density of T‐ and B‐cell epitopes but preserves MUC1 specificity. This phase I/II study assessed the safety, immunity and clinical response to 6 or 12 bi‐weekly intradermal ImMucin vaccines, co‐administered with human granulocyte‐macrophage colony‐stimulating factor to 15 MUC1‐positive multiple myeloma (MM) patients, with residual or biochemically progressive disease following autologous stem cell transplantation. Vaccination was well tolerated; all adverse events were temporal grade 1 2 and spontaneously resolved. ImMucin vaccination induced a robust increase in γ‐interferon (IFN‐γ‐producing CD4+ and CD8+ T‐cells (≤80‐fold), a pronounced population of ImMucin multimer CD8+ T‐cells (>2%), a 9·4‐fold increase in peripheral blood mononuclear cells proliferation and 6·8‐fold increase in anti‐ImMucin antibodies, accompanied with T‐cell and antibody‐dependent cell‐mediated cytotoxicity. A significant decrease in soluble MUC1 levels was observed in 9/10 patients. Stable disease or improvement, persisting for 17·5‐41·3 months (ongoing) was achieved in 11/15 patients and appeared to be associated with low‐intermediate PDL1 (CD274) bone marrow levels pre‐ and post‐vaccination. In summary, ImMucin, a highly tolerable cancerous vaccine, induces robust, diversified T‐ and B‐cell ImMucin‐specific immunity in MM patients, across major histocompatibility complex‐barrier, resulting in at least disease stabilization in most patients.

The use of signal peptide domains as vaccine candidates

“…52 Likewise, injection of naked peptides without adjuvant has typically been shown to be minimally immunogenic; and co-administration with immunologic adjuvants is typically required to induce detectable T-cell or B-cell responses. 52 However, in vitro and in vivo results with MUC1's TAA 45,48 and MTb-derived 43,46 SP domains, somewhat deviated from the general observations. SP domains directly activated in vitro proliferation of PBMC samples isolated from na€ ıve donors.…”

“…46 Similarly, these SP domains induced a strong and specific cellular immune response [45][46][47] and anti-tumor activity 45 in both mice and in a firstin-human study. 48 More recently, an additional support for the potency of SP domains was published by Kerzerho et al, which demonstrated the existence of multiple CD4…”

“…48 Despite the robust generated immunity, ImMucin was well tolerated, and no vaccine-related grade 3 adverse events (AE) were reported in over 160 vaccine (ImMucin plus hGM-CSF) administrations in patients. Common, primarily local vaccine administration-associated grade 1 or 2 AEs were observed, all of which self-resolved within 72 h (see also Table 1 for technology comparison).…”

“…Importantly, the induced anti-ImMucin antibodies mixed with autologous PBMCs induced specific antibody-dependent cellmediated cytotoxicity (ADCC) of autologous bone marrowderived tumor cells, confirming the presence of the MUC1 SP domain on primary tumors, and the selective and prominent antitumor properties of the generated anti-MUC1 SP antibodies. 48 The need for adjuvants and/or carriers Immunity to peptides, specifically those derived from selftumor antigens, usually require indirect presentation via DCs, as they are considered poor immunogens. 52 Likewise, injection of naked peptides without adjuvant has typically been shown to be minimally immunogenic; and co-administration with immunologic adjuvants is typically required to induce detectable T-cell or B-cell responses.…”

“…Moreover, immunization of HLA-A2.1 transgenic mice and BALB/c syngeneic mice with the MUC1 SP domain or MTb SP domains, alone or in combination with murine GM-CSF, induced a strong antigen-specific T-cell response, and to some extent an antibody response as well, without involving any adjuvant. 48 In humans, strong cellular and moderate humoral responses were obtained in MM patients treated with 100 mg naked ImMucin vaccine plus 250 mg of hGM-CSF, but without a carrier or B-cell adjuvant, 48 (see sections on T-cell and antibody response). We attribute the strong immune response observed with SP domains to the following factors: first, SP domains contain hydrophilic/lipophilic sequences which are known to be more immunogenic, mainly with regard to T-cell induction (by enhancing MHC binding and cell penetration), which, in select cases, is comparable to that achieved when administering a vaccine with incomplete Freund's adjuvant 53 (and authors unpublished data).…”