Abstract
Cancer vaccines have often failed to live up to their promise, although recent results with checkpoint inhibitors are reviving hopes that they will soon fulfill their promise. Although mutation-specific vaccines are under development, there is still high interest in an off-the-shelf vaccine to a ubiquitous antigen, such as MUC1, which is aberrantly expressed on most solid and many hematological tumors, including more than 90% of breast carcinomas. Clinical trials for MUC1 have shown variable success, likely because of immunological tolerance to a self-antigen and to poor immunogenicity of tandem repeat peptides. We hypothesized that MUC1 peptides could be optimized, relying on heteroclitic optimizations of potential anchor amino acids with and without tumor-specific glycosylation of the peptides. We have identified novel MUC1 class I peptides that bind to HLA-A*0201 molecules with significantly higher affinity and function than the native MUC1 peptides. These peptides elicited CTLs from normal donors, as well as breast cancer patients, which were highly effective in killing MUC1-expressing MCF-7 breast cancer cells. Each peptide elicited lytic responses in greater than 6/8 of normal individuals and 3/3 breast cancer patients. The CTLs generated against the glycosylated-anchor modified peptides cross reacted with the native MUC1 peptide, STAPPVHNV, suggesting these analog peptides may offer substantial improvement in the design of epitope-based vaccines.
Highlights
It has been difficult to develop effective vaccines for cancer, as the cancer cells are largely similar to normal cells and our immune system avoids attacking itself
The fifth proline in the P1:STAPPVHNV native peptide was changed to a threonine to allow for glycosylation in the fifth position
We have identified two novel major histocompatibility complex (MHC) class I peptides (an aberrantly glycosylated anchor-optimized heteroclitic peptide (P4:SLAPT(Tn)VHNV) and non-glycosylated heteroclitic counterparts (P15:SLAPPVHNV and P3:SLAPTVHNV) that bind to HLA-A*0201 molecules with high affinity (8- to 30-fold higher affinity, respectively, than the known M1.1 and M1.2 MUC1 peptides)
Summary
It has been difficult to develop effective vaccines for cancer, as the cancer cells are largely similar to normal cells and our immune system avoids attacking itself. Cancer immunotherapy is undergoing a revolution with the emergence of checkpoint inhibitors such as anti-PD-1 and anti-CTLA4. These antibodies strengthen natural immune responses against cancer by blocking the triggering of inhibitory receptors on activated T cells, resulting in major clinical responses in up to 40%–60% of patients with advanced melanoma [1]. The checkpoint inhibitors appear to work most effectively in immune-driven cancers or those with a high mutational load [6,7]. It is likely that tumors fortified with T cells that recognize their tumor may be rendered more responsive to checkpoint inhibitor therapy [3,8]
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