Anti‐tumor immune responses and tumor regression induced with mimotopes of a tumor‐associated T cell epitope

Abstract

Mimotopes provide an alternative to natural T cell epitopes for cancer immune therapy, as they can recruit and stimulate T cell repertoires that deviate from the repertoires engaged with the tumor and exposed to disease-related immune suppression. Here, mimotopes of a shared tumor-associated T cell epitope in cutaneous lymphoma were tested for their capacities to induce clinical and immunological responses in cancer patients. The mimotope sequences had been determined by a combinatorial peptide library approach without knowledge of the corresponding natural tumor-associated antigen. Vaccination with these mimotopes together with helper T cell-inducing antigens led to complete tumor remission in the two patients tested. After each booster vaccination, enhanced frequencies of mimotopespecific CD8 + T cells were detected in the peripheral blood of the patients, and the CTL proved to be cytotoxic and tumoricidal when tested in vitro. These data provide a first indication of clinical efficacy of mimotopes in cancer patients.

Cancer vaccines inducing antibody production: more pros than cons

“…We believe that vaccination with these mimotopes may overcome tolerance-cell mediated immune escape of the natural tumor antigen, as they are similar, but not identical to the original tumor antigen. In addition, mimotopes for T-cell epitopes of tumor antigens have been generated in the past [87][88][89][90]. In fact, the only clinical study so far was successfully performed with T-cell mimotopes in two human patients for cutaneous lymphoma [88].…”

“…In addition, mimotopes for T-cell epitopes of tumor antigens have been generated in the past [87][88][89][90]. In fact, the only clinical study so far was successfully performed with T-cell mimotopes in two human patients for cutaneous lymphoma [88]. However, like the original T-cell epitopes, T-cell mimotopes depend on the HLA type of the individual patient, which restricts their applicability largely.…”

“…Mimotope vaccines for epitope-specific antibody [52,53,60] or T-cell induction [87][88][89][90] need antigen density to achieve immunogenicity. Mimotopes can thus be applied either as multiple antigenic peptides (b) [66], displayed on phages when selected from phage display peptide libraries (c) [86], synthesized and chemically coupled to different carrier systems such as keyhole limpet hemocyanin (d) [60], presented on the surface of adeno-associated viruses (e) [82], as fusion constructs with immunoglobulin Fc-domains (f) [75] or in DNA form (g) [73].…”

“…Mimotopes can thus be applied either as multiple antigenic peptides (b) [66], displayed on phages when selected from phage display peptide libraries (c) [86], synthesized and chemically coupled to different carrier systems such as keyhole limpet hemocyanin (d) [60], presented on the surface of adeno-associated viruses (e) [82], as fusion constructs with immunoglobulin Fc-domains (f) [75] or in DNA form (g) [73]. (B) T-cell mimotopes can directly address T-effector cells via their TCR and thereby activate T-effector cell clones targeted against tumor cells [87][88][89]. This mechanism is dependent on HLA display of mimotopes to achieve full TCR activation capacity.…”

Evaluating strategies to enhance the anti-tumor immune response to a carbohydrate mimetic peptide vaccine

“…Peptide mimotopes have been described for GD2 (12)(13)(14), GD3 (15), sialylated Lewis a/x (16), and LeY (12,17). Peptide mimotopes of tumor antigenic epitopes potentially represent a novel vaccine approach to induce a tumor antigen-specific humoral and cellular response (18)(19)(20)(21)(22). Mimotopes function as xenoantigens and, consequently, can overcome tolerance to carbohydrate self-antigens.…”