Alkylating chemotherapy may exert a uniquely deleterious effect upon neo-antigen-targeting anticancer vaccination

Abstract

Alkylating chemotherapy exerts both antineoplastic and immunostimulatory effects. However, in addition to depleting regulatory T cells (Treg), alkylating agents also mediate a long lasting antiproliferative effect on responder lymphocytes. Our recent findings indicate that this antiproliferative effect profoundly impairs vaccination-induced immune responses, especially in the case of vaccines that target specific tumor-associated neo-antigens that do not require Treg depletion.

Keywords: alkylating chemotherapy; cancer vaccines; chemoimmunotherapy; neo-antigens; regulatory T cells.

Figure 1. Effects of alkylating chemotherapy on vaccine-induced immune responses. (A) Robust TCR signaling leads to DNA damage in lymphocytes previously exposed to alkylating chemotherapy. OT-I mice were treated with temozolomide or left untreated, and their splenocytes were stimulated with the indicated variants of the chicken ovalbumin-derived peptide SIINFEKL . Strongly immunogenic peptides (such as SIINFEKL, SIIQFEKL) led to a considerable accumulation of DNA double strand breaks (measured with an antibody against phosphorylated ATM) in proliferating (Ki67⁺) cells as compared with no antigenic stimulation or weak peptides (such as SIIGFEKL). (B) Compromised overall survival of metastatic melanoma patients upon the administration of an autologous vaccine alone or upon pre-treatment with cyclophosphamide. Patients enrolled in a clinical trial testing a large autologous multivalent vaccine were either treated with 300 mg/m² cyclophosphamide or left untreated, and subjected to vaccination one week later. Overall survival is depicted (n = 10 patients/group).

Figure 2. The outcome of vaccination upon alkylating chemotherapy may depend upon the type of antigenic target. The generation of robust immune responses against overexpressed self antigens is likely require to depletion of regulatory T cells (Tregs), providing a rationale for the use of immunostimulatory doses of alkylating chemotherapy. Conversely, mutated neo-antigens are recognized by T cells harboring high-affinity T-cell receptors in spite of the presence of normal amounts of Tregs. In this case, the DNA-damaging potential of alkylating chemotherapy is deleterious for the efficiency of vaccination.