Overall,
cancer vaccines have had a record of failure as an adjuvant
therapy for
malignancies that are treated with alkylating
chemotherapy, and the contribution of standard treatment to that failure remains unclear.
Vaccines aim to harness the proliferative potential of the immune system by expanding a small number of
tumor-specific lymphocytes into a large number of antitumor effectors. Clinical trials are often conducted
after treatment with alkylating
chemotherapy, given either as standard
therapy or for immunomodulatory effect. There is mounting evidence for synergy between
chemotherapy and adoptive immunotherapy or vaccination against self-Ags; however, the impact of
chemotherapy on lymphocytes primed against
tumor neoantigens remains poorly defined. We report that clinically relevant dosages of standard alkylating
chemotherapies, such as
temozolomide and
cyclophosphamide, significantly inhibit the proliferative abilities of lymphocytes in mice. This proliferative impairment was long-lasting and led to quantitative and qualitative defects in B and T cell responses to neoantigen
vaccines. High-affinity responder lymphocytes receiving the strongest proliferative signals from
vaccines experienced the greatest DNA damage responses, skewing the response toward lower-affinity responders with inferior functional characteristics. Together, these defects lead to inferior efficacy and overall survival in murine
tumor models treated by neoantigen
vaccines. These results suggest that clinical protocols for
cancer vaccines should be designed to avoid exposing responder lymphocytes to alkylating
chemotherapy.