Re-purposing cancer therapeutics for breast cancer immunotherapy

After decades of work to develop immunebased therapies for cancer, the Wrst drugs designed speciWcally to engage the host anti-Tumor immune response for therapeutic beneWt were recently approved for clinical use. Sipuleucel-T, a vaccine for advanced prostate cancer, and ipilimumab, a monoclonal antibody that mitigates the negative impact of cytotoxic T lymphocyte antigen-4 signaling on tumor immunity, provide a modest clinical beneWt in some patients. The arrival of these drugs in the clinic is a signiWcant advance that we can capitalize on for even better clinical outcomes. The strategic and scientiWcally rational integration of vaccines and other direct immunomodulators with standard cancer therapeutics should lead to therapeutic synergy and high rates of tumor rejection. This review focuses on the use of cyclophosphamide, doxorubicin, and HER-2-speciWc monoclonal antibodies to dissect mechanisms of immune tolerance relevant to breast cancer patients and illustrates how appropriate preclinical models can powerfully inform clinical translation. The immunemodulating activity of targeted, pathway-speciWc, small molecule therapeutics is also discussed. Fully understanding how cancer drugs impact the immune system should lead to the ultimate personalized cancer medicine: eVective combinatorial immunotherapy strategies that simultaneously target signaling pathways essential for tumor growth and progression, and systematically break multiple, distinct immune tolerance pathways to maximize tumor rejection and eVect cure.