2015 Nature- Big opportunities for small molecules in I-O.pdf

The critical relationship between immune function and cancer was first proposed by Rudolf Virchow 150?years ago when he observed the prevalence of leukocytes in tumours1. A few decades later, William Coley and col- leagues conducted the first experimental immunotherapy treatment of cancer based on the observation that some patients carrying a bacterial infection exhibited more extensive tumour regression compared with uninfected individuals2. For the next 100?years, there was little clini- cal demonstration that the immune system could be mobilized to provide a reproducible benefit for patients with cancer. Recent watershed moments evincing clinical success for cancer immunotherapy include the regulatory approvals of the T?cell checkpoint inhibitory antibodies ipilimumab (Yervoy; Bristol-Myers Squibb), pembrolizumab (Keytruda; Merck) and nivolumab (Opdivo; Bristol-Myers Squibb), and the dendritic cell therapy sipuleucel-T (Provenge; Dendreon). Sipuleucel-T comprises autologous dendritic cells primed with a recombinant protein to enhance the patient’s native immune response in prostate cancer3. Ipilimumab is a fully human IgG1 mAb that blocks ligand engagement and enhances T?cell activation by directly binding to the cytotoxic T lymphocyte-associated anti- gen 4 (CTLA4) receptor protein, thus blocking a critical inhibitory signal for activated T?cells4,5. Pembrolizumab and nivolumab are humanized mAbs that block ligand engagement, thus interfering with T cell signalling and cell death6,7. All of these mAbs have demonstrated sig- nificant clinical benefit as single agents in melanoma, and continue to be tested in clinical trials as both single agents and in combinations. Moreover, these mAbs show considerable promise for other solid tumour indi- cations, including lung cancer and renal cell carcinoma. These successful immuno-oncology medicines lever- age distinct immunological mechanisms in relation to cancer growth and treatment, ranging