MILESTONES MILESTONE 17 to mature. The pulsed dendritic cells are then reinfused into the patient over several cycles. A dendritic cell cancer vaccine Although sipuleucel-T has not been very widely adopted (and is no longer available in the European Union), it was recently announced that the combination of hormonal therapeutics with sipuleucel-T extended the survival of patients with metastatic castration-resistant prostate cancer. Other clinical trials combining sipuleucel-T with radiation, hormo- nal, targeted or other immunothera- pies are ongoing. So far sipuleucel-T remains the only vaccine-based immunotherapy approved for prostate cancer, and is also the only approved cell-based vaccine in the USA. Overall clinical responses to dendritic cell vaccines have been disappointing, but with increasing Credit: Science Photo Library / Alamy Stock Photo Science Photo Library Credit: knowledge, newer and more sophisti- cated strategies are being investigated In 1909 Paul Ehrlich postulated that T cells and induce protective T cell to improve the efficacy of dendritic the immune system may defend responses. If a cancer-specific antigen cell-based vaccines. Improved meth- the host against neoplastic cells and is presented, this can result in an Sipuleucel-T ods to generate more mature and hinder the development of cancers. anti-tumour response. As T cell became in ‘effective’ dendritic cells using ex vivo This concept has been widely recog- responses are indeed crucial for 2010 the first protocols, alternative combinations nized ever since, and eventually led eliciting an immune response against of antigens, optimized loading of to the development of novel cancer cancers, dendritic cells have for a approved dendritic cells and transfection of treatments in more recent years that long time been suggested as potential dendritic cell dendritic cells with RNA or DNA are revolutionized cancer care. cell-based vaccines. Crucial to the cancer vaccine among the strategies under investiga- While the vast majority of cancer development of dendritic cells as tion. The exploration of dendritic cell drugs target cancer cells directly, vaccines, in the 1990s researchers subsets and of other agents beyond immunotherapies set off the body’s developed the concept of loading, or GM-CSF that may mobilize dendritic own immune response against ‘pulsing’, dendritic cells ex vivo with cells in vivo, such as FLT3L, are also tumours. A complex network of tumour-specific antigens. being pursued. cells and soluble factors can thus be The multi-centre phase III One important consideration is mobilized as preventive and thera- IMPACT trial reported in 2010, that tumour-associated immunosup- peutic cancer vaccines, monoclonal and two supporting phase III trials pression can hamper the efficacy of antibodies that reactivate an immune reported in 2006, showed a benefit to the vaccines. In more recent years, response, or immune cell-based median survival, as well as induction T cell therapies — and in particular therapies. of a T cell response, in patients with antibody-based immunotherapies A common feature of cancer metastatic hormone-refractory that disarm inhibitory immune vaccines is the presentation of prostate cancer who were treated cell interactions (so called immune tumour-specific antigens (generated with the dendritic cell-based vaccine checkpoint inhibitors) — have for instance by somatic mutations or sipuleucel-T (trade name Provenge), proved very successful for some oncogenic viruses) to immune cells even though the time to disease patients across a wide range of cancer to elicit an immune response against progression was not altered. On this types. Vaccines designed to boost these cancer epitopes. Arguably the basis, in 2010, sipuleucel-T became these treatments are now in combina- greatest success of cancer vaccines the first approved dendritic cell tion trials and may yield even more has been the development of vaccines cancer vaccine, for the treatment of effective immunotherapies. against ‘high-risk’ strains of the late-stage prostate cancer. Barbara Marte, human papillomavirus (HPV) for Sipuleucel-T is a personalized Nature prevention of HPV-related cervical treatment. Dendritic cell precursors ORIGINAL ARTICLES Small, E. J. et al. Placebo-controlled phase III trial of and other cancers (MILESTONE 14). are extracted from each patient immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, Dendritic cells, discovered in and pulsed with a fusion protein of asymptomatic hormone refractory prostate cancer. J. Clin. Oncol. 24, 3089–3094 (2006) | Kantoff, P. W. et al. Sipuleucel-T immunotherapy for castration-resistant prostate 1973 by the late Ralph Steinman, are prostate acid phosphatase (PAP; an cancer. N. Engl. J. Med. 363, 411–422 (2010) the major antigen-presenting cells antigen present on most prostate can- FURTHER READING Saxena, M. & Bhardwaj, N. Re-emergence of dendritic cell vaccines in the body, which, once activated, cer cells) and the cytokine GM-CSF, for cancer treatment. Trends Cancer 4, 119–137 (2018) | Chen, D. S. & Mellman, I. Elements of cancer immunity and the cancer-immune set point. Nature 541, 321–330 (2017) present antigens to CD4+ and CD8+ which helps antigen-presenting cells NATURE MILESTONES | VACCINES NOVEMBER 2020 | S21.