Combination therapies utilizing neoepitope-targeted vaccines
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REVIEW
Combination therapies utilizing neoepitope‑targeted vaccines Karin L. Lee1 · Jeffrey Schlom1 · Duane H. Hamilton1 Received: 10 July 2020 / Accepted: 15 September 2020 © The Author(s) 2020
Abstract Clinical successes have been achieved with checkpoint blockade therapy, which facilitates the function of T cells recognizing tumor-specific mutations known as neoepitopes. It is a reasonable hypothesis that therapeutic cancer vaccines targeting neoepitopes uniquely expressed by a patient’s tumor would prove to be an effective therapeutic strategy. With the advent of high-throughput next generation sequencing, it is now possible to rapidly identify these tumor-specific mutations and produce therapeutic vaccines targeting these patient-specific neoepitopes. However, initial reports suggest that when used as a monotherapy, neoepitope-targeted vaccines are not always sufficient to induce clinical responses in some patients. Therefore, research has now turned to investigating neoepitope vaccines in combination with other cancer therapies, both immune and non-immune, to improve their clinical efficacies. Keywords Neoepitope vaccine · Combination therapy · Checkpoint blockade · Epitope spreading Abbreviations AlbiVax Albumin/albumin-binding vaccine APC Antigen-presenting cell DC Dendritic cell EGFRvIII Epidermal growth factor receptor class III variant GAd Great Ape–derived adenovirus GM-CSF Granulocyte macrophage-colony stimulating factor IDH1 Mutant isocitrate dehydrogenase 1 NGS Next generation sequencing mAb Monoclonal antibody NK Natural killer PD-1 Programmed death-1 PD-L1 Programmed death-ligand 1 TAA Tumor-associated antigen TIL Tumor-infiltrating lymphocytes TNF Tumor necrosis factor T-VEC Talimogene laherparepvec
* Jeffrey Schlom [email protected] 1
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Introduction In the past decade, immunotherapy has come to the forefront of cancer treatment. In particular, immune checkpoint blockade has shown remarkable efficacy in a subset of patients, particularly those with high tumor mutational burden [1]. It is hypothesized that these responses are a result of activating T cells within the tumor that are capable of targeting these neoepitopes. Although the majority of neoepitopes are unique to each patient’s tumor, there are shared neoepitopes, which are present in a large subset of patients. These common mutations are often in oncogenes or tumor-suppressor genes, including those found in epidermal growth factor receptor class III variant (EGFRvIII), mutant isocitrate dehydrogenase 1 (IDH1), RAS, BRAF, and TP53 [2–4]. Preclinical and clinical studies have shown that vaccines targeting these shared neoepitopes induce antigen-specific immunity and improve survival [3–6]. However, these shared neoepitopes are often tumor-type specific, and offer very few potential targets. Personalized vaccines targeting neoepitopes uniquely expressed by a patient’s
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