Cancer vaccines

Abstract

Cancer vaccines are designed to promote tumor specific immune responses, particularly cytotoxic CD8 positive T cells that are specific to tumor antigens. The earliest vaccines, which were developed in 1994-95, tested non-mutated, shared tumor associated antigens that had been shown to be immunogenic and capable of inducing clinical responses in a minority of people with late stage cancer. Technological developments in the past few years have enabled the investigation of vaccines that target mutated antigens that are patient specific. Several platforms for cancer vaccination are being tested, including peptides, proteins, antigen presenting cells, tumor cells, and viral vectors. Standard of care treatments, such as surgery and ablation, chemotherapy, and radiotherapy, can also induce antitumor immunity, thereby having cancer vaccine effects. The monitoring of patients' immune responses at baseline and after standard of care treatment is shedding light on immune biomarkers. Combination therapies are being tested in clinical trials and are likely to be the best approach to improving patient outcomes.

Fig 1 Determinant, or epitope, spreading. Central to this phenomenon is the activation of specific CD8⁺ T cells that recognize a particular MHC class I restricted peptide (derived from a tumor antigen) expressed on the surface of a tumor cell. These activated T cells kill and lyse the tumor cell, resulting in the release of a variety of tumor antigens. Endogenous antigen presenting cells (APCs) take up and present these newly released antigens to additional T cells that specifically recognize the newly released antigens, thereby broadening and spreading the response from one to multiple antigens

Fig 2 Cancer vaccine approaches. Vaccines include short peptides, full length proteins (with and without adjuvants), viruses, DNA (or virus plus DNA in sequence), dendritic cells, tumor cells (killed), and tumor lysates. These elements can be modified, added to adjuvants, or combined together. Standard of care approaches such as tumor ablation, certain chemotherapies, and radiation can also have vaccine-like effects, promoting tumor specific immunity

Fig 3 Immunologic monitoring approaches. Summary of the processing of patient specimens and the immune monitoring assays. Tumors can be frozen or formalin fixed and paraffin embedded and slices tested by immunohistochemistry (IHC). They can also be enzymatically digested into viable single cell suspensions. Blood can be separated using density gradient centrifugation (Ficoll-Paque) and a variety of tests performed; TIL=tumor infiltrating lymphocyte

Fig 4 Cancer vaccines can be combined with various other treatments such as standard of care approaches, checkpoint blockade, immunotherapy, and strategies to reduce suppression. CTLA-4=cytotoxic T lymphocyte associated protein 4; GM-CSF=granulocyte-macrophage colony stimulating factor; IFN=interferon; IL-2=interleukin 2; MDSC=myeloid derived suppressor cell; PD-1/L1=programmed death 1/L1; Tregs=circulating regulatory T cells