Precision Immunology: The Promise of Immunotherapy for the Treatment of Cancer

The landscape of therapeutic options for patients with cancer has changed dramatically in the last decade. Advances in understanding the role of driver mutations in mediating tumor growth and progression, coupled with the development of molecular inhibitors for defined mutations, has given rise to a new field of cancer therapy that is often termed precision medicine or precision oncology. The basic foundation of precision medicine is that each tumor in individual patients may harbor different subsets of genomic mutations. Targeted therapy can thus be designed on the basis of a knowledge of which mutations are present at any given time, and a precise and highly personalized treatment plan for each patient can be developed. Although promising, there are several barriers that limit widespread clinical adoption, including the need to collect and properly store tissue, the lack of cost-effective companion diagnostic tests, limited funding for bioinformatics infrastructure, issues related to patient accrual in clinical trials targeting highly selected subsets of patients, barriers across industry that block rational combination regimens, and the need to better understand mechanisms of drug resistance and how to monitor patients for the emergence of resistance. Similar to the advances in targeted therapy, significant progress in tumor immunotherapy has resulted in several new strategies for cancer therapy, including T-cell checkpoint inhibitors, oncolytic viruses, chimeric antigen receptor T cells, among others. Immunotherapy is associated with several unique features, most notably the potential for inducing durable clinical responses, lack of typical drug resistance, and induction of autoimmune-like toxicities. The practicing oncologist will need to be thoroughly familiar with the clinical application of targeted therapy and tumor immunotherapy to provide high-quality cancer care in this new era. Tumor immunotherapy is based on the immune system’s ability to recognize tumor-associated antigens and mediate a highly specific cytolytic attack on tumor cells. This process is complex and incompletely understood. During the 1980s and 1990s, several groups identified tumor antigens that could be recognized in a major histocompatibility complex (MHC) –dependent manner by T lymphocytes. In some cases, the antigens represented viral proteins, mutated self-antigens (some of which were part of driver oncogenes), derepressed embryonic antigens, or overexpressed differentiation or normal self-proteins. Chen and Mellman recently proposed the concept of the cancer-immunity cycle to explain how tumor antigens can initiate an immune response. In this cycle, antigens are released from tumor cells through a variety of mechanisms, including intracellular kinases, innate necrosis of tumor cells, or through the therapeutic use of radiation, cytotoxic chemotherapy, or targeted therapy. In addition to antigens, dying cells may release a variety of factors termed dangerassociated molecular patterns (DAMPs), which are generated under conditions of cellular stress, hypoxia, nutrient depletion, and trauma. DAMPs bind to cell surface and intracellular receptors, including the toll-like receptors, triggering innate immune responses. Furthermore, dying tumor cells and soluble antigens may be endocytosed by professional antigen-presenting cells, such as dendritic cells, within the tumor microenvironment. Dendritic cells undergo maturation and migrate to secondary lymphoid organs where they can present processed tumor antigens as peptides bound to class I and II MHC molecules to prime effector CD8 and helper CD4 T cells, respectively. To fully differentiate, T-cell priming also requires a secondary signal that is provided by a costimulatory molecule. In the presence of T-cell receptor engagement, the B7.1 costimulatory molecule on dendritic cells binds to CD28 on the surface of the T cell and helps coordinate T-cell differentiation, proliferation, and cytokine production, and blocks apoptosis. In the absence of costimulation, the T cell may become unresponsive as a protective mechanism for avoiding induction of self-reactive T cells and autoimmunity. Once primed, T cells can migrate back to the tumor microenvironment, likely through local chemokine concentration gradients. Once the T cell is colocalized near tumor cells, the T-cell receptor can recognize cognate antigen through class I MHC-peptide complexes on the surfaces of tumor cells. The T cell releases cytotoxic factors, such as granzyme B and perforins, that can mediate direct lysis of antigen-expressing tumor cells and a bystander effect on non–antigen-bearing tumor cells that may be in the vicinity. The validity of this process is supported by evidence that tumors associated with a high concentration of activated effector lymphocytes within the tumor microenvironment are associated with better prognosis, in general, and possibly better responses to tumor immunotherapy. Despite the cancer-immunity cycle, established tumors may escape immune detection and eradication through a variety of host, tumor, and immune mechanisms. For example, tumor cells may lose expression of tumor antigens or MHC molecules and/or release inhibitory soluble factors, such as interleukin-10, transforming growth factor , or vascular endothelial growth factor. Tumor cells can also express inhibitory receptors, such as Fas ligand or the programmed death ligand 1, which function to inhibit infiltrating T lymphocytes. In addition, a number of inhibitory immune cells have been described as JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 12 APRIL 2