Date Published: December 13, 2016
Publisher: Public Library of Science
Author(s): Mack Y. Su, David E. Fisher
Abstract: In a Perspective, Mack Su and David Fisher discuss the development of immunotherapies for treatment of melanoma and other cancer types.
Partial Text: Perhaps the most profound impacts of both immunotherapy and precision medicine, in the form of targeted therapy, can be appreciated in the transformation of treatment for metastatic melanoma during the past decade. The discovery of the oncogenic V600E driver mutation in BRAF, which is present in ~50% of melanomas, led to the development of vemurafenib and dabrafenib, which are inhibitors of the mutant BRAF kinase . Although targeting mutant BRAF kinase and inhibiting the downstream mitogen-activated protein kinase (MAPK) pathway produces high response rates in melanoma patients, the duration of responses is brief , highlighting the need for additional therapies. Meanwhile, preclinical evidence suggested that blocking negative regulators, or checkpoints, of T cell responses could improve antitumor immune responses (Fig 1). The first such negative regulator tested was cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), a T cell surface receptor that binds with high affinity to the costimulatory ligands B7-1 and B7-2 found on the surface of antigen-presenting cells. The interaction with CTLA-4 prevents binding of the costimulatory ligands to cluster of differentiation 28 (CD28), a major costimulatory receptor on the T cell necessary for a robust T cell response. Despite concerns about uncontrollable autoimmunity resulting from systemic CTLA-4 blockade, ipilimumab, a monoclonal antibody against CTLA-4, improved overall survival in patients with metastatic melanoma .
The rapid progress in cancer genomics in recent years has enabled a close examination of the genetic makeup of thousands of individual cancers across the entire spectrum of major cancer types. Amidst the search for mutations responsible for driving carcinogenesis, it has become evident that overall mutation rates vary dramatically both within and between cancer types . While the vast majority of mutations contribute little, if at all, to intrinsic biological function in tumor development and survival, they represent novel, “non-self” epitopes that, if processed and presented, carry the potential to elicit a tumor-specific immune response . By mining exome sequencing data to predict neoantigens present in a tumor, several groups have demonstrated a strong correlation between total neoantigen burden and positive response to immune checkpoint blockade [17,18]. These insights provide a mechanistic rationale to expand checkpoint inhibition to mismatch repair-deficient cancers of any type, because the dramatically elevated mutation rates in these cancers produce significantly more neoantigens and the potential for a more robust immune response .
Propelled by recent successes, enthusiasm for immunotherapy has surged beyond targeting CTLA-4 and PD-1 pathways. Many additional immune regulators, both stimulatory and inhibitory, are being explored as potential targets for cancer immunotherapy, each with a unique set of advantages and potential risks. Novel insights into neoantigens and combination with immune checkpoint inhibition have breathed new life into cancer vaccines, which had been tested for decades with little success. In addition, cell-based therapies may be required in some patients to elicit a robust antitumor response. Adoptive cell transfer of autologous T cells selected for tumor reactivity  and genetically engineered T cells with chimeric antigen receptors targeting tumor antigens  have demonstrated promise in melanoma and other cancer types. As new immunotherapies expand the arsenal of cancer therapies, deeper mechanistic insight will be required to inform clinical decisions. The exciting advances toward understanding and delivering precision immunotherapy are poised to change the way cancer is treated.