No abstract

Cancer remains a devastating disease as existing therapies are too often ineffective and toxicities remain unacceptably high. Immunotherapies for cancer offer the promise of the specificity and memory of the immune system against malignant cells to achieve durable cure with minimal toxicity. Beginning with the success of bone marrow transplantation for blood-borne cancers, and the more recent development of monoclonal antibody therapeutics for a variety of tumors, immunotherapies are already among the most successful class of treatments for cancer. Greater understanding of immunoregulatory mechanisms and improved techniques for immune cell manipulation and engineering have led to new immunomodulatory approaches and cell-based therapies for cancer that have generated great excitement within the biomedical community. As these technologies continue to improve, and as new approaches for harnessing the power and specificity of the immune system are developed, immunotherapies will play an increasingly important role in the treatment of cancer. Here, we review the history of immunotherapies for cancer and discuss existing and emerging immunotherapy technologies that hope to translate the promise of immunotherapy into clinical reality.

Substance P and its truncated receptor exert oncogenic effects. The high production of substance P in breast cancer cells (BCCs) is caused by the enhancement of tachykinin (TAC)1 translation by cytosolic factor. In vitro translational studies and mRNA stabilization analyses indicate that BCCs contain the factor needed to increase TAC1 translation and to stabilize the mRNA. Prediction of protein folding, RNA-shift analysis, and proteomic analysis identified a 40 kDa molecule that interacts with the noncoding exon 7. Western blot analysis and RNA supershift identified Musashi 1 (Msi1) as the binding protein. Ectopic expression of TAC1 in nontumorigenic breast cells (BCs) indicates that TAC1 regulates its stability by increasing Msi1. Using a reporter gene system, we showed that Msi1 competes with microRNA (miR)130a and -206 for the 3' UTR of exon 7/TAC1. In the absence of Msi1 and miR130a and -206, reporter gene activity decreased, indicating that Msi1 expression limits TAC1 expression. Tumor growth was significantly decreased when nude BALB/c mice were injected with Msi1-knockdown BCCs. In summary, the RNA-binding protein Msi1 competes with miR130a and -206 for interaction with TAC1 mRNA, to stabilize and increase its translation. Consequently, these interactions increase tumor growth.

Chimeric antigen receptor (CAR) T cells represent a medical and scientific breakthrough that may represent a paradigm for the future of personalized medicine in the age of cancer immunotherapy. As with many new cancer agents, such novel and incredible results come with a high price. At the time of the writing of this article, there are two CAR T cells available, Kymriah, produced by Novrtis with a price tag of US$475,000 and Yescarta produced by Gilead Pharmaceuticals with a price tag of US$373,000, neither price including the required hospital admission in order to administer the agent in addition to potential treatment of side effects. There are several issues that are imperative to recognize when understanding the high cost, however the two more pertinent issues are low availability of the agent and no billing code. While only approved for less than a year, there are thoughts about how to bring the price down with more approved CAR T cells and more center with the ability to administer this therapy, however results may be years away before they are realized. In the short term, insurance companies are grappling over how to pay for CAR T therapy, with one of the biggest voids concerning the absence of a billing code for CAR T cells. Regardless, its high price tag highlights moral issues underlying value-based payments and whether the treatment is worth the cost while evaluating the juxtaposition of life years and monetary values. As CAR T cells expand the boundaries of immunotherapy with extraordinary results, the need for a lower price in combination for more availability of CAR T cells will grow until some of these fundamental issues are addressed.