ReviewImmuno-oncologic Approaches: CAR-T Cells and Checkpoint Inhibitors
Introduction
There have been significant advances in the understanding of the biology of multiple myeloma (MM) in recent years. In the classic view of the pathogenesis of MM, an initiating hit is necessary to immortalize a myeloma-propagating cell. This cell then acquires additional genetic hits over time, mediated by translocation, loss of heterozygosity, gene amplification, mutation, or epigenetic changes, which further deregulate the behavior of the MM-propagating cell, leading step by step to the well-known MM features.1 Many of the genes and pathways mediating this transformation process have now been characterized. Nevertheless, disease progression is not only the consequence of intrinsic tumor changes. Interactions between the tumor and the microenvironment in which the cancer grows play an essential role,2 and the focus of studies has shifted from the disease itself alone to the disease in the context of the microenvironment in which the tumor grows. The immune system is an important component of the tumor microenvironment in MM, as well as in many other cancers, and is the focus of the immune-oncology approach.
Section snippets
Rationale for Immune-oncology
The immune system can potentially recognize and reject the tumor. Tumor cells can express aberrant antigens; that is, molecules expressed in tumor cells, but not in normal cells. These can be normal cellular proteins that are abnormally expressed as a result of genetic mutations, quantitative differences in expression, or differences in posttranslational modifications.3 In tumor types that have a well-documented viral origin, viral proteins also can serve as tumor antigens.4, 5 Tumor antigens
Immune-oncologic Approach in MM
Immune therapy can be directed against the tumor itself or toward immune cells. There are 2 strategies to act toward immune cells and boost antitumor immunity: one consists of increasing antitumor activity (acting on T and NK cytotoxic cells), the other in reducing immunosuppression (acting on MDSCs and Tregs). Treatment approaches include monoclonal antibodies (mAbs) targeting surface molecules present on MM cells, mAbs targeting checkpoint inhibitors on immune cells/tumor cells,
Conclusion
Advances in the understanding of MM biology and its clinical management have recently led to an increased survival rate, reaching up to 8 to 10 years. Several new agents, with different mechanisms of action and different targets, have increased the treatment armamentarium against a complex disease such as MM. These agents include chemotherapeutic agents, immunomodulatory drugs, and proteasome inhibitors, which are currently considered the backbone treatments for MM. Other agents more recently
Disclosure
Francesca Gay has served on the advisory board of Takeda, Seattle Genetics, and Roche, and received honoraria from Takeda, Amgen, Celgene, Janssen, and BMS. The other authors declare no potential conflicts.
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