Frontiers in immunology
-
Frontiers in immunology · Jan 2018
ReviewOsteoclast Immunosuppressive Effects in Multiple Myeloma: Role of Programmed Cell Death Ligand 1.
Immunomodulatory drugs and monoclonal antibody-based immunotherapies have significantly improved the prognosis of the patients with multiple myeloma (MM) in the recent years. These new classes of reagents target malignant plasma cells (PCs) and further modulate the immune microenvironment, which prolongs anti-MM responses and may prevent tumor occurrence. Since MM remains an incurable cancer for most patients, there continues to be a need to identify new tumor target molecules and investigate alternative cellular approaches using gene therapeutic strategies and novel treatment mechanisms. ⋯ Based on these findings and ongoing osteoimmunology studies, therapeutic interventions targeting OC number and function are under development to diminish both MM bone disease and related immune suppression. In this review, we discuss the classical and novel roles of OCs in the patho-immunology of MM. We also describe novel therapeutic strategies simultaneously targeting OCs and MM interactions, including PD-1/PD-L1 axis, to overcome the immune-suppressive microenvironment and improve patient outcome.
-
Frontiers in immunology · Jan 2018
ReviewCD38: A Target for Immunotherapeutic Approaches in Multiple Myeloma.
Multiple Myeloma (MM) is a hematological cancer characterized by proliferation of malignant plasma cells in the bone marrow (BM). MM represents the second most frequent hematological malignancy, accounting 1% of all cancer and 13% of hematological tumors, with ~9,000 new cases per year. Patients with monoclonal gammopathy of undetermined significance (MGUS) and asymptomatic smoldering MM (SMM) usually evolve to active MM in the presence of increased tumor burden, symptoms and organ damage. ⋯ Among them, immunotherapy represents a promising approach. Here, we summarized recent findings regarding CD38-targeted immunotherapy of MM in pre-clinical models and clinical trials, including (i) mAbs (daratumumab and isatuximab), (ii) radioimmunotherapy, and (iii) adoptive cell therapy, using chimeric antigen receptor (CAR)-transfected T cells specific for CD38. Finally, we discussed the efficacy and possible limitations of these therapeutic approaches for MM patients.
-
Frontiers in immunology · Jan 2018
ReviewCD38 Antibodies in Multiple Myeloma: Mechanisms of Action and Modes of Resistance.
MM cells express high levels of CD38, while CD38 is expressed at relatively low levels on normal lymphoid and myeloid cells, and in some non-hematopoietic tissues. This expression profile, together with the role of CD38 in adhesion and as ectoenzyme, resulted in the development of CD38 antibodies for the treatment of multiple myeloma (MM). At this moment several CD38 antibodies are at different phases of clinical testing, with daratumumab already approved for various indications both as monotherapy and in combination with standards of care in MM. ⋯ Differences in frequency or activity of effector cells may also contribute to differences in outcome. Furthermore, the microenvironment protects MM cells to CD38 antibody-induced ADCC by upregulation of anti-apoptotic molecules, such as survivin. Improved understanding of modes of action and mechanisms of resistance has resulted in rationally designed CD38-based combination therapies, which will contribute to further improvement in outcome of MM patients.
-
Frontiers in immunology · Jan 2018
ReviewBlood Transfusion Management for Patients Treated With Anti-CD38 Monoclonal Antibodies.
Daratumumab has proven to be highly efficacious for relapsed and refractory multiple myeloma (MM) and has recently been approved in the frontline setting for MM patients ineligible for transplantation. In the future, expanded indications are possible for daratumumab and other anti-CD38 monoclonal antibodies in development. ⋯ Given the anticipated increase in utilization of anti-CD38 monoclonal antibodies, as well as the transfusion needs of MM patients, it is critical to understand the nature of this interference with blood bank testing and to optimize clinical and laboratory procedures. In this review, we summarize the pathophysiology of this phenomenon, examine the clinical data reported to date, describe currently available methods to resolve this issue, and lastly provide a guide to clinical management of blood transfusions for patients receiving anti-CD38 monoclonal antibodies.
-
Frontiers in immunology · Jan 2018
ReviewNiches for the Long-Term Maintenance of Tissue-Resident Memory T Cells.
Tissue-resident memory T cells (TRM cells) are a population of immune cells that reside in the lymphoid and non-lymphoid organs without recirculation through the blood. These important cells occupy and utilize unique anatomical and physiological niches that are distinct from those for other memory T cell populations, such as central memory T cells in the secondary lymphoid organs and effector memory T cells that circulate through the tissues. CD8+ TRM cells typically localize in the epithelial layers of barrier tissues where they are optimally positioned to act as sentinels to trigger antigen-specific protection against reinfection. ⋯ The short-lived nature of RAMD potentially explains the short lifespans of CD8+ TRM cells in this particular tissue. Clearly, a better understanding of the niche-dependent maintenance of TRM cells will be important for the development of vaccines designed to promote barrier immunity. In this review, we discuss recent advances in our understanding of the properties and nature of tissue-specific niches that maintain TRM cells in different tissues.