According to a recent study published in the Journal for Immunotherapy of Cancer and titled “Combined immune checkpoint protein blockade and low dose whole body irradiation as immunotherapy for myeloma,“ blocking a combination of checkpoint receptors in a context of low-dose, lymphodepleting whole body radiation could result in increased anti-tumor immunity.
Multiple myeloma is characterized by the existence of modified neoplastic plasma cells in the bone marrow and is usually an incurable disease. To successfully address the disease, treatments must combined multi-faceted strategies in which immunotherapy, standard drug therapies and other new treatments are incorporated.
In this study, the research team lead by Dr. Bryon Johnson from the Medical College of Wisconsin, showed that a mixture of transient lymphodepletion (sub-lethal complete body irradiation) and PD-1/PD-L1 blockade could enhance T cell capacity to erradicate the established disease.
Researchers used a mouse model of multiple myeloma to test their hypothesis. Animals received treatment with a low dose of irradiation (whole body) and several combinations of blocking antibodies against TIM-3, PD-L1, CTLA4, LAG-3 and CD48 (ligand for 2B4), all immune checkpoint molecules.
Mice bone marrow showed an increased expression of 2B4, TIM-3, PD-1 and LAG-3 proteins on the surface of T cells. When PD-L1 blockade was combined with blocking antibodies against TIM-3, LAG-3 or CTLA4, the team observed increased survival rates correlated with higher frequencies of tumor-reactive CD4 and CD8 T cells. Furthermore, CD8 T cells in treated mice generated elevated levels of pro-inflammatory cytokines when stimulated with myeloma cells in vitro. Also, pro-inflammatory cytokines were released from CD4 T cells isolated from mice that received PD-L1 and CTLA4 blocking antibodies.
These results indicate that blocking PD-1/PD-L1 interactions together with other immune checkpoint proteins creates a synergistic anti-tumoral effect following lymphodepletive doses of whole body irradiation. As the authors state in their study, “Understanding the mechanisms of tumor cell elimination induced by combined checkpoint blockade and low dose WBI, and determining if other lymphodepleting strategies can be used, such as lymphodepleting drugs or low doses of T cell depleting antibodies, will help to expand the translational applications of this approach. Finally, this therapeutic approach could serve as a platform for other immune therapies, including T cell adoptive transfer.”
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