Combined immune checkpoint protein blockade and low dose whole body irradiation as immunotherapy for myeloma

Journal for ImmunoTherapy of Cancer

Bryon D Johnson¹  Catherine Sabatos-Peyton²  Laura McOlash¹  Dominique Tlomak¹  James Weber¹  Jill A Gershan¹  Weiqing Jing¹ 

[1] Division of Hematology/Oncology/Transplant, Department of Pediatrics, Medical College of Wisconsin, Milwaukee 53226, WI, USA;Novartis Institutes for BioMedical Research, Inc., Cambridge 02139, MA, USA

关键词: Myeloma;    2B4;    CTLA4;    LAG-3;    TIM-3;    PD-L1;    Blockade;    Immune checkpoint proteins;    Low dose whole body irradiation;   

Others  :  1133511
DOI  :  10.1186/s40425-014-0043-z

 received in 2014-08-26, accepted in 2014-12-01,  发布年份 2015

【 摘 要 】

Background

Multiple myeloma is characterized by the presence of transformed neoplastic plasma cells in the bone marrow and is generally considered to be an incurable disease. Successful treatments will likely require multi-faceted approaches incorporating conventional drug therapies, immunotherapy and other novel treatments. Our lab previously showed that a combination of transient lymphodepletion (sublethal whole body irradiation) and PD-1/PD-L1 blockade generated anti-myeloma T cell reactivity capable of eliminating established disease. We hypothesized that blocking a combination of checkpoint receptors in the context of low-dose, lymphodepleting whole body radiation would boost anti-tumor immunity.

Methods

To test our central hypothesis, we utilized a 5T33 murine multiple myeloma model. Myeloma-bearing mice were treated with a low dose of whole body irradiation and combinations of blocking antibodies to PD-L1, LAG-3, TIM-3, CD48 (the ligand for 2B4) and CTLA4.

Results

Temporal phenotypic analysis of bone marrow from myeloma-bearing mice demonstrated that elevated percentages of PD-1, 2B4, LAG-3 and TIM-3 proteins were expressed on T cells. When PD-L1 blockade was combined with blocking antibodies to LAG-3, TIM-3 or CTLA4, synergistic or additive increases in survival were observed (survival rates improved from ~30% to >80%). The increased survival rates correlated with increased frequencies of tumor-reactive CD8 and CD4 T cells. When stimulated in vitro with myeloma cells, CD8 T cells from treated mice produced elevated levels proinflammatory cytokines. Cytokines were spontaneously released from CD4 T cells isolated from mice treated with PD-L1 plus CTLA4 blocking antibodies.

Conclusions

These data indicate that blocking PD-1/PD-L1 interactions in conjunction with other immune checkpoint proteins provides synergistic anti-tumor efficacy following lymphodepletive doses of whole body irradiation. This strategy is a promising combination strategy for myeloma and other hematologic malignancies.

【 授权许可】

   
2015 Jing et al.; licensee BioMed Central.

【 图 表 】

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