A dual immune-checkpoint blockade efficiently controlled the development of chronic lymphocytic leukemia by restoring functional antitumor immune response.
A new immunotherapeutic strategy using 2 checkpoint inhibitors blocked the development of chronic lymphocytic leukemia (CLL) in preclinical stages and could serve as an effective method to restore anti-tumor immune response in patients with CLL, according to a study published in Blood.
CLL, a hematological malignancy that originates in the blood-forming cells of bone marrow, is currently not curable but different treatments can prolong survival. CLL can only develop in a tumor-supportive microenvironment in which the immune response is suppressed, which ensures their survival and growth, according to the study.
Researchers from the Laboratory of Experimental Cancer Research at LIH’s Department of Oncology analyzed the composition of immune cells in the tumor microenvironment to better understand how immune suppression is achieved.
In the study, the authors transferred spleen cells from diseased donor mice to healthy mice and monitored the cell populations with flow and mass cytometry after several weeks. When comparing samples of diseased mice to healthy mice, the researchers observed that the tumor microenvironment was mainly characterized by the presence of more regulatory immune cells, such as Tregs, that contribute to inhibiting immune responses. Additionally, many cell types also displayed a high quantity of immune checkpoint molecules on their surface.
The researchers investigated whether immunotherapeutic antibodies that act as inhibitors of immune checkpoints could block cancer development and restore immune response. The authors tested anti-PD1, anti-LAG3, and anti-KLRG1 antibodies as single and dual treatments in mice.
By simultaneously targeting the 2 immune checkpoints, PD1 and LAG3, the therapy kept the number of CLL cells low in the spleen and bloodstream, and even reduced the size of the spleen. According to the findings, the dual treatment was able to restore an immunocompetent environment containing more effector and less immune-regulating cells, and efficiently prevented the disease from developing when transferred to recipient mice.
The researchers concluded that because dual targeting of these immune checkpoints successfully controlled CLL development, the method could serve as an effective treatment to restore a functional antitumor immune response and prolong life expectancy for patients with the disease.
Wierz M, Pierson S, Guyonnet L, et al. Dual PD1/LAG3 immune checkpoint blockade limits tumor development in a murine model of chronic lymphocytic leukemia. Blood. 2018. doi: https://doi.org/10.1182/blood-2017-06-792267.
Efficient control of leukemia with treatment by dual immune-checkpoint blockade [news release]. LIH’s website. https://www.lih.lu/blog/our-news-1/post/efficient-control-of-leukaemia-with-treatment-by-dual-immune-checkpoint-blockade-190. Accessed April 18, 2018.