DALLAS – March 21, 2022 – Research led by UT Southwestern scientists suggests that an investigational drug could restore the ability of some non-small cell lung cancers (NSCLCs) to respond to an immune checkpoint blockade (ICB), a therapy that harnesses the immune system to fight malignant tumors. The findings, derived from a preclinical lab model and published in Cell Reports Medicine, could lead to more effective treatments for this subset of NSCLCs.
“These results provide hope that we can significantly enhance the efficacy of immune checkpoint blockade in non-small cell lung cancer patients for whom immunotherapies have not previously been effective,” said study leader Rolf Brekken, Ph.D., Professor of Surgery, Deputy Director of the Hamon Center for Therapeutic Oncology Research, and member of the Harold C. Simmons Comprehensive Cancer Center.
ICB has had a significant impact on outcomes in a variety of cancers since the first in this class of immunotherapies was approved by the U.S. Food and Drug Administration in 2011. Patients who respond to these treatments tend to survive significantly longer compared to those treated with chemotherapy, radiation, and/or surgery.
NSCLC patients whose cancers are driven by mutations in a gene called KRAS usually have a high response rate to ICBs. However, Dr. Brekken explained, about 20% of NSCLC tumors also carry mutations in a gene known as STK11/LKB1, which is associated with poor response to ICB therapy. The reason for this phenomenon has been unclear, preventing researchers from addressing it.
The new study by the Brekken lab and their colleagues shows that in mice with NSCLC carrying KRAS and STK11/LKB1 mutations, these tumors lacked a specific population of immune cells known as TCF1-expressing CD8+ T cells. These cells are key for effective response to ICBs known as PD-1/PD-L1 inhibitors that are commonly used to treat NSCLCs. Additional experiments showed that these immune cells were also largely absent in human NSCLC tumors carrying STK11/LKB1 mutations, suggesting that the lack of ICB response in these patients stems from a deficiency of these cells.
The key finding from the study came when the UT Southwestern group found that inhibiting a protein called AXL boosted the numbers of TCF1-expressing CD8+ T cells. This intervention restored the ability of mice harboring STK11/LKB1-mutated NSCLC tumors to respond to PD-1/PD-L1 inhibitors.
“While immune checkpoint blockade immunotherapy has revolutionized the treatment of lung cancer, unfortunately the majority of lung cancer patients still do not have long-term benefit from such therapy. This discovery of the addition of AXL-targeted therapy to immunotherapy provides an important clue and path forward to enhance the benefits of immunotherapy for more patients with lung cancer,” said study co-leader John D. Minna, M.D., Professor of Internal Medicine and Pharmacology and Director of the Hamon Center for Therapeutic Oncology Research.
A graphic summary illustrating why immune checkpoint blockade has low activity in a particular subset of lung cancer (left side) and how inhibition of AXL facilitates the anti-tumor activity of immune checkpoint blockade in this subset of lung cancer (right side).
To corroborate the preclinical findings, Dr. Brekken noted that an ongoing Phase 2 clinical trial testing the AXL inhibitor used in this study, known as bemcentinib and produced by BerGenBio ASA, showed promising results in NSCLC patients carrying the STK11/LKB1 mutation who are being co-treated with PD-1/PD-L1 inhibitors. The results from three of these patients are reported in the new study.
Other UT Southwestern researchers who contributed to this study include Huiyu Li, Zhida Liu, Longchao Liu, Hongyi Zhang, Chuanhui Han, Luc Girard, Hyunsil Park, Anli Zhang, Chunbo Dong, Jianfeng Ye, Michael Peyton, Xiaoguang Li, Kimberley Avila, Xuezhi Cao, Shuiqing Hu, Md Maksudul Alam, Esra Akbay, Bo Li, and Yang-Xin Fu.
Dr. Minna holds the Max. L. Thomas Distinguished Chair in Molecular Pulmonary Oncology and the Sara M. and Charles E. Seay Distinguished Chair in Cancer Research.
This work was supported by a sponsored research agreement from BerGenBio ASA; and grants from the National Institutes of Health (R01 CA243577, U54 CA210181, P30 CA142543), the National Institutes of Health SPORE (P50 CA070907 and U54 CA224065); the Cancer Prevention and Research Institute of Texas (CPRIT: RP160652, RP150072 and RP180725); the Effie Marie Cain Foundation; and a CPRIT training grant (RP210041).
Dr. Minna receives licensing royalties from the NIH and UTSW for distribution of human tumor lines. Drs. Huiyi Li, Zhida Liu, Minna, and Brekken are authors of a patent related to this study. Other researchers’ financial interests are disclosed in the study manuscript.