For many NSCLC (non-small cell lung cancer) patients the primary treatment using EGFR-targeted TKIs (tyrosine kinase inhibitors) works well, but some of the cells left behind, called persister cells, are most likely to cause a return of cancer, and it becomes harder to fight it because it becomes resistant to TKIs.
However, MD Anderson Center scientists at the University of Texas found a means to eradicate the remaining cells prior to complete resistance development. A scientist at at center stated that most of the NSCLC cases are identified at a later stage, and around 10% to 15% of such cases have EGFR mutations in them.
A new study was published in which the use of ADCs (antibody-drug conjugates) and cell therapies to remove the remaining NSCLC cells in animal models was discussed. MD Anderson’s head of Thoracic/Head and Neck Medical Oncology, John Heymach (M.D., Ph.D.) said, “The finding that CD70 is present on the most aggressive forms of EGFR TKI resistance as well as on the residual cells after initial TKI treatment raises the possibility that we could combine an EGFR inhibitor with CD70-targeting agents, which would eliminate the residual persister cells. We believe this combined approach could dramatically delay or prevent the emergence of drug resistance.”
AstraZeneca’s Tagrisso is among the first-line TKI medications that are effective in getting rid of tumors at the initial stage. The cells can start to expand again over time, at times through a process which is known as epithelial to mesenchymal transition, the result of which is the formation of the tumor.
To find out if the tumor can be stopped from returning, the researchers cultured the mutated NSCLC cell lines in the presence of inhibitors till they developed resistance. This was followed by RNA sequencing, which shows which genes appear in a cell. The search revealed two possible targets which were genes for the protein CD70 and EMP3.
They also found EMP3 in the tissues in the GI tract, kidneys, and lungs. CD70 was only found in the resistant cells. This is why further studies were conducted on CD70 with less risk of side effects. Further cell studies confirmed that CD70 was present in the cells that resisted treatment in the NSCLC patients. CD70 was also linked to lower survival rates. Scientists were surprised to find that CD70 was upregulating rapidly after the TKI medication in the persister cells, which means there is a possibility of treatment in the early stages of the disease.
The researchers tested therapeutics based on CD70 against resistant persister cells as well as non-resistant ones. It was revealed that CD70-targeted CAR T cells and CAR NKs (natural killer) cells were successful against all cell lines. These revelations were tested on animal models by treating them against the tumors with one of CD70 CAR NK cells and custauzuman-MMAE. However, both treatments resulted in the regression of the tumors and they did not rebound during the study period of 60 to 80 days.
There are clinical trials in the works on CD70-based CAR treatments for pancreatic, kidney, and other cancers. The researchers aim to add NSCLC to that list. They are of the opinion that EGFR inhibitor resistance could be used for other kinds of cancer as well.