A research was recently conducted on mouse models mutated with kinase-driven breast cancer and lung cancer, the effect of two therapies consisting of a manipulated dose and timing was investigated. The researchers in UT Southwestern Simmons Cancer Center observed significant cleavage of the tumor relapse with reduced side effects as compared to conventional cancer treatment.
The objective of the researchers was to identify the efficiency of the two therapies used together as first-line treatment.
The research findings are published in Science Immunology. The research suggests that giving the two therapies simultaneously as a short course is the best practice as it is proved to be more effective than the traditional methods of treatment.
A lead author of the research and a member of the Harold C. Simmons Comprehensive Cancer Center Dr. Yang-Xin Fu said; “This study reveals the importance of the proper combination and timing of tyrosine kinase inhibitors and immunotherapy such as the programmed death-ligand 1 (PD-L1) inhibitor, also known as immune checkpoint blockade.
If borne out by future research, these findings might open new treatment avenues for many cancer patients.” Mr. Fu is famous for his services at the Department of Pathology, Immunology, and Radiation Oncology.
“Many cancers have high and abnormal tyrosine kinase activities. Tyrosine kinase inhibitors, or TKIs—which target specific cancers—are a common first-line treatment for rapidly shrinking tumors such as those associated with kinase-driven breast cancer and lung cancer. But tumor relapse or resistance often occurs.
The standard of care is to use this first and then use immunotherapy such as PD-L1 inhibitors after relapse occurs,” Dr. Fu explained. “Our study showed that immunotherapy should be used together with the TKIs as the first-line—not second-line or third-line—treatment. We also demonstrated that the dose and timing of the TKI are important.”
The findings also showed that the administration of hypo-fractionated TKI (HypoTKI) has a shorter duration of action and a high dose, as compared to standard hyper-fractionated TKI, which has a longer duration of action with a lower dose. Thus, HypoTKI is more effective in treating kinase driven breast cancer and lung cancer in mutated mouse models, as it significantly shrinks the tumor and limits relapse with lesser side effects.
These results were presented by the first authors and postdoctoral researchers Drs. Zhida Liu and Chuanhui Han. Dr. Fu concluded in these findings that the use of HyperTKI in collaboration with TKIs and PD-L1 has greater side effects.
The team found that upon the administration of TKIs, it activates the innate immunity in case of any threat identification. In addition to it, adaptive immunity is also activated, recognizing the foreign particles and act against it to protect the body,
Dr. Fu explained that the acquired immune response is improved by PD-L1 inhibitors, thus protecting the tumor cells to become resistant to TKIs.
The HypoTKI treatment activates greater innate immune response which releases more influential type I interferons (IFNs) and other cytokines. Ultimately, increasing infiltration and reactivation of the tumor-specific T cell. Thus, concluded that as compared to HyperTKI, HypoTKI is more potent in controlling tumor relapse in the host.
Keeping the drug dose and timing in concern, they observed that PD-L1 blockade significantly increases the anti-cancer activity of HypoTKI therapy and limits the tumor relapse efficiently.
It is the very first findings ensuring the initiating effect of TKIs on the immune system, Dr. Fu said. “We think there might be a threshold effect with HypoTKI in which the treatment more effectively alerts the innate immune system. It appears that higher-dose/shorter duration TKI treatment may spark a more potent anti-tumor response by better triggering the innate immunity system.”
In consecutive experiments, tumors were observed to show complete resistance to PD-L1 inhibitor therapy alone, thus named monotherapy.
It was determined that HypoTKI alone shrinks the tumor initially but then relapsed over time.
To achieve the best tumor regression without tumor relapse, the two therapies were given coinciding as the first-line treatment, these findings were conducted over more than two months of follow-up. Within two to three weeks tumor relapse occurs in the mice.
Dr. Fu explained; “The maximum synergistic effect of combination therapy depends on the timing of the anti-PD-L1 treatment. When it was started within three days of TKI administration, there was total tumor regression and only two of eight tumors relapsed,”.
In case anti-PD-L1 treatment was provided a week after TKI therapy, almost no synergistic effect was reported.
“Our study demonstrates that HypoTKI and PD-L1 blockade can work in combination to effectively control advanced large tumors, increase overall survival, and reduce tumor relapse. These data suggest that proper timing—giving the two agents together at the start of treatment—provides maximum synergistic anti-tumor effects in these tumors and should be studied further,” Dr. Fu said.
The findings from the study will prove extremely beneficial in shaping cancer treatment in the future. A side-effect-free therapy would mean that more lives can be saved with minimal damage to the body.