A crucial challenge in cancer research is figuring out how to make immunotherapies more effective, channeling, and selectively guiding the body’s own immune responses in targeting and killing tumors.
It’s a challenge that Xiao-Jing Wang, MD, PhD, CU Cancer Center member and professor of pathology, has approached on various fronts for much of her career. In particular, her ongoing research that combines inhibiting TGFbeta secretion and blocking PD-L1 cells in a tumor has shown 70 to 80 percent response rates, compared with 20 to 30 percent response rates when targeting only PD-L1. This work is primarily performed by Alexander Strait, a PhD graduate student in her laboratory, in close collaborations with Jing H. Wang, MD, an immunologist and physician scientist colleague. The research findings were recently published in Communications Biology.
This research, which focuses on head and neck cancers, provided essential data to secure a prestigious Specialized Programs of Research Excellence (SPORE) grant from the National Cancer Institute (NCI). The grant, Wang says, will assist the research team in transitioning the study into clinical trials.
“We’ve seen such a strong response rate that it actually was the basis for the SPORE grant,” Wang explains. “The purpose of SPORE grants is to quickly move into the real clinical setting. First, you need to know whether it works. In our initial research we saw responses we’d never seen before, but this is a mouse tumor. We can cure mouse patients, but the goal is to learn whether we can cure human patients.”
Targeting head and neck cancers
Wang and her SPORE co-leader, Antonio Jimeno, MD, PhD, CU Cancer Center program co-leader for developmental therapeutics and professor of medical oncology, are leading research looking at squamous cell carcinomas (SCC) – squamous cells are found in the lining of the upper digestive and respiratory tracts, among other places – which cause the majority of head and neck cancers and are commonly associated with dysregulated TGFbeta signaling.
TGFbetas are signaling proteins that regulate T cell development and differentiation acting as an immune suppressor. They also promote tumor progression in many ways, including chronic inflammation. Wang and her research team have analyzed not only TGFbeta in squamous cell carcinoma, but also PD-L1, a protein that slows the body’s immune responses and keep them under control. Both are often overproduced in refractory SCC, or SCC that doesn’t respond to treatment.
Using a TGFbeta inhibitor in combination with a PD-L1 blocker targeting both TGFbeta and PD-L1, Wang and her research colleagues found in mouse trials that inhibiting TGFbetas enhanced PD-L1 block-induced tumor eradication.
While there currently are combined TGFbeta and PD-L1 blockers undergoing clinical trial, there still are no predictive markers for patients who respond to therapy, Wang says, so another goal of the SPORE-supported research is to continue stratifying responders vs. non-responders. They have found distinct cell populations in responders and non-responders to bintrafusp alfa, a fusion antibody that binds to and neutralizes activated TGFbeta and binds to PD-L1, which can inhibit tumor cell proliferation.
“When we look at the components of the immune cells in responders and non-responders, they’re different at the molecular level,” Wang says. Identifying these cellular and molecular signatures through genome-wide profiling has the potential to guide treatment when these markers are found in patients.
A two-armed approach to treatment
The two-armed approach of TGFbeta and PD-L1 targeting also helps to rescue exhausted immune cells in chronically inflamed head and neck cancers. The goal, Wang says, is to rescue the immune cells from the exhaustion of responding to so many mutations due to DNA damage and transition them to activation.
The five-year SPORE grant will allow the researchers to move into clinical trials and then data analysis, and partner with a handful of other research teams nationally conducting SPORE-funded head and neck cancer research, Wang says.
"The question is whether it works or not,” Wang says. “We began our research by studying whether, if we target TGFbeta and PD-L1, are they getting better, are the tumors being eradicated, and the answer is yes. It went from a 20 to 30 percent response rate to 70, 80 percent. If you take this two-armed approach, seven out of 10 tumors are gone, which is amazing.
“Then we still have some that are non-responders, so we’re also looking at the biomarkers so we can predict who will respond to treatment if these markers are present. So, this could have potential beyond head and neck cancers as well.”