Despite the strong anti-cancer effects of PD-1/L1 inhibitors, many patients still don’t respond to these drugs, which work by lifting the brakes tumors use to evade immune attacks. Scientists at Scholar Rock are reporting that selectively targeting one growth factor could overcome resistance to checkpoint inhibitors.
The target Scholar Rock pinpointed is TGF-beta1, a type of growth factor that when activated can lead to the proliferation of cancer cells and their surrounding fibroblast cells. Adding a TGF-beta1 inhibitor called SRK-181 to an anti-PD-1 antibody helped mice harboring tumors that were refractory to an anti-PD-1 treatment live significantly longer, according to a study published in Science Translational Medicine.
Previous studies identified TGF-beta signaling as a potential cause of a lack of response to checkpoint inhibitors. However, pan-TGF-beta inhibitors have resulted in severe cardiac problems in animal models, suggesting they would be unsuitable for use in people. Unlike those therapies, SRK-181 may sidestep those toxicities, the Scholar Rock researchers suggested.
After using RNA sequencing data from the Cancer Genome Atlas, the Scholar Rock team found that TGF-beta1 is the most prevalent form of the growth factor expressed in many human cancer types. Across the seven cancer types the researchers studied, TGF-beta1 expression significantly correlated with innate anti-PD-1 resistance, they discovered.
To test the theory, Scholar Rock identified SRK-181, a selective antibody inhibitor of TGF-beta1 activation. The researchers used three mouse models—for bladder cancer, melanoma and breast cancer—to recreate key features of primary resistance to PD-1 therapy in people.
Administering a PD-1 treatment or SRK-181 alone triggered no or little response in the animals. But combining the two led to a reduction in tumor burden and clear survival benefits, Scholar Rock reported.
For example, eight of 14 (57%) bladder cancer models responded to 10 mg/kg of treatment per week, and nine of 12 (75%) of the animals with melanoma responded to a three mg/kg dosage. The response also appeared to be long-lasting. Of the 12 mice with bladder cancer that responded to the combo at two different doses, the researchers found that 10 remained tumor-free seven weeks after the treatment was stopped.
In the breast cancer model, the scientists recorded complete responses in 50% of mice treated with the combo, as well as a significant survival benefit compared with single-agent treatments. And the responders remained tumor-free six weeks after the treatment ended.
“This observation suggested that selective TGF-beta1 inhibition may have therapeutic potential in overcoming primary checkpoint blockade therapy across a broad spectrum of cancers, irrespective of the expression of other TGF-beta isoforms,” the authors wrote in the study.
SRK-181 also demonstrated a better safety profile than pan-TGF-beta inhibitors historically have. In a four-week rat study, even the highest dose, 100 mg/kg per week, produced no adverse effects, and that was well above the dose necessary to elicit anti-tumor responses when combined with an anti-PD-1 drug.
TGF-beta has recently emerged as a popular anti-cancer target. Roche researchers in 2017 showed that TGF-beta contributed resistance to its PD-L1 inhibitor Tecentriq in a bladder cancer trial. That team found that inhibiting TGF-beta allowed more cancer-fighting T cells to enter the center of tumors and cause them to shrink.
The Scholar Rock team found adding SRK-181 also led to significant increases in intratumoral CD8 T cells and decreased immunosuppressive myeloid cells.
Scholar Rock has started testing SRK-181 in a phase 1 safety trial in solid tumors, during which it expects to gain early insights into its potential to overcome primary resistance to anti-PD1/L1 therapy, the company’s chief scientific officer Alan Buckler said in a statement.
Other companies targeting TGF-beta include Pfizer, whose PF-06952229 candidate is a TGF-beta receptor 1 inhibitor. GlaxoSmithKline and Merck KGaA are working on bintrafusp alfa, a bifunctional fusion protein targeting both TGF-beta and PD-L1.