Anti-PD-1/L1 therapies, which remove "checkpoints" that prevent the immune system from fighting cancer, have been hailed as a major treatment advance. But not all patients respond to checkpoint inhibitors. Researchers are exploring new ways to improve their efficacy, and a team led by Cedars-Sinai Medical Center has pinpointed a popular blood cancer drug by Bristol-Myers Squibb as a potential booster.
The helper is Sprycel, a drug that was approved by the FDA in 2006 and is listed as an essential medicine by the World Health Organization. The product generated revenues of $2 billion for BMS in 2018, and just recently, it nabbed expanded FDA approval as a first-line treatment for children with a form of acute lymphoblastic leukemia.
When given to mice along with an anti-PD-1 drug, Sprycel increased the therapy’s effectiveness across multiple tumor types, the team reported in a study published in the journal Science Advances. Scientists from Bristol-Myers and the University of Colorado also participated in the study.
The researchers started their search for an anti-PD-1 booster by using a genomic tool to screen tumor cell lines for targets for which there are FDA-approved therapies. They identified the gene DDR2 as the top candidate. The gene encodes a receptor tyrosine kinase that helps tumors spread into healthy tissue.
Sprycel works by inhibiting DDR2. The team chose the drug for further testing “due to its status as the most potent inhibitor of DDR2 both in vitro and in vivo and the prevalence of its use in clinical trials for tumors with DDR2-specific activating mutations,” the authors said in the study.
When they tested the combination of Sprycel and anti-PD-1, “we were seeing cures of mice go from 10-15% to some cases 90%,” said the study’s corresponding author, Dan Theodorescu, M.D., Ph.D., director of Cedars-Sinai Cancer, in a video interview.
“If our findings are confirmed in clinical trials, it means that by combining both types of drugs, we may be able to better shrink or even eliminate tumors in bladder, breast, colon, melanoma and sarcoma cancers,” he said in a statement.
Combination approaches to enhance immunotherapies have been widely studied across different cancer types. More than 1,100 clinical trials were investigating inhibition of PD-1 in combination with another treatment as of 2017, according to the authors. While many are using targeted therapies like Sprycel, some are pursuing different tactics.
Researchers from the University of Southampton, for example, previously showed that combining an anti-PD-1 with Celldex Therapeutics’ CD27-targeting immunotherapy varlilumab led to better results in mouse models of cancer. A team led by scientists at Massachusetts General Hospital recently found that adding Amgen’s cancer-killing virus Imlygic to PD-1 and Novartis’ MEK inhibitor Mekinist helped fend off tumors in nearly all animals in a study on mice with melanoma.
Columbia University scientists have also found that combining checkpoint inhibitors with pentoxifylline, a drug that’s used to improve blood flow, prevented regulatory T cells (Tregs) from suppressing cancer-killing T cells. And Seres Therapeutics, in collaboration with MD Anderson Cancer Center and Parker Institute, is exploring the use of gut microbiome to improve checkpoint responses.
BMS has already started evaluating its PD-1 inhibitor Opdivo with Sprycel in non-small cell lung cancer. The phase 2 study is expected to read out in April 2021.