Drug Combination Could Boost the Effectiveness of Immunotherapy against Pancreatic Cancer

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A drawing of a pancreatic tumor represented as a barren landscape, blood vessels as rivers, and immune cells as ships with ammunition.

Into the breach: Here a pancreatic tumor is portrayed as an arid desert landscape. Senescence, as represented by the rain cloud, stimulates the formation of rivers (blood vessels) that enable ships harboring ammunition and supplies (drugs and immune cells) to enter and heal this desolate terrain. Illustration credit: Gb Kim

Pancreatic cancer is one of the most challenging cancers to treat. In part, that’s because pancreatic tumors tend to be surrounded by scar tissue. This dense layer prevents cancer medicines and cancer-fighting immune cells from penetrating to the interior.

A new study from Scott Lowe’s lab in the Sloan Kettering Institute, published March 31 in the journal Cell, provides evidence that a two-drug combination can make pancreatic tumors more sensitive to cancer-fighting medicines by breaching their defensive shell.

The two drugs, trametinib (Mekinist®) and palbociclib (Ibrance®), do not by themselves kill tumor cells. Instead, they trigger a state called senescence.

“We think of senescence as an alarm state,” says Marcus Ruscetti, a postdoctoral fellow in the Lowe lab and the paper’s first author. “Cells in this state emit SOS signals that recruit other cells to come in and repair damage.”

As part of this coordinated response, these SOS signals promote the growth of new blood vessels into the tumor. Normally, that would be a bad thing, since blood nourishes tumors. But in this case, the new blood vessels serve as highways for cancer medicines and immune cells — in particular, cytotoxic T cells that have been shown to kill tumor cells — to reach deep within.

The drug combination of trametinib and palbociclib greatly reduced the size of pancreatic tumors, when given along with either the chemotherapy drug gemcitabine (Gemzar®) or a PD-1-blocking immunotherapy. This result occurred in both mouse tumors and human tumors growing in mice. The treatment also dramatically increased how long the mice survived, the researchers found.

Doctors have been trying to poke holes in pancreatic cancer's armor for a while now. This slightly counterintuitive approach just might be one way to do it.
Scott W. Lowe cancer biologist

According to Dr. Lowe, the findings suggest a potential way to convert what’s known as a “cold” tumor — one not vulnerable to attack by the immune system — to a “hot” tumor that is.

“Doctors have been trying to poke holes in pancreatic cancer’s armor for a while now,” he says. “This slightly counterintuitive approach just might be one way to do it.”

The SKI researchers plan to work with doctors at Memorial Sloan Kettering to translate the new findings into clinical trials for people with pancreatic cancer.

The other authors on the paper are John Morris IV, Riccardo Mezzadra, James Russell, Josef Leibold, Paul B. Romesser, Janelle Simon, Amanda Kulick, Yu-Jui Ho, Myles Fennell, Jinyang Li, Robert J. Norgard, John E. Wilkinson, Direna Alonso Curbelo, Ramya Sridharan, Daniel Heller, Elisa de Stanchina, Ben Z. Stanger, and Charles J. Sherr.

 

This work was supported by William Goodwin, Alice Goodwin, and the Commonwealth Foundation for Cancer Research; American Cancer Society grants (PF-16-115-01-TBG, PF-14-066-01-TBE, and GC230452); a Rubicon Fellowship; the German Research Foundation; the Alan and Sandra Gerry Metastasis and Ecosystem Center at MSK; the Blavatnik Family Foundation; a National Science Foundation grant (1752506); the Pershing Square Sohn Cancer Research Alliance; the Center for Experimental Therapeutics at MSK; the V Foundation; the Abramson Family Cancer Research Institute; a Herrick Foundation endowed chair; the American Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital; the Lustgarten Foundation; National Cancer Institute grants (CA013106, K99 CA241110, T32 CA062948, F31 CA 232665, and R01 CA215719); the Parker Institute for Cancer Immunotherapy at MSK; National Institutes of Health grants (U54 OD020355, R01 CA194321, K12 CA184746, and CA229803); an NCI Cancer Center Support Grant (P30 CA008748). Dr. Lowe is Chair of the Geoffrey Beene Cancer Research Center and an investigator in the Howard Hughes Medical Institute. He is a founder and scientific advisory board member of Blueprint Medicines, ORIC Pharmaceuticals, and Geras Bio, and he received an award and honorarium from Eli Lilly and Company. He has filed a US patent application related to this work.