The idea behind Aduro BioTech’s experimental cancer treatment—turning a dangerous food-borne bacterium into a Trojan horse against tumors—may seem startlingly new. But the project arose a dozen years ago, and incubated slowly in three different companies, before emerging this summer into a long-awaited splash of sunlight.
Just weeks ago, Berkeley, CA-based Aduro signed a licensing deal worth as much as $365 million with Johnson & Johnson (NYSE: JNJ) unit Janssen Biotech, which aims to use Aduro’s anti-tumor bacteria to develop prostate cancer drugs. That deal was followed shortly by a $55 million financing round, with J&J’s corporate venture arm as one of Aduro’s new investors. Those two transactions will allow Aduro to support its own trials of the bacteria-based immunotherapy in pancreatic cancer—an area of high unmet medical need that Aduro wants to keep for itself for now.
“It was really ideal for us,” says Aduro CEO Stephen Isaacs of the company’s first partnership. “To have a major pharma step up makes people think there must be something in this.”
The core of Aduro’s anti-cancer platform is a bacterium called Listeria monocytogenes, best known to doctors as a food contaminant that can cause life-threatening infections. But the Listeria germ has a property that has long made it interesting to cancer researchers—it strongly activates the immune system to fight against foreign invaders. Back in the 1890s, New York surgeon William Coley speculated that cancer cells might also be destroyed while bacteria were mobilizing the immune system, which otherwise often fails to attack tumors. Coley had seen tumors regress when patients were fighting infections.
But Listeria’s immune-stimulating properties would only be useful against cancer if it could be stopped from developing into a deadly infection. The rise of genetic engineering created that possibility. In 2002, Isaacs picked up the idea as a cancer immunotherapy project for Cerus of Concord, CA, a company he had founded in 1991. After Isaacs retired from Cerus, the Listeria program was spun out to Concord, CA-based Anza Therapeutics. Anza conducted several clinical trials before selling the technology to Aduro in 2009.
Over that period of 12 years, bioengineers have taken steps to make Listeria safe as a cancer treatment. They snipped out some of its genes to prevent the germ from infiltrating the liver or spreading from cell to cell. Aduro calls this tamed Listeria cell LADD, for live-attenuated double-deleted.
The next step was to make a variety of LADD cells targeted against different tumor types, such as pancreatic cancer or prostate cancer. The bioengineers added some genes to induce the bacteria to manufacture specific tumor antigens—molecules that serve as red flags signaling immune cells to attack and destroy.
Here’s how it’s designed to work in pancreatic cancer: The non-infectious Listeria germ is engineered to produce mesothelin, an antigen characteristic of pancreatic tumor cells. (The name for this specific LADD variation is CRS-207.) When these bioengineered bacteria are infused into the body, they are ingested by immune system cells called dendritic cells. The antigen molecules made by the bacteria are then displayed on the surface of the dendritic cells, which “teach” other blood cells called T-cells to attack pancreatic cancer cells that also bear those surface antigens.
Aduro has made Listeria cells that produce antigens from several other cancer types. Isaacs compares the non-infectious Listeria cell to a DVD player that can play different DVDs. “We have a set of DVDs for prostate cancer,” he says.
Those prostate “DVDs” caught the eye of Arturo Molina, who leads the scientific evaluation of opportunities in oncology for Johnson & Johnson’s California Innovation Center, which has been actively scouting early-stage projects for its parent company since it was set up in Menlo Park a year ago. In Aduro, Molina spotted a possible opportunity for J&J division Janssen Biotech—already a developer of prostate cancer drugs. The Janssen unit markets the approved prostate cancer drug abiraterone (Zytiga), and its pipeline includes ARN-509, an experimental anti-androgen being tested in prostate cancer that doesn’t respond to current hormone-blocking treatments.
“The Aduro opportunity fit with our prostate cancer focus and also with our interest in immuno-oncology,” Molina says. “We believe their preclinical data is scientifically compelling.”
Janssen Biotech and Aduro are now tinkering with the Listeria strains that produce prostate cancer antigens—and may modify them to induce a stronger immune response, Molina says. The J&J unit plans to try these bioengineered bacteria first as a solo therapy in small safety trials to determine the best dose, he says. But the long-term plan is to combine Aduro’s bacteria with other drugs. There are a host of possibilities, including J&J’s own abiraterone or its ARN-509, as well as GVAX—a second cancer vaccine platform that Aduro acquired in 2013.
Aduro’s own trials in pancreatic cancer have combined GVAX with CRS-207—the tamed Listeria strain that makes the pancreatic cancer antigen mesothelin. The results of an early stage trial, announced in January, encouraged Aduro to launch the larger ECLIPSE trial in February. That 240-patient, three-arm trial will compare overall survival times for those taking the GVAX/CRS-207 regimen, or CRS-207 alone, or chemotherapy.
GVAX, a set of cancer vaccines developed by Cell Genesys of South San Francisco, has had a bumpy history. Cell Genesys shut down the program after disappointing clinical trials, and in 2009 it merged with BioSante Pharmaceuticals (NASDAQ:BPAX), which sold GVAX to Aduro.
Despite Cell Genesys’ demise, a post-hoc analysis of its terminated GVAX trial later showed some hidden promise for the cancer vaccine as patient follow-up continued, Molina says. In an agreement with Aduro, Janssen Biotech gained the right to use the GVAX technology as one of the therapies that might be combined with Aduro’s Listeria strain in clinical trials in prostate cancer, Molina says.
“We should at least explore it,” Molina says.
Like the Listeria platform, the GVAX cancer vaccines are designed to arouse the immune system against a particular tumor type. For example, the GVAX prostate cancer vaccine is comprised of a human prostate cancer cell line with characteristic antigens on its surface that spur an attack from immune system cells. The cells are treated so they can’t multiply in the body. In addition, the GVAX vaccines are all engineered to release an agent that stimulates the immune system, granulocyte-macrophage colony-stimulating factor (GM-CSF).
While GVAX is in the running as a possible part of combination therapies with Aduro’s LADD cells, the companion drugs that seem to raise the most excitement both at J&J and at Aduro are the checkpoint inhibitors such as Bristol-Myers Squibb’s ipilimumab (Yervoy). This class of drugs—a hot topic in cancer research these days—turn off a molecular switch that otherwise protects cancer cells from the immune system.
In theory, the checkpoint inhibitors could boost the long-term effect of the T-cells that become dedicated to attacking cancer cells after exposure to the antigens produced by Aduro’s Listeria strains, Isaacs says. Aduro plans to explore this combination in pancreatic cancer. Isaacs says he has had discussions with BMS as well as Merck and Roche, which are also developing checkpoint inhibitors.
Janssen Biotech may pursue the same tactic. “We feel that parallel studies could be done in prostate cancer,” says J&J’s Molina.
Aduro and other companies are benefiting from “a new Renaissance for immunotherapy,” says William Chambers, national vice president for extramural research at the American Cancer Society. Chambers says Aduro’s approach—creating bacteria that live inside of dendritic cells—is unusual. In a more common tactic, researchers have tested bacteria as tools to kill tumors directly. Bioengineered bacteria have been designed to enter tumor cells, where they stay alive and manufacture drug agents to injure those host cells from within.
The technology of Princeton, NJ-based Advaxis (Nasdaq: ADXS) may be most similar to Aduro’s. Advaxis, which also uses bioengineered Listeria monocytogenes bacteria as a means to target the immune system against tumors, is testing its treatments in cervical cancer and other indications. Advaxis has formed partnerships with two biotechnology companies in Asia: Biocon of India and Global BioPharma of Taiwan.
Aduro will now have the resources to fund its own array of clinical trials. Isaacs says its licensing deal with Janssen Biotech, and its $55 million in new financing, will support the company’s operations into 2016. To date, Aduro has raised a total of $84 million in equity financing.
While pancreatic cancer is Aduro’s lead indication for CRS-207, the company has also conducted a small initial study of the Listeria-based therapy, along with chemotherapy, in patients with mesothelioma. This tumor type also bears the antigen mesothelin. Aduro plans to follow up with a randomized trial comparing the CRS-207 regimen with chemotherapy alone, Isaacs says.
In May, Aduro also began an initial safety trial of a different member of its Listeria vaccine family, ADU-623, in patients with high-grade glioma, a form of brain cancer.
Aduro also has a third technology in its toolchest: a group of compounds called cyclic dinucleotides, or CDNs. These are modified versions of naturally occurring small molecules that jump-start the immune response. In preclinical studies, the company has been evaluating combination therapies that include CDNs and GVAX—nicknamed STINGVAX.
“We’re all about combinations,” Isaacs says. “We’re in a very good position to address a variety of indications and work with multiple partners.”