July 1, 2015 | by Jyoti Madhusoodanan
The outlook and length of survival has not changed much in the past 25 years for patients suffering from an aggressive form of pancreatic cancer known as pancreatic ductal adenocarcinoma (PDAC). These patients still have few options for therapy; currently available therapies are generally toxic and do not increase survival by more than a few months.
Now, City of Hope researchers have identified a promising new strategy: a bacterial-based therapy that homes to tumors and provokes an extremely effective tumor-killing response.
In a study that appears in the journal Cancer Immunology Research, published by the American Association for Cancer Research, they report that the therapy frequently triggered the complete regression of pancreatic tumors and significantly extended survival in preclinical mouse studies. The study was led by Don J. Diamond, Ph.D., chair of the Department of Experimental Therapeutics at City of Hope, who believes that this method can be used to treat a variety of cancers that share similar features to PDAC.
Bacteria-based therapies have been used to treat solid tumors for decades and are commonly used to treat bladder cancer. Typically, an attenuated (i.e. weakened) form of the microbe is used as the therapy itself, or as a delivery vector to generate anti-tumor responses confined only to the cancer site.
Early attempts by clinicians to target melanoma or renal tumors with attenuated forms of Salmonella typhimurium (ST) yielded mixed results. Although the bacteria successfully reached the tumors, they appeared to do little else. Diamond’s own studies found a similar failure to cause remission by the unmodified bacterium. This occurred, in part, because PDAC tumors use two tactics to evade treatments.
First, they secrete a thick physical barrier of hyaluronan, a sugary molecule that blocks drugs from reaching tumor cells. Second, they also produce copious amounts of a potent immunosuppressive molecule named indoleamine 2, 3-dioxygenase (IDO). IDO camouflages cancer cells and prevents the immune system from recognizing and killing the tumor.
In this new study, Diamond and his colleagues engineered ST to crack these tumor defenses. The researchers transformed bacteria to carry a piece of DNA that encodes a molecule capable of blocking IDO, known as small hairpin RNA-IDO, or simply shIDO. The modified bacteria, dubbed shIDO-ST, was combined with an enzyme (PEGPH20) that digests hyaluronan, provided to City of Hope for the study by Halozyme Therapeutics. When tumors were first pretreated with PEGPH20, the modified bacteria penetrated them much more effectively. This unique combination of bacteria and the enzyme induced a very potent anti-tumor response.
The City of Hope group first tested the therapy against an aggressive form of melanoma, and found the treatment extended animals’ survival. When used in an animal model where pancreatic tumors were transplanted into mice, however, the effects were much more dramatic: It decreased tumor size in all the animals tested. In two-thirds of cases, treated animals showed a complete regression of their tumors.
In a second, even more challenging, model in which tumors spontaneously formed, akin to human disease, the researchers also observed complete regression and extended survival.
“The therapy is able to completely cure tumors in mice,” said Edwin R. Manuel, Ph.D, a staff scientist in the Department of Experimental Therapeutics and first author on the new study. “In two models of pancreatic cancer, the tumor regressed in the majority of animals. We observed the mice for a year or more and the cancer did not return.”
The treatment appears to work by recruiting the immune system to attack cancer cells. The enzyme punches holes in the physical hyaluronan barrier, while shIDO-ST lifts the tumor’s immunosuppressive defense.
In future work, Diamond, Manuel and their colleagues aim to tease apart the molecular mechanisms underlying these processes. Once this is clear, the treatment can be adapted and improved upon to be even more effective, including against other cancers which share characteristics such as hijacking IDO or secreting a dense surrounding matrix.
“We think this therapy has applications not just in pancreatic cancers, but in a whole slew of other cancers,” said Diamond. “About 50 percent of all solid tumors have an involvement with IDO and hyaluronan, including prostate, breast and ovarian cancers.”
The researchers are also in the process of developing the method in order to translate it into the clinic. “We’ve made great strides toward bringing this therapy into clinical trials,” said Diamond.
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