BioTechniques
01/22/2016 Kristie Nybo, PhD
The immune system is capable of defeating cancer. In fact, it regularly clears abnormal cells from the body, preventing tumor development. But some cells evade the immune system by creating microenvironments that suppress immune responses in their vicinity, allowing these cells to form tumors. Now, a team of researchers from Dartmouth University and Case Western Reserve University report an attractive new approach for immunotherapy against primary tumors and metastatic cancer in Nature Nanotechnology.
The team, led by Nicole Steinmetz and Steven Fiering, used in situ vaccination, an approach that involves applying an immunostimulatory reagent directly to the tumor. While this is not a new idea, it has not been widely explored, and previous attempts to use in situ vaccination to provoke anti-tumor immune responses achieved limited success.
The ideal immunostimulatory reagent should provoke a robust immune response without being infectious or pathogenic, be amenable to large scale production in a way that avoids potentially harmful contaminants, and be capable of carrying drug cargo. Steinmetz and Fiering turned to virus like particles (VLP)—hollow viral capsids that aren't infectious since they lack nucleic acids. These offer carrying capacity and some have demonstrated inherent immunogenic properties. The researchers decided to test cowpea mosaic virus (CPMV) VLP since it can be mass-produced in plants, thus avoiding endotoxin contamination from E. coli.
"It's not cytotoxic. There's no RNA involved or lipopolysaccharides that may be used as adjuvants. And it's not simply an irritant," Steinmetz said in a press release. The team tested the VLP by inhalation in mice carrying melanoma tumors in their lungs. The VLP were quickly taken up by neutrophils in the tumor microenvironment. "We see a specific immune response."
Treatment reduced both tumor size and metastatic lesion number in the mice. "The particles are shockingly potent," said Fiering. "They're easy to make and don't need to carry antigens, drugs, or other immunostimulatory agents on their surface or inside."
The team also directly injected the VLP into breast cancer metastases, colon tumors, ovarian carcinoma, and melanoma. After treatment, tumors quickly developed necrotic centers; in half of the mice, VLP treatment eliminated the tumors entirely after only two injections.
Four weeks later, the researchers re-introduced tumors into mice that had previously cleared primary tumors through VLP treatment. Three of the four mice did not re-develop tumors. "The cowpea virus-based nanoparticles act like a switch that turns on the immune system to recognize and fight against the tumor, as well as to remember it," commented Steinmetz.
Importantly, VLP treatment was accomplished without any toxicity to other tissues, which is a significant problem for many other current anti-cancer treatments such as chemotherapy and radiation.
Fiering and Steinmetz plan to explore the mechanism by which CPMV capsids stimulate neutrophils to bring about the anti-tumor immune response. They also plan to test the approach in larger animals with immune systems more similar to humans.
Reference
Lizotte PH, Wen AM, Sheen MR, Fields J, Rojanasopondist P, Steinmetz NF, Fiering S. In situ vaccination with cowpea mosaic virus nanoparticles suppresses metastatic cancer. Nat Nanotechnol. 2015 Dec 21.
01/22/2016 Kristie Nybo, PhD
The immune system is capable of defeating cancer. In fact, it regularly clears abnormal cells from the body, preventing tumor development. But some cells evade the immune system by creating microenvironments that suppress immune responses in their vicinity, allowing these cells to form tumors. Now, a team of researchers from Dartmouth University and Case Western Reserve University report an attractive new approach for immunotherapy against primary tumors and metastatic cancer in Nature Nanotechnology.
The team, led by Nicole Steinmetz and Steven Fiering, used in situ vaccination, an approach that involves applying an immunostimulatory reagent directly to the tumor. While this is not a new idea, it has not been widely explored, and previous attempts to use in situ vaccination to provoke anti-tumor immune responses achieved limited success.
The ideal immunostimulatory reagent should provoke a robust immune response without being infectious or pathogenic, be amenable to large scale production in a way that avoids potentially harmful contaminants, and be capable of carrying drug cargo. Steinmetz and Fiering turned to virus like particles (VLP)—hollow viral capsids that aren't infectious since they lack nucleic acids. These offer carrying capacity and some have demonstrated inherent immunogenic properties. The researchers decided to test cowpea mosaic virus (CPMV) VLP since it can be mass-produced in plants, thus avoiding endotoxin contamination from E. coli.
"It's not cytotoxic. There's no RNA involved or lipopolysaccharides that may be used as adjuvants. And it's not simply an irritant," Steinmetz said in a press release. The team tested the VLP by inhalation in mice carrying melanoma tumors in their lungs. The VLP were quickly taken up by neutrophils in the tumor microenvironment. "We see a specific immune response."
Treatment reduced both tumor size and metastatic lesion number in the mice. "The particles are shockingly potent," said Fiering. "They're easy to make and don't need to carry antigens, drugs, or other immunostimulatory agents on their surface or inside."
The team also directly injected the VLP into breast cancer metastases, colon tumors, ovarian carcinoma, and melanoma. After treatment, tumors quickly developed necrotic centers; in half of the mice, VLP treatment eliminated the tumors entirely after only two injections.
Four weeks later, the researchers re-introduced tumors into mice that had previously cleared primary tumors through VLP treatment. Three of the four mice did not re-develop tumors. "The cowpea virus-based nanoparticles act like a switch that turns on the immune system to recognize and fight against the tumor, as well as to remember it," commented Steinmetz.
Importantly, VLP treatment was accomplished without any toxicity to other tissues, which is a significant problem for many other current anti-cancer treatments such as chemotherapy and radiation.
Fiering and Steinmetz plan to explore the mechanism by which CPMV capsids stimulate neutrophils to bring about the anti-tumor immune response. They also plan to test the approach in larger animals with immune systems more similar to humans.
Reference
Lizotte PH, Wen AM, Sheen MR, Fields J, Rojanasopondist P, Steinmetz NF, Fiering S. In situ vaccination with cowpea mosaic virus nanoparticles suppresses metastatic cancer. Nat Nanotechnol. 2015 Dec 21.