Immune checkpoints are a crucial part of the body’s immune system, but cancer cells are often able to escape this tightly controlled surveillance system, in part by using checkpoint pathways to block anti-tumor responses.
New collaborative research between Rice University bioengineers Sheng Tong and Gang Bao and oncologist Cassian Yee from the University of Texas MD Anderson Cancer Center aims to engineer nanoscale systems that can disrupt these immunosuppressive pathways and subject tumors to attacks by the body’s natural defenses.
Tong says the work, which is supported by a new four-year, $2 million grant from the National Institutes of Health, will not only expand the understanding of cancer immunogenicity and tumor–immune system interactions, but also reveal new directions in multiplexed and personalized cancer immunotherapy.
Tong, a principal investigator on the project who joined the Rice faculty from the Georgia Institute of Technology with Bao in 2015, said clinicians and cancer researchers don’t yet fully understand all the methods tumors use to fool the immune system.
“There is a critical unmet medical need for many patients, particularly those diagnosed with the most lethal types of cancer, who do not benefit from current immunotherapies,” Tong said.
The team aims to develop a therapeutic genome editing system by packaging CRISPR/Cas9 machinery within a delivery system using baculoviral vectors (BV) that can target a tumor’s immune checkpoint inhibitors and immunosuppressive genes. Magnetic iron oxide nanoparticles (MNP) attached to the BV surface will serve as a switch to induce controlled, local gene editing under an applied magnetic field.
“BV is a cylindrically shaped vector derived from an insect virus that can carry large DNA molecules, so it allows for the packaging of multiple genes,” said Bao, Rice’s Foyt Family Professor of Bioengineering, CPRIT Scholar in Cancer Research and professor of chemistry.
Bao said the CPISPR/Cas9 system is an efficient genome-editing tool that can induce sequence-specific gene disruption, modification or regulation. “But the in vivo delivery of genome editing machinery using typical viral-vectors can induce cutting activities in normal tissues, causing genotoxicity and side effects,” he said. “This delivery challenge has been a big hurdle for the clinical translation of the genome editing technique.”
Recent studies in the Bao lab have focused on targeted nucleic acid delivery methods that involve the use of a locally applied magnetic field serving as a precise external control and as an “on-off” switch for controlled tissue-specific genome editing in vivo.
In addition to serving as the magnetic switch for local viral transduction, the biocompatible MNPs attached to the surface of the BV vector serve as an imaging contrast agent for tracking the BV vector. This information will allow the team to rigorously quantify the in vivo delivery efficiency and biodistribution of the MNP-BV-CRISPR, as well as examine the off-target effects induced by the gene-editing machinery.
Yee, a pioneer of cancer immunotherapy in the Department of Melanoma Medical Oncology at MD Anderson, will help evaluate and optimize the anti-tumor immunity of the new therapy in animal models.
“There is a lot of enthusiasm in the use of combination strategies such as this to improve the prognosis for patients battling the toughest cancers,” Tong said. “If we’re successful, we’ll develop an efficient immunotherapy in which the genetic targets can be easily designed and implemented according to the immunological profile of individual cancer patients.”
– Shawn Hutchins is a science writer and web specialist for Rice University’s Department of Bioengineering.
Source : Rice University