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Key points
- Cancer of the brain and nervous system accounted for over 250,000 deaths worldwide in 2020.
- A new cancer vaccine repurposes living tumor cells instead of using inactivated tumor cells.
- Researchers used gene engineering to repurpose living cancer cells as therapeutic tumor cells to release an agent that terminates cancer cells.
- The vaccine also primes the immune system for a long-term antitumor response to prevent cancer.
Innovative technologies such as the gene-editing tool CRISPR-Cas9 enable pioneering scientists to develop novel treatments for diseases such as cancer. A new study published in Science Translational Medicine funded by the National Institutes of Health unveils an innovative cancer vaccine developed with CRISPR-Cas9 that both terminates and prevents tumors from recurring in mice for a deadly type of brain cancer called glioblastoma (GBM).
“Here, we developed a bifunctional whole cancer cell-based therapeutic with direct tumor killing and immunostimulatory roles,” wrote Khalid Shah, MS, Ph.D., Vice Chairman, Department of Neurosurgery at Brigham and Women's Hospital, along with the researchers from his lab where the study was performed. Shah is also a founding member of the Mass General Brigham healthcare system and an Associate Professor at Harvard Medical School.
Glioblastoma, also called glioblastoma multiforme (GBM), is the most common cancer that originates in the brain. Cancer of the brain and nervous system accounted for over 250,000 deaths worldwide in 2020, according to Global Cancer Statistics (GLOBOCAN). Glioblastoma is an incurable disease with poor overall survival and a high rate of recurrence that forms from glial cells that surround and support neurons. It is one of the most treatment-resistant, complex, and deadliest types of cancer.
Cancer treatment vaccines are a type of therapy that uses the body’s own defenses to fight cancer by stimulating or suppressing the immune system called immunotherapy. The history of regulatory-approved cancer vaccines spans a little over a decade.
The first U.S. Food and Drug Administration (FDA) cancer vaccine was approved in 2010 for the treatment of castration-resistant prostate cancer called sipuleucel-T (Provenge)–an autologous cellular immunotherapy that stimulates the immune system. A year later, in 2011, the FDA approved a cancer vaccine for melanoma called ipilimumab (Yervoy)—a monoclonal antibody targeting CTLA-4 (cytotoxic T-lymphocyte antigen-4).
Today Ipilimumab has FDA approval to treat a wide range of cancers. The first programmed death receptor-1 (PD-1) immune checkpoint inhibitor called nivolumab (Opdivo) was approved in 2014 in Japan to treat unresectable melanoma–skin cancer that could not be removed through surgery. Another immune checkpoint inhibitor that works by blocking programmed death receptor-1 is the monoclonal antibody cancer immunotherapy drug pembrolizumab (Keytruda) which was FDA approved in 2014. Initially, pembrolizumab was approved to treat melanoma. Today it is used for a variety of cancers.
What is innovative about this new cancer vaccine is that it repurposes living tumor cells instead of using inactivated tumor cells. Given that living cancer tumor cells will migrate a great distance to join other tumor cells in the brain, the researchers decided to re-engineer live cancer cells to improve treatment precision and efficacy.
“The administration of inactivated tumor cells is known to induce a potent antitumor immune response; however, the efficacy of such an approach is limited by its inability to kill tumor cells before inducing the immune responses,” wrote the scientists. “Unlike inactivated tumor cells, living tumor cells have the ability to track and target tumors. We developed a bifunctional whole cancer cell-based therapeutic with direct tumor killing and immunostimulatory roles.”
The researchers used gene engineering to repurpose living cancer cells as therapeutic tumor cells (ThTCs) to release an agent that terminates cancer cells and express factors that will also prime the immune system for a long-term antitumor response to prevent cancer.
CRISPR-Cas9 is a gene editing tool. CRISPR-Cas9 has proven capable of editing human and animal DNA. Genome editing was at the center of the Nobel Prize in Chemistry in 2020 as pioneering scientists Emmanuelle Charpentier and Jennifer A. Doudna were jointly awarded for developing a method for gene editing called CRISPR-Cas9, referred to as CRISPR. The trailblazing duo were the first to discover CRISPR-Cas9 capabilities with their research colleagues and published their landmark study in Science in 2012.
In genomics, DNA sequencing, PCR (polymerase chain reaction), recombinant DNA, genetics, precision medicine, and biotechnology fields, the term CRISPR refers to a specialized gene-editing technique, such as CRISPR-Cas9, where Cas is short for CRISPR-associated. CRISPR is an acronym that stands for Clustered Regularly Interspaced Short Palindromic Repeats—a series of short repeating DNA sequences with spacers in between that is the distinctive characteristic of the genomes of prokaryotic organisms. Prokaryotes are single-celled organisms, such as bacteria and archaea, that lack a nucleus and membrane-bound organelles. When Cas genes located near CRISPR are activated, they produce Cas enzymes, which are proteins that have the ability to cut DNA.
The scientists used CRISPR-Cas9 to knock out the IFN-β–specific receptor making the tumor cells resistant to interferon-β (IFN-β), then engineered these cells to release immunomodulatory agents IFN-β and granulocyte-macrophage colony-stimulating factor.
“These engineered therapeutic tumor cells (ThTCs) induced improved survival and long-term immunity in glioblastoma humanized mice,” the scientists reported.
This proof-of-concept represents a giant leap forward in precision oncology using the innovative technology of CRISPR-Cas9 to tackle glioblastoma, one of the deadliest cancers.
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