mRNA Vaccines will Soon Prevent Cancer

In the early 1990s, mRNA technology emerged as an alternative to traditional vaccine development, building on research conducted by Wolff et al. involving direct gene transfer into mouse muscle in vivo. Initially, mRNA technology came with drawbacks as it caused severe inflammation upon administration, degraded quickly in the body and was difficult to move across the membrane into the cell. However, breakthroughs using nanotechnology overcame some of these challenges; scientists encased the RNA and used synthetic RNA that the body’s immune system recognizes.

Other major technological innovation and research investment has improved the delivery, translation and stability, enabling mRNA to become a promising tool for vaccine development. These breakthroughs have allowed further research and development of mRNA vaccines, particularly against viruses such as HIV and influenza. In 2020, when the COVID-19 pandemic hit, several human clinical trials were underway to test mRNA vaccines against influenza and HIV. As a result of the pandemic, research efforts, funding and facilities prioritized the development of mRNA vaccines for COVID-19. Combined efforts of global research teams working on COVID-19 mRNA vaccinations accelerated the field of research, improving the knowledge, understanding and methods of mRNA vaccine technology. This allowed the progression of mRNA vaccines for other diseases, such as cancer, and clinical trials for mRNA cancer vaccinations are now underway. The MD Anderson Cancer Center (TX, USA) is conducting a clinical trial to test whether mRNA technology can be used to prevent the recurrence of colorectal cancer.

A B cell displays antibodies specific to antigens on a colorectal cancer cell and signals killer T cells to destroy it.

People with colorectal cancer often undergo surgery to remove the cancerous tumor; however, cancer cells remain in the body and shed DNA into the bloodstream, which is known as circulating tumor DNA (ctDNA) and can cause further complications and metastasis. Van Morris and Scott Kopetz are leading the Phase II trial (NCT04486378) for a personalized mRNA cancer vaccine. People who have stage II or III colorectal cancer are given a blood test after their surgery to check for ctDNA. The patient’s tumor tissue is genetically profiled to identify mutations that fuel cancer growth. The tumor mutations are then ranked from the most to the least common to create a personalized mRNA vaccine for the patient. “We’re hopeful that with the personalized vaccine, we’re priming the immune system to go after the residual tumor cells, clear them out and cure the patient,” explains Morris.


CRISPR Treatment Destroys Cancer Cells

Researchers at Tel Aviv University (TAU) have demonstrated that the CRISPR/Cas9 system is very effective in treating metastatic cancers, a significant step on the way to finding a cure for cancer. The researchers developed a novel lipid nanoparticle-based delivery system that specifically targets cancer cells and destroys them by genetic manipulation. The system, called CRISPR-LNPs, carries a genetic messenger (messenger RNA), which encodes for the CRISPR enzyme Cas9 that acts as molecular scissors that cut the cells’ DNA.

The revolutionary work was conducted in the laboratory of Prof. Dan Peer at TAU. Dr. Daniel Rosenblum led the research together with Ph.D. student Anna Gutkin and colleagues.

To examine the feasibility of using the technology to treat cancer, Prof. Peer and his team chose two of the deadliest cancers: glioblastoma and metastatic ovarian cancer. Glioblastoma is the most aggressive type of brain cancer, with a life expectancy of 15 months after diagnosis and a five-year survival rate of only 3%. The researchers demonstrated that a single treatment with CRISPR-LNPs doubled the average life expectancy of mice with glioblastoma tumors, improving their overall survival rate by about 30%. Ovarian cancer is a major cause of death among women and the most lethal cancer of the female reproductive system. Most patients are diagnosed at an advanced stage of the disease when metastases have already spread throughout the body. Despite progress in recent years, only a third of the patients survive this disease. Treatment with CRISPR-LNPs in a metastatic ovarian cancer mice model increased their overall survival rate by 80%.

The CRISPR genome editing technology, capable of identifying and altering any genetic segment, has revolutionized our ability to disrupt, repair or even replace genes in a personalized manner,” said Prof. Peer. “Despite its extensive use in research, clinical implementation is still in its infancy because an effective delivery system is needed to safely and accurately deliver the CRISPR to its target cells. The delivery system we developed targets the DNA responsible for the cancer cells’ survival. This is an innovative treatment for aggressive cancers that have no effective treatments today.

This is the first study in the world to prove that the CRISPR genome editing system can be used to treat cancer effectively in a living animal,” explained Prof. Peer. “It must be emphasized that this is not chemotherapy. There are no side effects, and a cancer cell treated in this way will never become active again. The molecular scissors of Cas9 cut the cancer cell’s DNA, thereby neutralizing it and permanently preventing replication.”

The results of the groundbreaking study were published in November 2020 in Science Advances.


CRISPR Halts Growth of Breast Cancer

Triple-negative breast cancer (TNBC), lacking estrogen, progesterone and HER2 receptors, has the highest mortality rate of all breast cancers. It more frequently strikes women under age 50, African American women, and women carrying a BRCA1 gene mutation. The highly aggressive, frequently metastatic cancer is in urgent need of more effective targeted therapeutics.

A new tumor-targeted CRISPR gene editing system, encapsulated in a nanogel and injected into the body, could offer a genetic treatment, suggest researchers at Boston Children’s Hospital. In a proof-of-principle study, conducted in human tumor cells and live, tumor-bearing mice, the CRISPR system effectively halted the growth of TNBC while sparing normal cells. Peng Guo, PhD,Marsha Moses, PhD and their colleagues have reported the findings in the journal PNAS.

To date, a lack of effective delivery systems has limited the translation of CRISPR gene editing into therapies. One method uses a virus to deliver CRISPR, but the virus cannot carry large payloads and potentially can cause side effects if it “infectscells other than those targeted. Another method packages the CRISPR tools inside a cationic polymer or lipid nanoparticles. But these elements can be toxic to cells, and the body often traps or breaks down the nanoparticles before they reach their destination.

The new approach encapsulates the CRISPR editing system inside a soft “nanolipogel” made up of a nontoxic double layer of fatty molecules and a hydrogel. Antibodies attached to the gel’s surface then guide the CRISPR nanoparticles to the tumor site. (The antibodies are designed to recognize and target ICAM-1, a therapeutic target for TNBC discovered by the Moses Lab in 2014.)

Because the particles are soft and flexible, they can enter cells more efficiently than their stiffer counterparts. Stiffer nanoparticles tend to get trapped by the cell’s ingestion machinery, while the soft particles fused with the tumor cell membrane and delivered their CRISPR payloads directly inside the cell, the researchers found.

Using a soft particle allows us to penetrate the tumor better, without side effects, and with bigger cargo,” says Guo, the study’s first author. “Our system can substantially increase tumor delivery of CRISPR.”


How To Turn Breast Cancer Cells Into Fat to Stop Them From Spreading

Researchers have been able to coax human breast cancer cells to turn into fat cells in a new proof-of-concept study in mice. To achieve this feat, the team exploited a weird pathway that metastasising cancer cells have; their results are just a first step, but it’s a truly promising approach. When you cut your finger, or when a foetus grows organs, the epithelium cells begin to look less like themselves, and more ‘fluid’ – changing into a type of stem cell called a mesenchyme and then reforming into whatever cells the body needs.

This process is called epithelial-mesenchymal transition (EMT) and it’s been known for a while that cancer can use both this one and the opposite pathway called MET (mesenchymal‐to‐epithelial transition), to spread throughout the body and metastasise. The researchers took mice implanted with an aggressive form of human breast cancer, and treated them with both a diabetic drug called rosiglitazone and a cancer treatment called trametinib. Thanks to these drugs, when cancer cells used one of the above-mentioned transition pathways, instead of spreading they changed from cancer into fat cells – a process called adipogenesis.

The image  shows this process, with the cancer cells tagged with a green fluorescent protein and normal red fat cell on the left. The cancer-turned-fat cells display as brown (on the right) because the red of the fat cells combines with the green of the protein cancer cell tag.

The models used in this study have allowed the evaluation of disseminating cancer cell adipogenesis in the immediate tumour surroundings,” the team wrote in their paper, published in January 2019. “The results indicate that in a patient-relevant setting combined therapy with rosiglitazone and trametinib specifically targets cancer cells with increased plasticity and induces their adipogenesis.

Although not every cancer cell changed into a fat cell, the ones that underwent adipogenesis didn’t change back. “The breast cancer cells that underwent an EMT not only differentiated into fat cells, but also completely stopped proliferating,” said senior author Gerhard Christofori, a biochemist at the University of Basel, in Switzerland. “As far as we can tell from long-term culture experiments, the cancer cells-turned-fat cells remain fat cells and do not revert back to breast cancer cells.

So how does this work? Well, as a drug trametinib both increases the transition process of cells – such as cancer cells turning into stem cells – and then increases the conversion of those stem cells into fat cellsRosiglitazone was less important, but in combination with trametinib, it also helped the stem cells convert into fat cells. “Adipogenic differentiation therapy with a combination of rosiglitazone and [trametinib] efficiently inhibits cancer cell invasion, dissemination, and metastasis formation in various preclinical mouse models of breast cancer,” wrote the team.


Most Metastatic Colorectal Cancers Have Spread Before Diagnosis

Colorectal cancers often spread before the initial tumor is detected, according to a new Stanford study. Identifying patients in whom early metastasis is likely could better guide treatment decisions. Up to 80% of metastatic colorectal cancers are likely to have spread to distant locations in the body before the original tumor has exceeded the size of a poppy seed, according to a study of nearly 3,000 patients by researchers at the Stanford University School of MedicineIdentifying patients with early-stage colorectal tumors that are born to be bad may help doctors determine who should receive early treatments, such as systemic chemotherapy, to kill cancer cells lurking far from the tumor’s original location.

This finding was quite surprising,” said Christina Curtis, PhD, assistant professor of medicine and of genetics at Stanford. “In the majority of metastatic colorectal cancer patients analyzed in this study, the cancer cells had already spread and begun to grow long before the primary tumor was clinically detectable. This indicates that metastatic competence was attained very early after the birth of the cancer. This runs counter to the prevailing assumption that metastasis occurs late in advanced primary tumors and has implications for patient stratification, therapeutic targeting and earlier detection.”

Researchers and clinicians have assumed that cancers acquire the ability to metastasize through the gradual accumulation of molecular changes over time. These changes, the thinking goes, confer specific traits that eventually allow cancer cells to escape the surrounding tissue, enter the bloodstream and take up residence in new locations. In this scenario, metastasis, if it occurs, would be a relatively late event in the evolution of the primary cancer.

Curtis, who co-directs the molecular tumor board at the Stanford Cancer Institute, is the senior author of the study, which was published online June 17 in Nature Genetics. Postdoctoral scholar Zheng Hu, PhD, is the lead author.