Cost-effective cancer vaccine offers promise for prevention, treatment


May 8, 2020

Being diagnosed with cancer is always alarming and too often, grim. An ancient disease, cancer is still with us, though treatment options remain limited, painful and frequently unsuccessful. What if we could treat cancer the same way we do other leading killers, like smallpox? What if we could prevent it — or even treat it — with a vaccine?

There is a lot about cancer we don’t yet understand, but we do understand the complexities associated with treating it. Cancer defies the normal standards of a healthy cell, such as maintaining sustainable replication and the even distribution of nutrients. Instead, cancer cells replicate uncontrollably, hijacking the environment they inhabit, and are characterized by an extremely high mutation rate. Vaccine In a new study appearing in the journal BMC Immunology, lead researcher Milene Peterson along with a team of researchers including Stephen Johnston, all in the Biodesign Center for Innovations in Medicine, took a look at the efficacy of personal vaccines versus shared vaccines, which target mutations shared by the majority of individuals with a cancer subtype. Download Full Image

Targeting cancer mutations with a vaccine is particularly vexing, as most are unique to each individual. But researchers at the Biodesign Institute may have a solution to these challenges.

In a new study appearing in the journal BMC Immunology, lead researcher Milene Peterson along with a team of researchers including Stephen Johnston, all in Arizona State University's Biodesign Center for Innovations in Medicine, took a look at the efficacy of personal vaccines versus shared vaccines, which target mutations shared by the majority of individuals with a cancer subtype.

To understand how shared vaccines are created, we first must understand how cancer vaccines came about.

“There were about 30 years where people were trying to make cancer vaccines, but these efforts were a total failure,” said Johnston, director of the Biodesign Center for Innovations in Medicine. “More recently, there was the realization that they were using the wrong material in those vaccines, and what was really happening was that the immune system was engaging with all those mutations occurring in the tumor.”

A more targeted approach to the problem was needed, so researchers started taking samples from tumors and sequencing them to identify potential mutations that could activate the immune system.

“The problem was when they started sequencing these tumors, they found that all those mutations in the DNA were personal. Everybody’s tumor had different mutations in it — I am sure you’ve probably heard that cancer is personal. And at the DNA-level, that is clearly the case,” Johnston added.

Despite this limitation, various pharmaceutical companies have pursued this vaccine strategy. In the ongoing clinical trials, patients are having their tumors sampled and sequenced to find DNA mutations unique to their cancer. Upon identifying these, clinical researchers create personal vaccines to generate an immune response and stifle the growth of the tumor, for that individual alone.

But this brings up another important point — by the time a tumor is big enough to generate a large enough sample for sequencing, the cancer is already late-stage. And as one can imagine, the resources needed to carry out such sequencing for each cancer patient racks up a formidable cost.

“It takes about one to three months to make that personal vaccine. And it is expensive — it is probably going to cost about $100,000 dollars for each person to make that vaccine. It’s an exciting new idea, but it has its difficulties,” Johnston said.

To mediate this challenge, Biodesign researchers sought an alternative vaccine strategy, one where they could utilize mutations that arise in the majority of individuals with a given cancer. Researchers found that most of the mutations seen in DNA were personal and did not activate the immune system to the extent they needed, so they turned to RNA instead.  

“Most of the mutations that occur in the DNA result in single amino acid changes, so most of those will not elicit an immune response,” Johnston said. “The mutations, or the variance that we find in RNA, they tended to be fairly long tracks of mutant peptides.”

Johnston went on to liken these mutant peptides to that of a pathogen, suggesting they would have a stronger impact on immune activation. Not only were these mutations more likely to trigger immune action, but many of them were conserved between individuals with a cancer subtype. This has strong implications for a broadly applicable vaccine.

“For example, we can find RNA mutations that 70% of women with breast cancer have in their tumor. That gave us the idea that we can make an off-the-shelf, premade vaccine by just putting enough of the frequent mutations together.”

Utilizing these shared mutations, or RNA frameshift mutations, the researchers made what they called a FAST shared cancer vaccine. They tested this out in a mouse model with breast cancer and compared its performance to that of the personal vaccine. This would naturally be less expensive, but how effective would it be?

The results were highly encouraging. When researchers tested the shared vaccine in the breast cancer mouse model, they found that it was just as effective as the personal vaccine.

“Our results clearly proved that the frameshifts are potent antigens and that both vaccine strategies were successful and have comparable anticancer efficacy,” Peterson said.

This is a testament to the viability of this vaccine as a more cost-effective alternative.

“When patients are diagnosed, we could give them a premade vaccine that is 1,000 times less expensive and much simpler to make,” Johnston said.

To further reduce the cost, the researchers measured the efficacy of checkpoint inhibitors when combined with the vaccines. Checkpoint inhibitors block checkpoint proteins that downplay the immune system from binding to their corresponding receptors.

“Most of the clinical trials that are out there now for personal vaccines are combining them with checkpoint inhibitors, and it remains to be seen if that improves the outcome, but it does double the cost of the personal vaccine treatment. A course of checkpoint inhibitors costs $100,000. We found that when we made a vaccine for breast cancer, adding the checkpoint inhibitors didn’t improve the vaccine — it wasn’t necessary. It didn’t hurt it, but it didn’t improve it.”

The opportunities born from these discoveries are boundless — in addition to lowering cost and lessening the resources needed to develop the vaccine while providing a similar effect postdiagnosis, the shared vaccine may also be used as a preventative measure.

Once we understand what mutations arise in a subtype of cancer, we can prep the immune system to react were that cancer to develop, using the same vaccine.

In fact, the researchers in this study are testing the shared vaccine as a preventative measure in a clinical trial using dogs, and they are preparing to start a clinical trial for the shared vaccine as a form of treatment for pediatric brain cancer this year.

Oftentimes in research, there is a demand for the most effective, state-of-the art treatment, but on a global scale, that is not always a feasible route. With this study, the researchers took the state of public health into consideration.

“Everything we have done both on the diagnostic side and the vaccine side, we have designed with the idea that it will be inexpensive. Our rationale is that 70% of the cancer in the world doesn’t develop in developed countries. They will never be able to afford a $100,000 course of therapy for each individual.”

Gabrielle Hirneise

Assistant science writer , Biodesign Institute

480-433-4272

ASU engineers reveal new understanding of synthetic gene circuits


May 8, 2020

Recent discoveries by two research teams in the Ira A. Fulton Schools of Engineering at Arizona State University are advancing the field of synthetic biology.

Assistant Professor Xiaojun Tian and Associate Professor Xiao Wang conducted a yearlong collaboration with their laboratory groups in the School of Biological and Health Systems Engineering, one of the six Fulton Schools. Results from their novel research into ways that engineered gene circuits interact with biological host cells have been published this week in the scientific journal Nature Chemical Biology. Synthetic gene circuit graphic Newly published research led by Ira A. Fulton Schools of Engineering faculty Xiaojun Tian and Xiao Wang explores the relationship between engineered gene circuits and their host cells. The results represent a first in the field of synthetic biology. Image courtesy of Shutterstock Download Full Image

Synthetic biology applies engineering methods to design new biological networks or redesign aspects of existing biological systems. It is a rapidly emerging field of study, and many significant advances have been made during the past 20 years.

Early work included creating synthetic gene circuits and placing them within natural host cells.

“But the concept of a circuit here is an abstract one,” Wang said. “Imagine a sequence of genetic segments in which the first one encodes or produces a particular protein. That protein, in turn, can either activate or inhibit the expression or protein production from another segment in the genetic sequence. If you keep expanding this idea, you can imagine it’s like a network.”

It is this chain of influence or inducement that is functioning as a circuit, rather than the physical connections within the genetic sequence. However, previous research has focused on just the behaviors of engineered genetic circuits themselves, with little attention to the background or context represented by host cells.

“It is hard to predict how these interactions affect the functions of the engineered genetic circuits,” Tian said, “not to mention how to control them and make the circuits operate as desired within complicated, real-life environments.” 

Indeed, these synthetic gene circuits generally work only in a laboratory environment, not in more lifelike conditions. And this limitation greatly inhibits the application of engineered gene circuits in clinical settings. 

Seeking to advance the field in that practical direction, the new research by Tian and Wang explored the relationship between the synthetic gene circuits and their host cells. Specifically, they examined the impact of “memory” circuits implanted within host cells, and the influence of gene circuit “topologies,” or the architecture of interconnections among circuit components, in relation to host cell growth.

In the context of this work, the idea of memory relates to the continuation of influence or inducement within an engineered gene circuit even with the absence of a stimulus.

“Think about a light switch in your house,” Wang said. “The light stays on even when you remove your finger from the switch. We refer to that persistent state as memory.”

Tian and Wang’s new research revealed that memory circuit topologies are significantly influenced by host cell behavior.

“We verified that influences are exchanged between the gene circuit and the host cell,” Tian said. “That is, the circuit impacts the host cell, which in return has an impact on the circuit. It’s like a loop.

“But we also demonstrated that the impact on a circuit’s functionality is dependent on its topology,” he said. “So, one circuit topology shows better performance than others within a dynamic host environment.”

Their discovery relating circuit topology to a host cell’s impact on circuit function is a first in the field of synthetic biology, and it expands meaningful scientific understanding of these complex interactions.

“It paves the way for building robust, engineered gene circuits,” Tian said. “These could one day enhance interventions against the metastasis of cancer, for example, by slowing the ability of cancer cells to translate their development.”

Progressing from the research that Tian and Wang have published includes examining the impact of adding additional synthetic gene circuits or modules into host cells, which substantially elevates the level of complexity as modules compete for resources within the cellular system.

Wang says that the School of Biological and Health Systems Engineering within the Fulton Schools is particularly well-placed for discoveries in synthetic biology.

“We have a critical mass of dedicated people who are strategically invested in advancing this area of research for the long term,” he said. “So, we are seeking to be a leader in this field.”

Gary Werner

Science writer, Ira A. Fulton Schools of Engineering

480-727-5622