Engineered cells touted to treat the most aggressive cancers in the world

"Our focus is on how we use stem cells and cancer cells from humans to treat cancer," said Dr. Shah, vice chair of research at Brigham and Women's Hospital (BWH) Neurosurgery.

BWH is the second largest teaching hospital of Harvard Medical School in the US.

"Recently, we also used a patient's own tumor cells, gene-engineered them, to treat the patient's cancer. In a nutshell, we play with cells, repurpose them and use them for cancer therapy," said Dr. Shah, who is also the director of the BWH's Center for Stem Cell and Translational Immunotherapy and the KACST-BWH Center of Excellence in Biomedicine, a joint collaboration between Brigham and Women's Hospital and Saudi Arabia's King Abdulaziz City for Science and Technology.

Dr. Shah's laboratory repurposes cancer cells through reverse engineering. It uses them as therapeutics to treat cancer –– a massive leap in personalized medicine, where a patient's own cells are used to treat a medical condition with almost no chance of an immune reaction from the patient's body.

"It is a technology that scientists have been innovating on to decrease the chances of implant failure or immune rejection in transplant biology or regenerative medicine," the scientist told Interesting Engineering.

Aggressive tumor

Dr. Shah said his lab mainly works on glioblastoma (GBM) – a type of cancer that can occur in the brain or spinal cord. It is considered one of the most aggressive in nature and has the lowest survival rates among cancer patients.

In the last few decades, very little has changed in conventional therapies in the treatment of primary and metastatic tumors in the brain.

"Time has remained static for GBM," said Dr. Shah, adding, "One of the reasons is that it is a very aggressive tumor and to deliver drugs to the brain is extremely difficult."

"A change was required," he said.

One of the ways to treat or potentially cure cancers is with a treatment that can be developed and delivered locally, he said, adding, "one of the best options is to use viruses or cells that can deliver therapeutics locally."

Many cell-based therapies for cancer are derived from a patient's own stem cells or immune cells (personalized medicine).

However, in the case of GBM, most patients undergo chemotherapy and radiation therapies within as little as a week of its detection, leaving little time to develop personalized therapeutics. Treatments based on drugs which are taken orally or injected do not reach the brain because of the blood-brain barrier.

Approximately 85 percent of the patients with highly aggressive brain tumors of this type need surgery to remove the tumor within a week of its detection.

The five-year survival rate for glioblastoma patients is only around 6.8%, and the average length of survival for glioblastoma patients is estimated to be only eight months.

Programing normal cells to kill aggressive cancerous cells

Considering the limitations of conventional therapies, Dr. Shah and his team of scientists developed a novel approach of using cells from healthy individuals so that the remedy can be readily available to administer immediately at the time of tumor resection surgery.

He and colleagues tested the efficacy of various modalities to transport stem-cell therapies into the brain.

They discovered that encapsulating the therapeutic cells in biodegradable hydrogel prevented them from being washed away by cerebrospinal fluid and had the best therapeutic efficacy in murine models.

The Havard lab's unique work, he said, has helped them to understand the biology behind various brain cancers, not just GBM.

"The study didn't focus only on brain cancers like GBM, but also metastatic cancers that originate in the brain, breast, and skin (melanoma) and end up in the brain," the expert said.

"What we have tried is not just developing therapies for tumors, but also understanding their biology to develop models in preclinical settings that would allow easy translation into the clinic," Dr. Shah explained.

Target receptors on tumor cells prior to initiating therapy

Dr. Shah's lab was the first to identify target receptors on tumor cells prior to using receptor-targeted therapeutic cells encapsulated in the biodegradable gel after GBM tumor resection surgery.

"In the future, we will be applying this strategy to identify target receptors promptly after [patients] receive a GBM diagnosis," he said.

His lab is also the first to identify target receptors on circulating tumor cells (CTC) in the bloodstream of tumor-bearing animals and will use this diagnostic test to stratify patients for different cell-based therapies his lab is developing.

In the majority of the gene-edited and engineered cells that Dr. Shah has developed, his team of scientists has incorporated a "built-in safety switch" into the cells that allow imaging to track stem cells and, when activated, eradicates different therapeutic cells.

Technology to gene-edit tumor cells

Clustered regularly interspaced short palindromic (CRISPR) is a 2020 Nobel Prize-winning technology used to edit DNA. It is considered by many to be a real game changer, due to its simplicity and efficiency.

The CRISPR system uses the same mechanism which enables bacteria to recognize genetic sequences of invaders and target these sequences for destruction using specialized enzymes. These enzymes are called CRISPR-associated proteins (Cas) and include the DNA endonuclease Cas9.

Dr. Shah's lab used CRISPR Cas9 technology to edit genes for the cancer cell killing program.

"We gene-edited tumor cells using CRISPR. We knocked out receptors in the cells," he said, adding, "after that, we made cancer cells resistant to the therapy and then engineered therapeutics that can kill the target tumor cell."

"We, again, were the first laboratory to gene edit a cancer cell and repurpose it for therapeutics," Dr. Shah added.

Integrating old and new medicine to end pill culture

Another interesting area of research coming out of Dr. Shah's lab is taking a new perspective in looking at the treatment of some diseases. "Some 50 years ago, we weren't as health conscious as we are today. So why is that happening now?" Dr. Shah asked.

Traditional medicines, like those used in many Chinese, African, and South Asian cultures, are known to have focused on preventing the disease rather than treating it.

"I think if we can combine allopathic medicine, focused on treating the disease, with something that prevents the [spread of] disease, we might have a better chance to innovate therapeutics," said Dr. Shah.

The gut is considered the key to treating diseases in many types of traditional medicine.

"If you ever met a Hakeem [the term for a traditional healer in South Asia], he/she would ask you, how is your gut? This is true about all old medicinal practices," he said.

"The pill culture is going to end at some point because we are using pills as band-aids, but it doesn't fix the disease," Shah added.

Although the use of pills and other allopathic treatments are necessary for certain diseases and conditions, they are not always the answer but are often only a part of the answer. Traditional medicine uses medications and surgery but also looks holistically at the entire patient - their diet, lifestyle, psychology, and other factors, and how these interact.

These traditional practices piqued the scientist's interest and research.

"And that's what led me to the microbiome story. I firmly believe that the gut is the key."

"We know the brain-gut connection. We know that in many neurodegenerative diseases, the gut has a role. So we cannot ignore it," Dr. Shah said.

When it hit home

"I love to hone innovative ideas and orchestrate them to develop the next generation of therapies for cancer. It drives me," said Dr. Shah, who started brain tumor research way back in 2005.

Dr. Shah often wondered why he was drawn to this area of research until it hit home.

Dr. Shah lost his father to deadly brain cancer.

"My father passed away in 2018. I was already established, and that's when I got the answer. I never thought that brain cancer would hit home."

"It further strengthened my resolve to find treatment for the most lethal cancer," he told Interesting Engineering.

Dr. Khalid Shah presently holds 15 patents and has founded two biotech companies with the primary goal of clinical translation of therapeutic cells in cancer patients.

He is a prolific innovator, published researcher, and author who is keen to bridge the barriers between traditional and modern medicine and ultimately find a cure for cancer.