One of the key launch points for the modern biotechnology industry was not in the Bay Area or San Diego or Cambridge, Massachusetts: It took place some 50 years ago in the San Gabriel Valley at the City of Hope research center and cancer hospital in Duarte.

That’s when and where a team of researchers, led by the late Arthur Riggs and the still-living Keiichi Itakura made one of the first therapeutic uses of recombinant DNA technology to genetically modify bacteria.

That enabled them to produce synthetic insulin, which in ensuing decades would become the lifeblood for many patients suffering from diabetes.

Riggs and Itakura teamed up with Herbert Boyer, one of the founders of a then little-known startup called Genentech to develop the synthetic insulin; they eventually licensed their technology to Genentech.

In 1982 Genentech, in partnership with pharma giant Eli Lilly and Co., won approval to market the synthetic insulin developed with Riggs and Itakura. That milestone helped turn Genentech into the world’s first successful biotech company.

Emergence as research powerhouse

For City of Hope, this was a key milestone for its research programs targeting cancer and diabetes treatments that would eventually turn the nonprofit institution into a major research powerhouse.

Since 1985, City of Hope has received nearly $1.4 billion in research grants from the National Institutes of Health – the main federal medical research funder – and another $218 million in research grants from the California Institute for Regenerative Medicine (better known as the Stem Cell Institute). City of Hope research programs have also received hundreds of millions of dollars in research funds from private foundations and from pharmaceutical companies.

This is a long way from City of Hope’s relatively humble beginnings in 1913 as a sanitorium for tuberculosis patients. After World War II, with tuberculosis on the wane, the sanitorium’s scientists turned their research focus to treatments for two seemingly intractable diseases: cancer and diabetes; in 1949, it rebranded as City of Hope.

In the mid-1950s, scientists there developed one of the world’s first radiation therapy machines to treat cancer patients. Three decades later, researchers helped develop the next generation of cancer treatments, notably the monoclonal antibody drugs Herceptin and Avastin.

In 1998, the National Cancer Institute, part of the National Institutes of Health, designated City of Hope as a comprehensive cancer center, the cream of the crop in centers devoted to cancer research, prevention and clinical services; it is now one of 57 such centers around the country. Locally, the City of Hope joined two longstanding comprehensive cancer centers: USC’s Norris (1973) and UCLA’s Jonsson (1976). Cedars-Sinai Medical Center became the county’s fourth comprehensive cancer center in 2009.

City of Hope is unique among these local institutions in that it is not affiliated with a larger university or medical center.

“We are an independent, standalone organization,” said Robert Stone, City of Hope’s chief executive. “One of our strengths is to bring research together with care, together with philanthropy – all for the benefit of our patients.”

Despite its impressive track record in cancer and diabetes research, City of Hope is still better known for treating cancer patients.

“City of Hope is the most significant (cancer) research institution in the region that few people in the broader population know about,” said Stephanie Hsieh, who led a spinout company, Meditope Biosciences Inc., for several years and is now interim chief executive of industry catalyst organization Bioscience L.A.

New frontiers in cancer research

Stone, who has been with City of Hope for nearly 30 years, said this is one of the more exciting times for the institution’s research efforts.

“The ability to use data and artificial intelligence has been transformative,” Stone said. With this access, the pace of research has accelerated, as has the ability to turn that research into therapies for patients, he added.

In cancer research, a main focus of City of Hope researchers in recent years has been on immunotherapy, specifically honing the development and use of chimeric antigen receptor T-cell therapy, known better by its acronym CAR-T. This cell therapy harvests the body’s T cells, reprograms them to better recognize tumor cells, grows more of these cells in the lab and then infuses them back into the patient, where they are better equipped to recognize and kill specific types of cancer cells.

“We are among the first to develop the use of CAR-T therapies,” said Marcel van den Brink, president of City of Hope. “We also have three cell manufacturing practice centers. That is a very large number of manufacturing centers – almost no other academic center has that.”

He noted that those cell manufacturing centers are not just being used for internal research and treatment but that pharmaceutical companies also sign agreements to use them to create cells for their own research and to target specific types of cancers.

The latest front in cancer research being conducted at City of Hope is focused on the microbiome – basically bacteria, fungi and viruses in the gut.

“Changes in the gut fauna have major impacts on the outcomes of how the body modulates immunity and T-cells,” van den Brink said.

Understanding in more detail this relationship between cancer immunotherapy and the gut microbiome can improve the outcomes of CAR-T-cell and other immunotherapy treatments, he added.

The use of artificial intelligence and big data is accelerating this cancer research and its clinical applications, according to John Carpten, director of the Beckman Research Institute at City of Hope.

Carpten also cited advances in cancer detection through blood samples (“liquid biopsies”) and biomarkers that can be used in genetic profiling.

In the immediate future, though, Carpten said there is a more urgent challenge. He said he and other senior City of Hope executives have been in constant meetings regarding actions of the Trump administration to reduce funding for the National Institutes of Health.

On Feb. 7, the NIH announced it would cap indirect costs for future research funding at 15% of the total funding. Indirect costs include items such as lab equipment, support staff and utilities; they typically make up more than a third of the total funding amount for a project.

In response, attorneys general from 22 states – including California – filed suit last week to block the move. Dozens of research universities across the country, including the California Institute of Technology in Pasadena and the University of California Board of Regents, have filed a separate lawsuit to block the action.

Diabetes: boosting the body’s insulin production

On the diabetes front, some of the latest research is focusing on increasing the body’s own insulin production.

“We are working on a drug that helps grow a patient’s own insulin cells,” said Debbie Thurmond, director of the Arthur Riggs Diabetes and Metabolism Research Institute at the City of Hope.

After making his discoveries related to artificial insulin at City of Hope, Riggs went on to lead much of the institution’s research efforts in coming decades. He also amassed a fortune in patent and licensing agreement royalties that enabled him to donate more than $300 million to City of Hope, becoming by far its largest donor.

In an ironic twist, if the drug candidate is successful, it could sharply reduce or even eliminate the need for artificial insulin, the very technology that Riggs, the institute’s main benefactor, helped develop.

Thurmond added that research is ongoing into the links between diabetes and the onset of pancreatic and other types of cancers.

Research spawning spinoffs

Over the past 50 years, City of Hope has both worked with existing biotech and pharma companies and spun off new ones.

According to Linda Malkas, a researcher and dean of translational science at City of Hope, researchers with technologies and drug therapies that show commercial potential can take them to a board within City of Hope that decides whether the nonprofit institution will itself invest in the technology and keep it in-house or whether to let the researchers form their own company and seek outside funding for commercialization. Some researchers decide against seeking City of Hope funding and go directly to the spinout route.

Once a company forms, Malkas said a technology licensing deal must be worked out with the City of Hope’s office of technology licensing.

In 2012, Meditope Biosciences was spun out through this process and made its home in nearby Pasadena. Its technology that was developed at City of Hope focused on using an antibody platform to deliver drugs to the target cancer cells.

Stephanie Hsieh, the chief executive at the time, said that the spinoff and licensing process went smoothly, and that City of Hope has backed the company over the long haul. She also noted that Riggs was the company’s first investor.

Another more recent spinout is Irvine-based Pepromene Bio Inc., a CAR-T cell company that is one of the first to target leukemia and lymphoma cancers. Pepromene was launched in 2016 through the efforts of Larry Kwak, who is deputy director of City of Hope’s comprehensive cancer center and director of the Toni Stephenson Lymphoma Center.

Hazel Cheng, Pepromene Bio’s chief operating officer, said the company has maintained a close working relationship with City of Hope.

“We use City of Hope as a backup in terms of research and regulatory strategy, as well as running the clinical trials,” Cheng said.

Nationwide expansion gives research boost

In the last three years, City of Hope has transformed into a nationwide organization, opening cancer research and treatment hospitals in Phoenix, Chicago and Atlanta. A fifth hospital is set to open later this year in Irvine in Orange County.

“When that hospital opens, 86 million Americans – that’s one out of every four Americans – will be within easy driving range of a City of Hope hospital,” Stone, the chief executive, said. “This is the fulfillment of one of our key mission goals: expanding access to the best in cancer research and treatment.”

But Stone said this access is a two-way street. Not only does it help cancer and diabetes patients, but it also helps researchers.

“It gives our researchers access to a much larger group of patients and their data to help with clinical trials and speed development of new therapies,” he said.