The first-of-its-kind FDA approval of an immune cell therapy for cancer was big news on Penn's campus. It marked the culmination of a chapter of discovery, collaboration, and spectacular feats of surviving once-deadly cancers. And it's the start of much more.
By Steve Graff
On the morning of August 30, 2017, the U.S. Food and Drug Administration announced what was called an “historic action”: A University of Pennsylvania-developed personalized cellular therapy was approved for the treatment of advanced acute lymphoblastic leukemia (ALL) in children and young adults. Hours later, the newly minted director of the Abramson Cancer Center (ACC), Robert Vonderheide, MD, DPhil, found himself atop a coffee stand in the lobby of the Perelman Center for Advanced Medicine, looking out over a crowd that numbered in the thousands who had gathered to celebrate, all beaming with pride and joy.
Carl June, MD, the pioneer who led Penn’s charge into this new cancer frontier, had just arrived.
“This is absolutely an amazing day,” Vonderheide said. “There’s just one thing I want to tell you…‘the Abramson Cancer Center is on fire.’”
Robert Vonderheide, MD, DPhil and Carl June, MD
Before that bright crowd, Vonderheide didn’t have to explain much.
They knew that it was the first time the FDA had approved a therapy based on gene-transfer technology that used a viral vector to insert genetic material into a T cell. It was the first time the agency had approved a personalized therapy that used a modified version of a patient’s own cells as a treatment. And it was a major moment in the unfolding renaissance of exciting developments of therapies that empower the body’s immune system to fight cancer. They had seen the lives saved in their own hospital during the early, experimental days of using the treatment, and they knew what its approval signified, for more lives in more places.
The Radical Idea
Even 10 years ago, the moment would have been considered a pipe dream.
The immunotherapy field was still relatively small, with few research groups around the world investigating ways to manipulate the immune system’s T cells to fight disease. Pharmaceutical companies had little interest. Funding was scarce. And people from other biomedical fields largely viewed as a low priority.
None of this seemed to discourage June, an immunologist who had been working with modified T cells to develop experimental HIV therapies since the mid-1980s. By the time he and his then-postdoctoral researcher Bruce Levine, PhD, now the Barbara and Edward Netter Professor of Cancer Gene Therapy in the department of Pathology and Laboratory Medicine, landed at Penn in 1999, they had cracked the code on how to get T cells to grow outside the body, and safely infused a small group of HIV patients with first-generation chimeric antigen receptor (CAR) T cells that enhanced their immune function. Blood cancers would be next.
Journey to FDA Approval
A timeline of the Penn-developed engineered cell therapy for cancer called CTL019 before being approved for sale by Novartis as Kymriah.
January 1999 – Carl June and Bruce Levine arrive at Penn.
Late 2005 – Following several earlier versions, June’s lab develops the CD19-directed CAR T cell that will become the CTL019 therapy.
August 2010 – Bill Ludwig becomes first patient to be infused with CTL019 therapy. Two other patients with chronic lymphocytic leukemia follow shortly thereafter.
August 2011 – June, Levine, and David Porter publish results from first clinical study with three patients in New England Journal of Medicine and Science Translational Medicine.
April 2012 – Emily Whitehead, a 7-year-old with advanced acute lymphoblastic leukemia (ALL), becomes the first pediatric patient to receive CTL019 at CHOP.
August 2012 – Penn enters exclusive licensing agreement with Novartis to ramp up CAR therapy research, development, and commercialization.
December 2012 – Whitehead, now in remission for seven months, is featured on front page of New York Times. First two CLL patients remain cancer free.
December 2013 – Penn and CHOP researchers present data on first children and young adults and adults with ALL treated with CTL019: 25 out of 27 achieve complete remission.
July 2014 – FDA grants CTL019 its Breakthrough Therapy designation for the treatment of relapsed and refractory adult and pediatric ALL, a step intended to expedite its development and review.
December 2014 – Penn and CHOP researchers present latest pediatric CTL019 trial results, with 90 percent of ALL patients achieving complete remission. Global trial in ALL pediatric patients begins.
February 2016 – Novartis-Penn Center for Advanced Cellular Therapeutics opens its doors.
December 2016 – Penn and CHOP researchers present results from global ALL trial with 68 children and young adults: 82 percent achieve complete remission.
July 2017 – FDA panel unanimously recommends approval of CTL019.
August 2017 – FDA approves CTL019 therapy for treatment of advanced ALL in children and young adults. Novartis files for FDA approval of therapy for non-Hodgkin’s lymphoma.
“People advised me to think carefully about working with Carl because they said the work he was doing was high-risk and unlikely to be successful,” said Michael Milone, MD, PhD, GME’02, an associate professor of Pathology and Laboratory Medicine, who joined June’s lab in 2003 as a postdoc and helped develop a CAR T cell designed to find the CD19 protein expressed on B cells. “Happy to prove them wrong!”
By 2009, the team, which by then included David Porter, MD, director of Blood and Marrow Transplantation in the ACC, was ready for human testing of that CAR T cell, which became known as CART19 and later, as CTL019. The National Institutes of Health had declined to fund the work several times over the years, but help from private funders allowed the researchers to now conduct a small trial—just three patients. Out of options to treat aggressive chronic lymphocytic leukemia (CLL), these three Penn patient-pioneers said yes to trying one more thing.
A billion or so of their T cells were removed, reprogrammed with a modified, harmless HIV virus and taught to seek out that CD19 protein on cancer cells, and then infused back into their bodies to multiply and attack.
A year later, results from that trial—two of the three patients experienced complete remissions of their disease, and a third had a partial response—published in the New England Journal of Medicine and Science Translational Medicine grabbed people's attention. Headlines the next day read “'Huge' Results Raise Hope for Cancer Breakthrough” and “Immune System, Loaded with Remade T-cells, Vanquishes Cancer.” Calls and emails from more than 5,000 patients and desperate family members poured in to the research team, asking if the therapy was ready to help them, too. And the news caught the pharmaceutical industry's eye.
By 2012, June and his team, in close partnership with the Center for Technology Transfer (now the Penn Center for Innovation), formed an alliance with global giant Novartis to accelerate research, development, and commercialization of CAR therapies. Trials in adults and pediatric patients from Children's Hospital of Philadelphia (CHOP) with another blood cancer known as acute lymphoblastic leukemia (ALL) also got underway, with Stephan Grupp, MD, PhD, director of the Cancer Immunotherapy Frontier Program at CHOP and the Novotny Professor of Pediatrics at Penn, taking the clinical trial helm at CHOP. Noelle Frey, MD, an assistant professor of Hematology-Oncology at Penn, joined Porter to lead the adult trials.
“These patients in general had a life expectancy of three months, and 90 percent of them had complete remission,” June said. “It was just spectacular.”
Success of the pediatric trial led to a global trial for advanced ALL that began in 2015 at 25 centers around the world. The results were equally spectacular: Of 68 children and young adults, 52 patients achieved complete remission.
Verge of Approval
Six months after researchers published those results, in July 2017, Tom Whitehead, the father of Emily Whitehead, Grupp’s patient at CHOP and the first pediatric patient to receive CTL019, stood before an FDA panel in Washington, D.C., imploring them to recommend the drug’s approval. Emily, who was near death on her seventh birthday, has since been cancer free for over five years. “We believe that when this treatment is approved, it will save thousands of children’s lives around the world,” he told them.
The committee reviewed the data and said yes, in a unanimous vote. Forty-nine days later, the therapy, marketed by Novartis as Kymriah, officially became approved. Now, patients with ALL up to age 25 who have exhausted all other options can receive it at roughly 30 centers across the country, including Penn and CHOP. That’s about 600 patients per year. In the aftermath of the approval, questions about costs of the therapy remained a part of the public discussion. But on August 30, the focus was on celebration of this historic moment.
Back at Penn’s Perelman Center, June was now walking through the crowd like an esteemed conductor heading to his orchestra. Vonderheide stepped down from the coffee stand, and June took his place. He kept it short, too.
“Today, the cancer world has changed forever,” he said. “And I will never forget it.”
Cheers erupted from the crowd.
Talk to immunotherapy researchers around Penn's campus, and they'll likely say the same thing: It's just getting started.
“We are driven by the desire to make these types of therapies as widely available and applicable as possible,” said Robert Vonderheide, MD, DPhil, director of the Abramson Cancer Center. “We're looking justifiably at ramping up the scale of this to never before seen dimensions because it's working…it's time for these therapies to become mainstay.”
Getting to this point did not happen quickly or alone, of course. It took time and visionary funders, not to mention an infrastructure buildup and the right industry partner to move the first chimeric antigen receptor (CAR) T cell therapy from the bench to the clinic.
“Much of the [investments in the therapy] were unheard of when we started…15 to 20 years ago,” said Kevin Mahoney, executive vice president and chief administrative officer for the University of Pennsylvania Health System. “We were ahead of the curve.”
Support from the Abramson family and Barbara and Edward Netter's foundation, Alliance for Cancer Gene Therapy, as well as the Leukemia & Lymphoma Society, helped get Carl June's cell therapy lab and production facility up and running in the early 2000s and his first CAR clinical trial open in 2010.
“When the first patient results were published in the summer of 2011 we were inundated almost immediately by expressions of extreme interest from the biopharmaceutical industry, the venture capital community and independent entrepreneurs,” said John Swartley, associate vice provost for research and managing director of the Penn Center for Innovation.
As a result, within a decade, the early philanthropic commitments had paid off. Penn had formed an exclusive licensing agreement with the global pharmaceutical company Novartis to ramp up CAR research and development. Next came the Penn-Novartis Center for Advanced Cellular Therapeutics, a state-of-the-art, 30,000-square foot facility above the Perelman Center for Advanced Medicine, that upped Penn's capacity to investigate new uses for the technology, conduct clinical trials, and hire researchers.
That alliance has undoubtedly taken the institution into a new era of commercialization for cellular therapies, and solidified its position at the center of “Cellacon Valley,” a nickname coined at Penn for the bustling, cell and gene therapy hub that is Philadelphia.
It is a position not sustained by just one industry partnership, but by the university's capacity to forge multiple connections and collaborations to develop discoveries into commercial therapies.
“The best way for us to make connections with the [biotech and pharmaceutical companies] are with assets that we excel at,” Mahoney said. “And cell gene therapy is something the Children's Hospital of Philadelphia and Penn are international leaders in.”
Collaborations with other biotech companies researching cellular and gene therapies in cancer and other diseases, such as Celgene and Biogen, have since materialized, as did the partnership with the two-year-old Parker Institute for Cancer Immunotherapy. The $250 million effort brings together scientists from six other medical schools and cancer centers, as well as industry partners. It's an unprecedented move from the inventor of the music-sharing program Napster, with an ambitious, underlying goal: expedite discoveries into the clinic.
“These teams enable us to work outside our own comfort zone, and tackle problems we wouldn't otherwise do,” said June, who serves as the director of the Parker Institute at Penn. “It allows us to recruit new scientists and promote the careers of some junior scientists and faculty. It's early on, but so far, it's enabling some interesting trials that would not have been here otherwise.”
Altogether, Penn now has over 40 clinical trials investigating cellular therapies in a host of both blood and solid cancers and other diseases. And trials are what attract outsiders— “good, human clinical data,” Mahoney said—making them a priority area for investment and growth in the eyes of Penn Medicine leadership.
So is sprouting new companies. Penn's entrepreneurial ecosystem—shaped by the Penn Center for Innovation and its UPstart program—has helped both senior and junior faculty navigate the waters of business development and jumpstart their ventures. June's company, Tmunity, which focuses on different CAR T cells and other engineered T cell therapies, and CARMA, from Saar Gill, MD, PhD, an assistant professor of Hematology-Oncology, which puts CARs into another type of immune cells, macrophages, are just two examples.
“The explosion of commercial interest in cell and gene therapy over the last decade has been driven in large part by the monumental scientific and clinical discoveries and developments made by groundbreaking faculty leaders at Penn such as Carl June and Jim Wilson,” Swartley said.
Patient Number One
After Alison Loren, MD, delivered the news to Bill Ludwig that his body was free of leukemia, he lay down in his bed in the Hospital of the University of Pennsylvania, looked around the room, and let the doctor's words sink in.
After an hour, he walked out to the nurses' station. “Has Dr. Loren been on this floor this morning?” he asked. She had checked in with them on her way to his room, the nurses said. “She didn't see you?” they asked.
“Oh yeah, she saw me,” he said. “I was just making sure that I remembered it correctly. Because I could be hallucinating.”
But this time, he wasn't. After weeks of chaos—fevers and chills, hallucinations, legs swelled up to three times their size, he had ended up in the intensive care unit. But now his oncologist, Loren, delivered this good news. It was the chimeric antigen receptor (CAR) T cells that had sent his immune system into cataclysmic overdrive, and they had been doing their job all along: finding his B-cell chronic lymphocytic leukemia (CLL) and destroying it. Five and a half pounds of cancer were wiped out in less than a month.
Ludwig would forever be known as the first person to be successfully treated with a cellular therapy designed to hunt down and kill cancer cells with his own immune system.
“I'm looking for [extending life by] a day, a week, or a month, and here they are telling me I don't have cancer,” Ludwig said. “It was just like someone told you, 'You won the lottery.'”
It had been an arduous, nearly 10-year path to get to this unprecedented result. Diagnosed with CLL in early 2001, Ludwig spent the better part of that decade undergoing round after round of different chemotherapies that ultimately stopped working. He didn't qualify for a bone marrow transplant. And a clinical trial at the National Institutes of Health in Bethesda, Md., proved fruitless for him. In early 2010, he found himself back at HUP under Loren's care, and seemingly out of options.
That's when she brought up an experimental therapy from the team led by Carl June.
“[Penn] had kept me alive for nine years. They needed someone to go into a clinical trial,” Ludwig said. “Why not?”
He received his first infusion on Tuesday, Aug. 3, 2010. Two others followed that week. Then the chaos ensued that sent him to intensive care. But initially, no one was sure what was happening to him.
“This was brand new territory and we didn't know what to expect,” said David Porter, MD, director of Blood and Marrow Transplantation in the Abramson Cancer Center, and a clinical leader on the CAR team. “And he was getting sicker, and I will freely admit that I was convinced he had pneumonia.”
Researchers would later discover that the billion engineered T cells placed back in Ludwig's body grew to a trillion and went on a war path to kill his B cells. All the symptoms his body had experienced were the casualties from that all-out attack. It's called cytokine release syndrome.
“The elation when he started getting better, and you realize that his leukemia is rapidly disappearing is incredible,” Porter said. “You start becoming a little more convinced that the illness period really did have something to do with the T cells, and it wasn't an infection.”
Not one, but two bone marrow biopsies showed no sign of cancer cells, and his lymph nodes now appeared normal sized on an X-ray. This was the news that Loren delivered in the aftermath of Ludwig's three-week ordeal.
Back from the nurses' station, Ludwig waited for his wife, Darla. “She walked in and I told her,” said Ludwig, his voice cracking. “We just hugged each other. And we both cried.”
The next day, they left the hospital.
That was seven and a half years ago. Ludwig remains in remission and in good health, enjoying each day with Darla, their kids, and their kids' kids, traveling around the country in their RV or just being at home.
“I know it's a cliché, but everything's precious,” said Ludwig, now 72 and retired from his career as a corrections officer. “I just keep thinking of the things that I would have missed… seeing granddaughters in college and watching grandsons grow up.”
There's profound gratitude and emotion in Ludwig's voice when he talks of his experience at Penn—and everything that has unfolded with the “living drug" since.
After Ludwig, over 330 more adults (and counting) would go onto be treated with CTL019 therapy at Penn. His trial also paved the way for the clinical trials in children and young adults with acute lymphoblastic leukemia (ALL) that ultimately led to the therapy's approval.
In a way, he went along on that journey.
He remembers crying—“like a baby”— in his living room watching NBC's Nightly News when they featured the story of Emily Whitehead, the first child to successfully be treated with CTL019 at the Children's Hospital of Philadelphia. He's thankful to have met Doug Olson, the other patient who had a complete response to the therapy in 2010 and remains well today, and others whose lives were saved or improbably extended by the therapy, when attending a 2013 ceremony where June and his team received the Philadelphia Award.
And when he found out the therapy had been approved—via a Facebook post from his daughter—he was overwhelmed with excitement, mostly over what's to come.
“Hopefully there is no end to the cancers that ultimately the immune system will be able to eliminate,” Ludwig said. “Let's hope this is the beginning of something large that maybe future generations will take for granted.”
The Next Generation
Researchers have only just begun to write the book on immunotherapy and already the pages are filling up fast. Penn's personalized cellular therapy for leukemia is only one of its chapters.
“We have plans in almost any kind of cancer you can think of,” said Carl June, MD, director of Penn's Center for Cellular Immunotherapies.
The same therapy that proved itself in pediatric and young adult advanced leukemia patients has shown its power in trials for multiple myeloma and non-Hodgkin's lymphoma. In a recent New England Journal of Medicine study, a team led by Stephen Schuster, MD, director of the Lymphoma Program, showed that up to 71 percent of adult non-Hodgkin's lymphoma patients who didn't respond to conventional therapies or relapsed had a complete response with the CAR T cells known as CTL019.
The trajectory is strikingly familiar: powerful data from a Penn trial of patients with otherwise intractable cancers, a U.S. Food and Drug Administration Breakthrough Therapy designation that helped fast-track the leukemia approval, and an equally impressive global trial. This story could very well unfold like the last.
Engineered CAR T cells can do wonders in blood cancer patients, but there is still a cadre of people who don't respond. “The idea of combining different approaches with the CAR T cells to help them work better is very logical,” said David Porter, MD, director of Blood and Marrow Transplantation. “And early experiences show that it's very promising.” In a pilot trial, eight out of 10 patients with chronic lymphocytic leukemia receiving the drug ibrutinib had a complete response after being infused with CAR T cells known as CTL119. The drug, Porter said, makes the T cells more functional and the cancer cells easier to kill.
More combination trials, some with the hot immunotherapy drugs, known as checkpoint inhibitors, are also underway at Penn and Children's Hospital of Philadelphia.
The biggest challenge CARs face now is the solid tumor. The so-called tumor microenvironment, the normal cells and blood vessels that surround and feed a tumor, puts up a tough fight that's keeping these engineered cells out of the tumor to do their job.
In a brain tumor trial led by Donald O'Rourke, MD, an associate professor of Neurosurgery, cells called CART-EGFRvIII T cells have made their way to brain tumors—and elicited a few promising responses—but they're triggering an immunosuppressive response that's undermining the approach.
Newer trials for melanoma and triple negative breast cancer have also begun, as has a prostate cancer trial led by Naomi Haas, MD, director of the Abramson Cancer Center's Prostate and Kidney Cancer Program, that targets a prostate-specific membrane antigen—CART-PSMA for short.
A Different Target, and Epigenetic Approach, for Pancreatic Cancer
An engineered T cell called CAR-meso has shown the most promise in solid tumors. Instead of targeting the proteins found on B cells, CAR-meso goes after mesothelin, an antigen on mesothelial cells that line a lot of the body's cavities and organs. It's also overexpressed in lung, mesothelioma, ovarian, and pancreatic tumors, making it an ideal target for an engineered T cell. Early trials have proven it's up to the task, and now a trio of investigators is pushing it further with a unique genetics approach to better understand why some respond and others don't, under a Stand Up to Cancer grant for pancreatic cancer.
They want to know: Could epigenetic changes in the tumor and T cells be behind the variability in patient response? If so, perhaps existing drugs that target such changes could somehow make the CARs more potent and release the brakes that tumors put on the immune system. Linked to several cancers, epigenetic factors can turn a gene on or off, without changing the underlying DNA sequence. The all-star team is co-led by E. John Wherry, PhD, director of Penn's Institute for Immunology, Shelley L. Berger, PhD, director of Penn's Epigenetics Institute, and June.
“This Stand Up to Cancer grant is bringing together scientists with different expertise and knowledge: Carl works on immunotherapy. I'm an epigenetic scientist. John is a T cell biologist,” Berger said. “The advances are amazing when you get people together. The speed of the advance is so much greater.”
Another engineered cancer-fighting immune cell—known as CARMA—stands out because it's not a T cell, rather a macrophage, another type of white blood cell known to flock to solid tumors. Saar Gill, MD, PhD, saw that as an opportunity.
“We reasoned a cell that is already predisposed to trafficking into the solid tumor, like the macrophage, might be a good one to genetically engineer and actually make it a cancer killer instead of what it normally does, which is act as an accomplice to help the tumor grow,” Gill said.
A study from last year showed it's working, and Gill's lab has spun the technology into a company, CARMA Therapeutics, that aims to get it into solid tumor clinical trials sometime in 2019.
Researchers are also thinking outside the cancer box.
Mouse studies from Michael Milone, MD, PhD, Aimee Payne, MD, PhD, an associate professor of Dermatology, and their colleagues, have shown that chimeric autoantibody receptor, or CAAR, T cells can destroy the rogue immune cells that make antibodies that cause the blistering skin autoimmune disease known as pemphigus vulgaris (PV), while sparing the good ones.
This is an important finding because if they can engineer a CAR T cell to attack rogue immune cells, they can likely make them for other autoimmune diseases and perhaps even for patients who suffer some types of immune rejection after an organ transplant, Milone said. A clinical trial in PV is slated to begin this year.
It will join nearly 240 other clinical trials exploring engineered CAR cell therapies at institutions around the world. So far, at Penn and CHOP, more than 450 patients have been treated with some type of engineered cell therapy.
“There are very few places in the world that have comparable resources to what Penn has in the cellular therapy space," Milone said. “We have a huge team that runs the gamut, from basic science to translational medicine... It's the place to do it with efficiency.”
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