Short Story Contest Winner: "The Gerry Program"
It's an odd sensation knowing you're going to die, but it was a feeling Gerry Ferguson had become relatively acquainted with over the past two years. What most perplexed the terminally ill, he observed, was not the concept of death so much as the continuation of all other life.
Gerry's secret project had been in the works for two years now, ever since they found the growth.
Who will mourn me when I'm gone? What trait or idiosyncrasy will people most recall? Will I still be talked of, 100 years from now?
But Gerry didn't worry about these questions. He was comfortable that his legacy would live on, in one form or another. From his cozy flat in the west end of Glasgow, Gerry had managed to put his affairs in order and still find time for small joys.
Feeding the geese in summer at the park just down from his house, reading classics from the teeming bookcase in the living room, talking with his son Michael on Skype. It was Michael who had first suggested reading some of the new works of non-fiction that now littered the large oak desk in Gerry's study.
He was just finishing 'The Master Algorithm' when his shabby grandfather clock chimed six o'clock. Time to call Michael. Crammed into his tiny study, Gerry pulled his computer's webcam close and waved at Michael's smiling face.
"Hi Dad! How're you today?"
"I'm alright, son. How're things in sunny Australia?"
"Hot as always. How's things in Scotland?"
"I'd 'ave more chance gettin' a tan from this computer screen than I do goin' out there."
Michael chuckled. He's got that hearty Ferguson laugh, Gerry thought.
"How's the project coming along?" Michael asked. "Am I going to see it one of these days?"
"Of course," grinned Gerry, "I designed it for you."
Gerry's secret project had been in the works for two years now, ever since they found the growth. He had decided it was better not to tell Michael. He would only worry.
The two men chatted for hours. They discussed Michael's love life (or lack thereof), memories of days walking in the park, and their shared passion, the unending woes of Rangers Football Club. It wasn't until Michael said his goodbyes that Gerry noticed he'd been sitting in the dark for the best part of three hours, his mesh curtains casting a dim orange glow across the room from the street light outside. Time to get back to work.
*
Every night, Gerry sat at his computer, crawling forums, nourishing his project, feeding his knowledge and debating with other programmers. Even at age 82, Gerry knew more than most about algorithms. Never wanting to feel old, and with all the kids so adept at this digital stuff, Gerry figured he should give the Internet a try too. Besides, it kept his brain active and restored some of the sociability he'd lost in the previous decades as old friends passed away and the physical scope of his world contracted.
This night, like every night, Gerry worked away into the wee hours. His back would ache come morning, but this was the only time he truly felt alive these days. From his snug red brick home in Scotland, Gerry could share thoughts and information with strangers from all over the world. It truly was a miracle of modern science!
*
The next day, Gerry woke to the warm amber sun seeping in between a crack in the curtains. Like every morning, his thoughts took a little time to come into focus. Instinctively his hand went to the other side of the bed. Nobody there. Of course; she was gone. Rita, the sweetest woman he'd ever known. Four years this spring, God rest her soul.
Puttering around the cramped kitchen, Gerry heard a knock at the door. Who could that be? He could see two women standing in the hallway, their bodies contorted in the fisheye glass of the peephole. One looked familiar, but Gerry couldn't be sure. He fiddled with the locks and pulled the door open.
"Hi Gerry. How are you today?"
"Fine, thanks," he muttered, still searching his mind for where he'd seen her face before.
Noting the confusion in his eyes, the woman proffered a hand. "Alice, Alice Corgan. I pop round every now and again to check on you."
It clicked. "Ah aye! Come in, come in. Lemme get ya a cuppa." Gerry turned and shuffled into the flat.
As Gerry set about his tiny kitchen, Alice called from the living room, "This is Mandy. She's a care worker too. She's going to pay you occasional visits if that's alright with you."
Gerry poked his head around the doorway. "I'll always welcome a beautiful young lady in ma home. Though, I've tae warn you I'm a married man, so no funny business." He winked and ducked back into the kitchen.
Alice turned to Mandy with a grin. "He's a good man, our Gerry. You'll get along just fine." She lowered her voice. "As I said, with the Alzheimer's, he has to be reminded to take his medication, but he's still mostly self-sufficient. We installed a medi-bot to remind him every day and dispense the pills. If he doesn't respond, we'll get a message to send someone over."
Mandy nodded and scribbled notes in a pad.
"When I'm gone, Michael will have somethin' to remember me by."
"Also, and this is something we've been working on for a few months now, Gerry is convinced he has something…" her voice trailed off. "He thinks he has cancer. Now, while the Alzheimer's may affect his day-to-day life, it's not at a stage where he needs to be taken into care. The last time we went for a checkup, the doctor couldn't find any sign of cancer. I think it stems from--"
Gerry shouted from the other room: "Does the young lady take sugar?"
"No, I'm fine thanks," Mandy called back.
"Of course you don't," smiled Gerry. "Young lady like yersel' is sweet enough."
*
The following week, Mandy arrived early at Gerry's. He looked unsure at first, but he invited her in.
Sitting on the sofa nurturing a cup of tea, Alice tried to keep things light. "So what do you do in your spare time, Gerry?"
"I've got nothing but spare time these days, even if it's running a little low."
"Do you have any hobbies?"
"Yes actually." Gerry smiled. "I'm makin' a computer program."
Alice was taken aback. She knew very little about computers herself. "What's the program for?" she asked.
"Well, despite ma appearance, I'm no spring chicken. I know I don't have much time left. Ma son, he lives down in Australia now, he worked on a computer program that uses AI - that's artificial intelligence - to imitate a person."
Alice still looked confused, so Gerry pressed on.
"Well, I know I've not long left, so I've been usin' this open source code to make ma own for when I'm gone. I've already written all the code. Now I just have to add the things that make it seem like me. I can upload audio, text, even videos of masel'. That way, when I'm gone, Michael will have somethin' to remember me by."
Mandy sat there, stunned. She had no idea anybody could do this, much less an octogenarian from his small, ramshackle flat in Glasgow.
"That's amazing Gerry. I'd love to see the real thing when you're done."
"O' course. I mean, it'll take time. There's so much to add, but I'll be happy to give a demonstration."
Mandy sat there and cradled her mug. Imagine, she thought, being able to preserve yourself, or at least some basic caricature of yourself, forever.
*
As the weeks went on, Gerry slowly added new shades to his coded double. Mandy would leaf through the dusty photo albums on Gerry's bookcase, pointing to photos and asking for the story behind each one. Gerry couldn't always remember but, when he could, the accompanying stories were often hilarious, incredible, and usually a little of both. As he vividly recounted tales of bombing missions over Burma, trips to the beach with a young Michael and, in one particularly interesting story, giving the finger to Margaret Thatcher, Mandy would diligently record them through a Dictaphone to be uploaded to the program.
Gerry loved the company, particularly when he could regale the young woman with tales of his son Michael. One day, as they sat on the sofa flicking through a box of trinkets from his days as a travelling salesman, Mandy asked why he didn't have a smartphone.
He shrugged. "If I'm out 'n about then I want to see the world, not some 2D version of it. Besides, there's nothin' on there for me."
Alice explained that you could get Skype on a smartphone: "You'd be able to talk with Michael and feed the geese at the park at the same time," she offered.
Gerry seemed interested but didn't mention it again.
"Only thing I'm worried about with ma computer," he remarked, "is if there's another power cut and I can't call Michael. There's been a few this year from the snow 'n I hate not bein' able to reach him."
"Well, if you ever want to use the Skype app on my phone to call him you're welcome," said Mandy. "After all, you just need to add him to my contacts."
Gerry was flattered. "That's a relief, knowing I won't miss out on calling Michael if the computer goes bust."
*
Then, in early spring, just as the first green buds burst forth from the bare branches, Gerry asked Mandy to come by. "Bring that Alice girl if ya can - I know she's excited to see this too."
The next day, Mandy and Alice dutifully filed into the cramped study and sat down on rickety wooden chairs brought from the living room for this special occasion.
An image of Gerry, somewhat younger than the man himself, flashed up on the screen.
With a dramatic throat clearing, Gerry opened the program on his computer. An image of Gerry, somewhat younger than the man himself, flashed up on the screen.
The room was silent.
"Hiya Michael!" AI Gerry blurted. The real Gerry looked flustered and clicked around the screen. "I forgot to put the facial recognition on. Michael's just the go-to name when it doesn't recognize a face." His voice lilted with anxious excitement. "This is Alice," Gerry said proudly to the camera, pointing at Alice, "and this is Mandy."
AI Gerry didn't take his eyes from real Gerry, but grinned. "Hello, Alice. Hiya Mandy." The voice was definitely his, even if the flow of speech was slightly disjointed.
"Hi," Alice and Mandy stuttered.
Gerry beamed at both of them. His eyes flitted between the girls and the screen, perhaps nervous that his digital counterpart wasn't as polished as they'd been expecting.
"You can ask him almost anything. He's not as advanced as the ones they're making in the big studios, but I think Michael will like him."
Alice and Mandy gathered closer to the monitor. A mute Gerry grinned back from the screen. Sitting in his wooden chair, the real Gerry turned to his AI twin and began chattering away: "So, what do you think o' the place? Not bad eh?"
"Oh aye, like what you've done wi' it," said AI Gerry.
"Gerry," Alice cut in. "What did you say about Michael there?"
"Ah, I made this for him. After all, it's the kind o' thing his studio was doin'. I had to clear some space to upload it 'n show you guys, so I had to remove Skype for now, but Michael won't mind. Anyway, Mandy's gonna let me Skype him from her phone."
Mandy pulled her phone out and smiled. "Aye, he'll be able to chat with two Gerry's."
Alice grabbed Mandy by the arm: "What did you tell him?" she whispered, her eyes wide.
"I told him he can use my phone if he wants to Skype Michael. Is that okay?"
Alice turned to Gerry, who was chattering away with his computerized clone. "Gerry, we'll just be one second, I need to discuss something with Mandy."
"Righto," he nodded.
Outside the room, Alice paced up and down the narrow hallway.
Mandy could see how flustered she was. "What's wrong? Don't you like the chatbot? I think it's kinda c-"
"Michael's dead," Alice spluttered.
"What do you mean? He talks to him all the time."
Alice sighed. "He doesn't talk to Michael. See, a few years back, Michael found out he had cancer. He worked for this company that did AI chatbot stuff. When he knew he was dying he--" she groped in the air for the words-- "he built this chatbot thing for Gerry, some kind of super-advanced AI. Gerry had just been diagnosed with Alzheimer's and I guess Michael was worried Gerry would forget him. He designed the chatbot to say he was in Australia to explain why he couldn't visit."
"That's awful," Mandy granted, "but I don't get what the problem is. I mean, surely he can show the AI Michael his own chatbot?"
"No, because you can't get the AI Michael on Skype. Michael just designed the program to look like Skype."
"But then--" Mandy went silent.
"Michael uploaded the entire AI to Gerry's computer before his death. Gerry didn't delete Skype. He deleted the AI Michael."
"So… that's it? He-he's gone?" Mandy's voice cracked. "He can't just be gone, surely he can't?"
The women stood staring at each other. They looked to the door of the study. They could still hear Gerry, gabbing away with his cybercopy.
"I can't go back in there," muttered Mandy. Her voice wavered as she tried to stem the misery rising in her throat.
Alice shook her head and paced the floor. She stopped and stared at Mandy with grim resignation. "We don't have a choice."
When they returned, Gerry was still happily chatting away.
"Hiya girls. Ya wanna ask my handsome twin any other questions? If not, we could get Michael on the phone?"
Neither woman spoke. Gerry clapped his hands and turned gaily to the monitor again: "I cannae wait for ya t'meet him, Gerry. He's gonna be impressed wi' you."
Alice clasped her hands to her mouth. Tears welled in the women's eyes as they watched the old man converse with his digital copy. The heat of the room seemed to swell, becoming insufferable. Mandy couldn't take it anymore. She jumped up, bolted to the door and collapsed against a wall in the hallway. Alice perched on the edge of her seat in a dumb daze, praying for the floor to open and swallow the contents of the room whole.
Oblivious, Gerry and his echo babbled away, the blue glow of the screen illuminating his euphoric face. "Just wait until y'meet him Gerry, just wait."
A blood test may catch colorectal cancer before it's too late
Soon it may be possible to find different types of cancer earlier than ever through a simple blood test.
Among the many blood tests in development, researchers announced in July that they have developed one that may screen for early-onset colorectal cancer. The new potential screening tool, detailed in a study in the journal Gastroenterology, represents a major step in noninvasively and inexpensively detecting nonhereditary colorectal cancer at an earlier and more treatable stage.
In recent years, this type of cancer has been on the upswing in adults under age 50 and in those without a family history. In 2021, the American Cancer Society's revised guidelines began recommending that colorectal cancer screenings with colonoscopy begin at age 45. But that still wouldn’t catch many early-onset cases among people in their 20s and 30s, says Ajay Goel, professor and chair of molecular diagnostics and experimental therapeutics at City of Hope, a Los Angeles-based nonprofit cancer research and treatment center that developed the new blood test.
“These people will mostly be missed because they will never be screened for it,” Goel says. Overall, colorectal cancer is the fourth most common malignancy, according to the U.S. Centers for Disease Control and Prevention.
Goel is far from the only one working on this. Dozens of companies are in the process of developing blood tests to screen for different types of malignancies.
Some estimates indicate that between one-fourth and one-third of all newly diagnosed colorectal cancers are early-onset. These patients generally present with more aggressive and advanced disease at diagnosis compared to late-onset colorectal cancer detected in people 50 years or older.
To develop his test, Goel examined publicly available datasets and figured out that changes in novel microRNAs, or miRNAs, which regulate the expression of genes, occurred in people with early-onset colorectal cancer. He confirmed these biomarkers by looking for them in the blood of 149 patients who had the early-onset form of the disease. In particular, Goel and his team of researchers were able to pick out four miRNAs that serve as a telltale sign of this cancer when they’re found in combination with each other.
The blood test is being validated by following another group of patients with early-onset colorectal cancer. “We have filed for intellectual property on this invention and are currently seeking biotech/pharma partners to license and commercialize this invention,” Goel says.
He’s far from the only one working on this. Dozens of companies are in the process of developing blood tests to screen for different types of malignancies, says Timothy Rebbeck, a professor of cancer prevention at the Harvard T.H. Chan School of Public Health and the Dana-Farber Cancer Institute. But, he adds, “It’s still very early, and the technology still needs a lot of work before it will revolutionize early detection.”
The accuracy of the early detection blood tests for cancer isn’t yet where researchers would like it to be. To use these tests widely in people without cancer, a very high degree of precision is needed, says David VanderWeele, interim director of the OncoSET Molecular Tumor Board at Northwestern University’s Lurie Cancer Center in Chicago.
Otherwise, “you’re going to cause a lot of anxiety unnecessarily if people have false-positive tests,” VanderWeele says. So far, “these tests are better at finding cancer when there’s a higher burden of cancer present,” although the goal is to detect cancer at the earliest stages. Even so, “we are making progress,” he adds.
While early detection is known to improve outcomes, most cancers are detected too late, often after they metastasize and people develop symptoms. Only five cancer types have recommended standard screenings, none of which involve blood tests—breast, cervical, colorectal, lung (smokers considered at risk) and prostate cancers, says Trish Rowland, vice president of corporate communications at GRAIL, a biotechnology company in Menlo Park, Calif., which developed a multi-cancer early detection blood test.
These recommended screenings check for individual cancers rather than looking for any form of cancer someone may have. The devil lies in the fact that cancers without widespread screening recommendations represent the vast majority of cancer diagnoses and most cancer deaths.
GRAIL’s Galleri multi-cancer early detection test is designed to find more cancers at earlier stages by analyzing DNA shed into the bloodstream by cells—with as few false positives as possible, she says. The test is currently available by prescription only for those with an elevated risk of cancer. Consumers can request it from their healthcare or telemedicine provider. “Galleri can detect a shared cancer signal across more than 50 types of cancers through a simple blood draw,” Rowland says, adding that it can be integrated into annual health checks and routine blood work.
Cancer patients—even those with early and curable disease—often have tumor cells circulating in their blood. “These tumor cells act as a biomarker and can be used for cancer detection and diagnosis,” says Andrew Wang, a radiation oncologist and professor at the University of Texas Southwestern Medical Center in Dallas. “Our research goal is to be able to detect these tumor cells to help with cancer management.” Collaborating with Seungpyo Hong, the Milton J. Henrichs Chair and Professor at the University of Wisconsin-Madison School of Pharmacy, “we have developed a highly sensitive assay to capture these circulating tumor cells.”
Even if the quality of a blood test is superior, finding cancer early doesn’t always mean it’s absolutely best to treat it. For example, prostate cancer treatment’s potential side effects—the inability to control urine or have sex—may be worse than living with a slow-growing tumor that is unlikely to be fatal. “[The test] needs to tell me, am I going to die of that cancer? And, if I intervene, will I live longer?” says John Marshall, chief of hematology and oncology at Medstar Georgetown University Hospital in Washington, D.C.
Ajay Goel Lab
A blood test developed at the University of Texas MD Anderson Cancer Center in Houston helps predict who may benefit from lung cancer screening when it is combined with a risk model based on an individual’s smoking history, according to a study published in January in the Journal of Clinical Oncology. The personalized lung cancer risk assessment was more sensitive and specific than the 2021 and 2013 U.S. Preventive Services Task Force criteria.
The study involved participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial with a minimum of a 10 pack-year smoking history, meaning they smoked 20 cigarettes per day for ten years. If implemented, the blood test plus model would have found 9.2 percent more lung cancer cases for screening and decreased referral to screening among non-cases by 13.7 percent compared to the 2021 task force criteria, according to Oncology Times.
The conventional type of screening for lung cancer is an annual low-dose CT scan, but only a small percentage of people who are eligible will actually get these scans, says Sam Hanash, professor of clinical cancer prevention and director of MD Anderson’s Center for Global Cancer Early Detection. Such screening is not readily available in most countries.
In methodically searching for blood-based biomarkers for lung cancer screening, MD Anderson researchers developed a simple test consisting of four proteins. These proteins circulating in the blood were at high levels in individuals who had lung cancer or later developed it, Hanash says.
“The interest in blood tests for cancer early detection has skyrocketed in the past few years,” he notes, “due in part to advances in technology and a better understanding of cancer causation, cancer drivers and molecular changes that occur with cancer development.”
However, at the present time, none of the blood tests being considered eliminate the need for screening of eligible subjects using established methods, such as colonoscopy for colorectal cancer. Yet, Hanash says, “they have the potential to complement these modalities.”
Study Shows “Living Drug” Can Provide a Lasting Cure for Cancer
Doug Olson was 49 when he was diagnosed with chronic lymphocytic leukemia, a blood cancer that strikes 21,000 Americans annually. Although the disease kills most patients within a decade, Olson’s case progressed more slowly, and courses of mild chemotherapy kept him healthy for 13 years. Then, when he was 62, the medication stopped working. The cancer had mutated, his doctor explained, becoming resistant to standard remedies. Harsher forms of chemo might buy him a few months, but their side effects would be debilitating. It was time to consider the treatment of last resort: a bone-marrow transplant.
Olson, a scientist who developed blood-testing instruments, knew the odds. There was only a 50 percent chance that a transplant would cure him. There was a 20 percent chance that the agonizing procedure—which involves destroying the patient’s marrow with chemo and radiation, then infusing his blood with donated stem cells—would kill him. If he survived, he would face the danger of graft-versus-host disease, in which the donor’s cells attack the recipient’s tissues. To prevent it, he would have to take immunosuppressant drugs, increasing the risk of infections. He could end up with pneumonia if one of his three grandchildren caught a sniffle. “I was being pushed into a corner,” Olson recalls, “with very little room to move.”
Soon afterward, however, his doctor revealed a possible escape route. He and some colleagues at the University of Pennsylvania’s Abramson Cancer Center were starting a clinical trial, he said, and Olson—still mostly symptom-free—might be a good candidate. The experimental treatment, known as CAR-T therapy, would use genetic engineering to turn his T lymphocytes (immune cells that guard against viruses and other pathogens) into a weapon against cancer.
In September 2010, technicians took some of Olson’s T cells to a laboratory, where they were programmed with new molecular marching orders and coaxed to multiply into an army of millions. When they were ready, a nurse inserted a catheter into his neck. At the turn of a valve, his soldiers returned home, ready to do battle.
“I felt like I’d won the lottery,” Olson says. But he was only the second person in the world to receive this “living drug,” as the University of Pennsylvania investigators called it. No one knew how long his remission would last.
Three weeks later, Olson was slammed with a 102-degree fever, nausea, and chills. The treatment had triggered two dangerous complications: cytokine release syndrome, in which immune chemicals inflame the patient’s tissues, and tumor lysis syndrome, in which toxins from dying cancer cells overwhelm the kidneys. But the crisis passed quickly, and the CAR-T cells fought on. A month after the infusion, the doctor delivered astounding news: “We can’t find any cancer in your body.”
“I felt like I’d won the lottery,” Olson says. But he was only the second person in the world to receive this “living drug,” as the University of Pennsylvania investigators called it. No one knew how long his remission would last.
An Unexpected Cure
In February 2022, the same cancer researchers reported a remarkable milestone: the trial’s first two patients had survived for more than a decade. Although Olson’s predecessor—a retired corrections officer named Bill Ludwig—died of COVID-19 complications in early 2021, both men had remained cancer-free. And the modified immune cells continued to patrol their territory, ready to kill suspected tumor cells the moment they arose.
“We can now conclude that CAR-T cells can actually cure patients with leukemia,” University of Pennsylvania immunologist Carl June, who spearheaded the development of the technique, told reporters. “We thought the cells would be gone in a month or two. The fact that they’ve survived 10 years is a major surprise.”
Even before the announcement, it was clear that CAR-T therapy could win a lasting reprieve for many patients with cancers that were once a death sentence. Since the Food and Drug Administration approved June’s version (marketed as Kymriah) in 2017, the agency has greenlighted five more such treatments for various types of leukemia, lymphoma, and myeloma. “Every single day, I take care of patients who would previously have been told they had no options,” says Rayne Rouce, a pediatric hematologist/oncologist at Texas Children’s Cancer Center. “Now we not only have a treatment option for those patients, but one that could potentially be the last therapy for their cancer that they’ll ever have to receive.”
Immunologist Carl June, middle, spearheaded development of the CAR-T therapy that gave patients Bill Ludwig, left, and Doug Olson, right, a lengthy reprieve on their terminal cancer diagnoses.
Penn Medicine
Yet the CAR-T approach doesn’t help everyone. So far, it has only shown success for blood cancers—and for those, the overall remission rate is 30 to 40 percent. “When it works, it works extraordinarily well,” says Olson’s former doctor, David Porter, director of Penn’s blood and bone marrow transplant program. “It’s important to know why it works, but it’s equally important to know why it doesn’t—and how we can fix that.”
The team’s study, published in the journal Nature, offers a wealth of data on what worked for these two patients. It may also hold clues for how to make the therapy effective for more people.
Building a Better T Cell
Carl June didn’t set out to cure cancer, but his serendipitous career path—and a personal tragedy—helped him achieve insights that had eluded other researchers. In 1971, hoping to avoid combat in Vietnam, he applied to the U.S. Naval Academy in Annapolis, Maryland. June showed a knack for biology, so the Navy sent him on to Baylor College of Medicine. He fell in love with immunology during a fellowship researching malaria vaccines in Switzerland. Later, the Navy deployed him to the Fred Hutchinson Cancer Research Center in Seattle to study bone marrow transplantation.
There, June became part of the first research team to learn how to culture T cells efficiently in a lab. After moving on to the National Naval Medical Center in the ’80s, he used that knowledge to combat the newly emerging AIDS epidemic. HIV, the virus that causes the disease, invades T cells and eventually destroys them. June and his post-doc Bruce Levine developed a method to restore patients’ depleted cell populations, using tiny magnetic beads to deliver growth-stimulating proteins. Infused into the body, the new T cells effectively boosted immune function.
In 1999, after leaving the Navy, June joined the University of Pennsylvania. His wife, who’d been diagnosed with ovarian cancer, died two years later, leaving three young children. “I had not known what it was like to be on the other side of the bed,” he recalls. Watching her suffer through grueling but futile chemotherapy, followed by an unsuccessful bone-marrow transplant, he resolved to focus on finding better cancer treatments. He started with leukemia—a family of diseases in which mutant white blood cells proliferate in the marrow.
Cancer is highly skilled at slipping through the immune system’s defenses. T cells, for example, detect pathogens by latching onto them with receptors designed to recognize foreign proteins. Leukemia cells evade detection, in part, by masquerading as normal white blood cells—that is, as part of the immune system itself.
June planned to use a viral vector no one had tried before: HIV.
To June, chimeric antigen receptor (CAR) T cells looked like a promising tool for unmasking and destroying the impostors. Developed in the early ’90s, these cells could be programmed to identify a target protein, and to kill any pathogen that displayed it. To do the programming, you spliced together snippets of DNA and inserted them into a disabled virus. Next, you removed some of the patient’s T cells and infected them with the virus, which genetically hijacked its new hosts—instructing them to find and slay the patient’s particular type of cancer cells. When the T cells multiplied, their descendants carried the new genetic code. You then infused those modified cells into the patient, where they went to war against their designated enemy.
Or that’s what happened in theory. Many scientists had tried to develop therapies using CAR-T cells, but none had succeeded. Although the technique worked in lab animals, the cells either died out or lost their potency in humans.
But June had the advantage of his years nurturing T cells for AIDS patients, as well as the technology he’d developed with Levine (who’d followed him to Penn with other team members). He also planned to use a viral vector no one had tried before: HIV, which had evolved to thrive in human T cells and could be altered to avoid causing disease. By the summer of 2010, he was ready to test CAR-T therapy against chronic lymphocytic leukemia (CLL), the most common form of the disease in adults.
Three patients signed up for the trial, including Doug Olson and Bill Ludwig. A portion of each man’s T cells were reprogrammed to detect a protein found only on B lymphocytes, the type of white blood cells affected by CLL. Their genetic instructions ordered them to destroy any cell carrying the protein, known as CD19, and to multiply whenever they encountered one. This meant the patients would forfeit all their B cells, not just cancerous ones—but regular injections of gamma globulins (a cocktail of antibodies) would make up for the loss.
After being infused with the CAR-T cells, all three men suffered high fevers and potentially life-threatening inflammation, but all pulled through without lasting damage. The third patient experienced a partial remission and survived for eight months. Olson and Ludwig were cured.
Learning What Works
Since those first infusions, researchers have developed reliable ways to prevent or treat the side effects of CAR-T therapy, greatly reducing its risks. They’ve also been experimenting with combination therapies—pairing CAR-T with chemo, cancer vaccines, and immunotherapy drugs called checkpoint inhibitors—to improve its success rate. But CAR-T cells are still ineffective for at least 60 percent of blood cancer patients. And they remain in the experimental stage for solid tumors (including pancreatic cancer, mesothelioma, and glioblastoma), whose greater complexity make them harder to attack.
The new Nature study offers clues that could fuel further advances. The Penn team “profiled these cells at a level where we can almost say, ‘These are the characteristics that a T cell would need to survive 10 years,’” says Rouce, the physician at Texas Children’s Cancer Center.
One surprising finding involves how CAR-T cells change in the body over time. At first, those that Olson and Ludwig received showed the hallmarks of “killer” T-cells (also known as CD8 cells)—highly active lymphocytes bent on exterminating every tumor cell in sight. After several months, however, the population shifted toward “helper” T-cells (or CD4s), which aid in forming long-term immune memory but are normally incapable of direct aggression. Over the years, the numbers swung back and forth, until only helper cells remained. Those cells showed markers suggesting they were too exhausted to function—but in the lab, they were able not only to recognize but to destroy cancer cells.
June and his team suspect that those tired-looking helper cells had enough oomph to kill off any B cells Olson and Ludwig made, keeping the pair’s cancers permanently at bay. If so, that could prompt new approaches to selecting cells for CAR-T therapy. Maybe starting with a mix of cell types—not only CD8s, but CD4s and other varieties—would work better than using CD8s alone. Or perhaps inducing changes in cell populations at different times would help.
Another potential avenue for improvement is starting with healthier cells. Evidence from this and other trials hints that patients whose T cells are more robust to begin with respond better when their cells are used in CAR-T therapy. The Penn team recently completed a clinical trial in which CLL patients were treated with ibrutinib—a drug that enhances T-cell function—before their CAR-T cells were manufactured. The response rate, says David Porter, was “very high,” with most patients remaining cancer-free a year after being infused with the souped-up cells.
Such approaches, he adds, are essential to achieving the next phase in CAR-T therapy: “Getting it to work not just in more people, but in everybody.”
Doug Olson enjoys nature - and having a future.
Penn Medicine
To grasp what that could mean, it helps to talk with Doug Olson, who’s now 75. In the years since his infusion, he has watched his four children forge careers, and his grandkids reach their teens. He has built a business and enjoyed the rewards of semi-retirement. He’s done volunteer and advocacy work for cancer patients, run half-marathons, sailed the Caribbean, and ridden his bike along the sun-dappled roads of Silicon Valley, his current home.
And in his spare moments, he has just sat there feeling grateful. “You don’t really appreciate the effect of having a lethal disease until it’s not there anymore,” he says. “The world looks different when you have a future.”
This article was first published on Leaps.org on March 24, 2022.