New Hope for Organ Transplantation: Life Without Anti-Rejection Drugs
Rob Waddell dreaded getting a kidney transplant. He suffers from a genetic condition called polycystic kidney disease that causes the uncontrolled growth of cysts that gradually choke off kidney function. The inherited defect has haunted his family for generations, killing his great grandmother, grandmother, and numerous cousins, aunts and uncles.
But he saw how difficult it was for his mother and sister, who also suffer from this condition, to live with the side effects of the drugs they needed to take to prevent organ rejection, which can cause diabetes, high blood pressure and cancer, and even kidney failure because of their toxicity. Many of his relatives followed the same course, says Waddell: "They were all on dialysis, then a transplant and ended up usually dying from cancers caused by the medications."
When the Louisville native and father of four hit 40, his kidneys barely functioned and the only alternative was either a transplant or the slow death of dialysis. But in 2009, when Waddell heard about an experimental procedure that could eliminate the need for taking antirejection drugs, he jumped at the chance to be their first patient. Devised by scientists at the University of Louisville and Northwestern University, the innovative approach entails mixing stem cells from the live kidney donor with that of the recipient to create a hybrid immune system, known as a chimera, that would trick the immune system and prevent it from attacking the implanted kidney.
The procedure itself was done at Northwestern Memorial Hospital in Chicago, using a live kidney donated by a neighbor of Waddell's, who camped out in Chicago during his recovery. Prior to surgery, Waddell underwent a conditioning treatment that consisted of low dose radiation and chemotherapy to weaken his own immune system and make room for the infusion of stem cells.
"The low intensity chemo and radiation conditioning regimen create just enough space for the donor stem cells to gain a foothold in the bone marrow and the donor's immune system takes over," says Dr. Joseph Levanthal, the transplant surgeon who performed the operation and director of kidney and pancreas transplantation at Northwestern University Feinberg School of Medicine. "That way the recipient develops an immune system that doesn't see the donor organ as foreign."
"As a surgeon, I saw what my patients had to go through—taking 25 pills a day, dying at an early age from heart disease, or having a 35% chance of dying every year on dialysis."
A week later, Waddell had the kidney transplant. The following day, he was infused with a complex cellular cocktail that included blood-forming stem cells derived from his donor's bone marrow mixed what are called tolerance inducing facilitator cells (FCs); these cells help the foreign stem cells get established in the recipient's bone marrow.
Over the course of the following year, he was slowly weaned off of antirejection medications—a precaution in case the procedure didn't work—and remarkably, hasn't needed them since. "I felt better than I had in decades because my kidneys [had been] degrading," recalls Waddell, now 54 and a CPA for a global beverage company. And what's even better is that this new approach offers hope for one of his sons who has also inherited the disorder.
Kidney transplants are the most frequent organ transplants in the world and more than 23,000 of these procedures were done in the United States in 2019, according to the United Network for Organ Sharing. Of this, about 7,000 operations are done annually using live organ donors; the remainder use organs from people who are deceased. Right now, this revolutionary new approach—as well as a similar strategy formulated by Stanford University scientists--is in the final phase of clinical trials. Ultimately, this research may pave the way towards realizing the holy grail of organ transplantation: preventing organ rejection by creating a tolerant state in which the recipient's immune system is compatible with the donor, which would eliminate the need for a lifetime of medications.
"As a surgeon, I saw what my patients had to go through—taking 25 pills a day, dying at an early age from heart disease, or having a 35% chance of dying every year on dialysis," says Dr. Suzanne Ildstad, a transplant surgeon and director of the Institute for Cellular Therapeutics at the University of Louisville, whose discovery of facilitator cells were the basis for this therapeutic platform. Ildstad, who has spent more than two decades searching for a better way, says, "This is something I have worked for my entire life."
The Louisville group uses a combination of chemo and radiation to replace the recipient's immune and blood forming cells with that of the donor. In contrast, the Stanford protocol involves harvesting the donor's blood stem cells and T-cells, which are the foot soldiers of the immune system that fight off infections and would normally orchestrate the rejection of the transplanted organ. Their transplant recipients undergo a milder form of "conditioning" that only radiates discrete parts of the body and selectively targets the recipient's T-cells, creating room for both sets of T-cells, a strategy these researchers believe has a better safety profile and less of a chance of rejection.
"We try to achieve immune tolerance by a true chimerism," says Dr. Samuel Strober, a professor of medicine for immunology and rheumatology at Stanford University and a leader of this research team. "The recipients immune system cells are maintained but mixed in the blood with that of the donor."
Studies suggest both approaches work. In a 2018 clinical trial conducted by Talaris Therapeutics, a Louisville-based biotech founded by Ildstad, 26 of 37 (70%) of the live donor kidney transplant recipients no longer need immunosuppressants. Last fall, Talaris began the final phase of clinical tests that will eventually encompass more than 120 such patients.
The Stanford group's cell-based immunotherapy, which is called MDR-101 and is sponsored by the South San Francisco biotech, Medeor Therapeutics, has had similar results in patients who received organs from live donors who were either well matched, such as one from siblings, meaning they were immunologically identical, or partially matched; Talaris uses unrelated donors where there is only a partial match.
In their 2020 clinical trial of 51 patients, 29 were fully matched and 22 were a partial match; 22 of the fully matched recipients didn't need antirejection drugs and ten of the partial matches were able to stop taking some of these medications without rejection. "With our fully matched, roughly 80% have been completely off drugs up to 14 years later," says Strober, "and reducing the number of drugs from three to one [in the partial matches] means you have far fewer side effects. The goal is to get them off of all drugs."
But these protocols are limited to a small number of patients—living donor kidney recipients. As a consequence, both teams are experimenting with ways to broaden their approach so they can use cadaver organs from deceased donors, with human tests planned in the coming year. Here's how that would work: after the other organs are removed from a deceased donor, stem cells are harvested from the donor's vertebrae in the spinal column and then frozen for storage.
"We do the transplant and give the patient a chance to recover and maintain them on drugs," says Ildstad. "Then we do the tolerance conditioning at a later stage."
If this strategy is successful, it would be a genuine game changer, and open the door to using these protocols for transplanting other cadaver organs, including the heart, lungs and liver. While the overall procedure is complex and costly, in the long run it's less expensive than repeated transplant surgeries, the cost of medications and hospitalizations for complications caused by the drugs, or thrice weekly dialysis treatments, says Ildstad.
And she adds, you can't put a price tag on the vast improvement in quality of life.
It looked like only good things were ahead of Taylor Schreiber in 2010.
Schreiber had just finished his PhD in cancer biology and was preparing to return to medical school to complete his degree. He also had been married a year, and, like any young newlyweds up for adventure, he and his wife Nicki decided to go backpacking in the Costa Rican rainforest.
He was 31, and it was April Fool's Day—but no joke.
During the trip, he experienced a series of night sweats and didn't think too much about it. Schreiber hadn't been feeling right for a few weeks and assumed he had a respiratory infection. Besides, they were sleeping outdoors in a hot, tropical jungle.
But the night sweats continued even after he got home, leaving his mattress so soaked in the morning it was if a bucket of water had been dumped on him overnight. On instinct, he called one of his thesis advisors at the Sylvester Comprehensive Cancer Center in Florida and described his symptoms.
Dr. Joseph Rosenblatt didn't hesitate. "It sounds like Hodgkins. Come see me tomorrow," he said.
The next day, Schreiber was diagnosed with Stage 3b Hodgkin Lymphoma, which meant the disease was advanced. He was 31, and it was April Fool's Day—but no joke.
"I was scared to death," he recalls. "[Thank] goodness it's one of those cancers that is highly treatable. But being 31 years old and all of a sudden being told that you have a 30 percent of mortality within the next two years wasn't anything that I was relieved about."
For Schreiber, the diagnosis was a personal and professional game-changer. He couldn't work in the hospital as a medical student while undergoing chemotherapy, so he wound up remaining in his post-doctorate lab for another two years. The experience also solidified his decision to apply his scientific and medical knowledge to drug development.
Today, now 39, Schreiber is co-founder, director and chief scientific officer of Shattuck Labs, an immuno-oncology startup, and the developer of several important research breakthroughs in the field of immunotherapy.
After his diagnosis, he continued working full-time as a postdoc, while undergoing an aggressive chemotherapy regimen.
"These days, I look back on [my cancer] and think it was one of the luckiest things that ever happened to me," he says. "In medical school, you learn what it is to treat people and learn about the disease. But there is nothing like being a patient to teach you another side of medicine."
Medicine first called to Schreiber when his maternal grandfather was dying from lung cancer complications. Schreiber's uncle, a radiologist at the medical center where his grandfather was being treated, took him on a tour of his department and showed him images of the insides of his body on an ultrasound machine.
Schreiber was mesmerized. His mother was a teacher and his dad sold windows, so medicine was not something to which he had been routinely exposed.
"This weird device was like looking through jelly, and I thought that was the coolest thing ever," he says.
The experience led him to his first real job at the Catholic Medical Center in Manchester, NH, then to a semester-long internship program during his senior year in high school in Concord Hospital's radiology department.
"This was a great experience, but it also made clear that there was not any meaningful way to learn or contribute to medicine before you obtained a medical degree," says Schreiber, who enrolled in Bucknell College to study biology.
Bench science appealed to him, and he volunteered in Dr. Jing Zhou's nephrology department lab at the Harvard Institutes of Medicine. Under the mentorship of one of her post-docs, Lei Guo, he learned a range of critical techniques in molecular biology, leading to their discovery of a new gene related to human polycystic kidney disease and his first published paper.
Before his cancer diagnosis, Schreiber also volunteered in the lab of Dr. Robert "Doc" Sackstein, a world-renowned bone marrow transplant physician and biomedical researcher, and his interests began to shift towards immunology.
"He was just one of those dynamic people who has a real knack for teaching, first of all, and for inspiring people to want to learn more and ask hard questions and understand experimental medicine," Schreiber says.
It was there that he learned the scientific method and the importance of incorporating the right controls in experiments—a simple idea, but difficult to perform well. He also made what Sackstein calls "a startling discovery" about chemokines, which are signaling proteins that can activate an immune response.
As immune cells travel around our bodies looking for potential sources of infection or disease, they latch onto blood vessel walls and "sniff around" for specific chemical cues that indicate a source of infection. Schreiber and his colleagues designed a system that mimics the blood vessel wall, allowing them to define which chemical cues efficiently drive immune cell migration from the blood into tissues.
Schreiber received the best overall research award in 2008 from the National Student Research Foundation. But even as Schreiber's expertise about immunology grew, his own immune system was about to fight its hardest battle.
After his diagnosis, he continued working full-time as a postdoc in the lab of Eckhard Podack, then chair of the microbiology and immunology department at the University of Miami's Leonard M. Miller School of Medicine.
At the same time, Schreiber began an aggressive intravenous chemotherapy regimen of adriamycin, bleomycin, vincristine and dacarbazine, every two weeks, for 6 months. His wife Nicki, an obgyn, transferred her residency from Emory University in Atlanta to Miami so they could be together.
"It was a weird period. I mean, it made me feel good to keep doing things and not just lay idle," he said. "But by the second cycle of chemo, I was immunosuppressed and losing my hair and wore a face mask walking around the lab, which I was certainly self-conscious. But everyone around me didn't make me feel like an alien so I just went about my business."
The experience reinforced his desire to stay in immunology, especially after having taken the most toxic chemotherapies.
He stayed home the day after chemo when he felt his worst, then rested his body and timed exercise to give the drugs the best shot of targeting sick cells (a strategy, he says, that "could have been voodoo"). He also drank "an incredible" amount of fluids to help flush the toxins out of his system.
Side effects of the chemo, besides hair loss, included intense nausea, diarrhea, a loss of appetite, some severe lung toxicities that eventually resolved, and incredible fatigue.
"I've always been a runner, and I would even try to run while I was doing chemo," he said. "After I finished treatment, I would go literally 150 yards and just have to stop, and it took a lot of effort to work through it."
The experience reinforced his desire to stay in immunology, especially after having taken the most toxic chemotherapies.
"They worked, and I could tolerate them because I was young, but people who are older can't," Schreiber said. "The whole field of immunotherapy has really demonstrated that there are effective therapies out there that don't come with all of the same toxicities as the original chemo, so it was galvanizing to imagine contributing to finding some of those."
Schreiber went on to complete his MD and PhD degrees from the Sheila and David Fuente Program in Cancer Biology at the Miller School of Medicine and was nominated in 2011 as a Future Leader in Cancer Research by the American Association for Cancer Research. He also has numerous publications in the fields of tumor immunology and immunotherapy.
Sackstein, who was struck by Schreiber's enthusiasm and "boundless energy," predicts he will be a "major player in the world of therapeutics."
"The future for Taylor is amazing because he has the capacity to synthesize current knowledge and understand the gaps and then ask the right questions to establish new paradigms," said Sackstein, currently dean of the Herbert Wertheim College of Medicine at Florida International University. "It's a very unusual talent."
Since then, he has devoted his career to developing innovative techniques aimed at unleashing the immune system to attack cancer with less toxicity than chemotherapy and better clinical results—first, at a company called Heat Biologics and then at Pelican Therapeutics.
His primary work at Austin, Texas-based Shattuck is aimed at combining two functions in a single therapy for cancer and inflammatory diseases, blocking molecules that put a brake on the immune system (checkpoint inhibitors) while also stimulating the immune system's cancer-killing T cells.
The company has one drug in clinical testing as part of its Agonist Redirected Checkpoint (ARC) platform, which represents a new class of biological medicine. Two others are expected within the next year, with a pipeline of more than 250 drug candidates spanning cancer, inflammatory, and metabolic diseases.
Nine years after his own cancer diagnosis, Schreiber says it remains a huge part of his life, though his chances of a cancer recurrence today are about the same as his chances of getting newly diagnosed with any other cancer.
"I feel blessed to be in a position to help cancer patients live longer and could not imagine a more fulfilling way to spend my life," he says.
The Stunning Comeback of a Top Transplant Surgeon Who Got a New Heart at His Own Hospital
Having spent my working life as a transplant surgeon, it is the ultimate irony that I have now become a heart transplant patient. I knew this was a possibility since 1987, when I was 27 years old and I received a phone call from my sister-in-law telling me that my 35-year-old brother, Rich, had just died suddenly while water skiing.
Living from one heartbeat to the next I knew I had to get it right and nail my life—and in that regard my disease was a blessing.
After his autopsy, dots were connected and it was clear that the mysterious heart disease my father had died from when I was 15 years old was genetic. I was evaluated and it was clear that I too had inherited cardiomyopathy, a progressive weakening condition of the heart muscle that often leads to dangerous rhythm disturbances and sudden death. My doctors urged me to have a newly developed device called an implantable cardioverter-defibrillator (ICD) surgically placed in my abdomen and chest to monitor and shock my heart back into normal rhythm should I have a sudden cardiac arrest.
They also told me I was the first surgeon in the world to undergo an ICD implant and that having one of these devices would not be compatible with the life of a surgeon and I should change careers to something less rigorous. With the support of a mentor and armed with what the British refer to as my "bloody-mindedness," I refused to give up this dream of becoming a transplant surgeon. I completed my surgical training and embarked on my career.
What followed were periods of stability punctuated by near-death experiences. I had a family, was productive in my work, and got on with life, knowing that this was a fragile situation that could turn on its head in a moment. In a way, it made my decisions about how to spend my time and focus my efforts more deliberate and purposeful. Living from one heartbeat to the next I knew I had to get it right and nail my life—and in that regard my disease was a blessing.
In 2017 while pursuing my passion for the outdoors in a remote part of Patagonia, I collapsed from bacterial pneumonia and sepsis. Unknowingly, I had brought in my lungs one of those super-bugs that you read about from the hospital where I worked. Several days into the trip, the bacteria entered my blood stream and brought me as close to death as a human can get.
I lay for nearly 3 weeks in a coma on a stretcher in a tiny hospital in Argentina, septic and in cardiogenic shock before stabilizing enough to be evaced to NYU Langone Hospital, where I was on staff. I awoke helpless, unable to walk, talk, or swallow food or drink. It was a long shot but I managed to recover completely from this episode; after 3 months, I returned to work and the operating room. My heart rebounded, but never back to where it had been.
Then, on the eve of my mother's funeral, I arrested while watching a Broadway show, and this time my ICD failed to revive me. There was prolonged CPR that broke my ribs and spine and a final shock that recaptured my heart. It was literally a show stopper and I awoke to a standing ovation from the New York theatre audience who were stunned by my modern recreation of the biblical story of Lazarus, or for the more hip among them, my real-life rendition of the resurrection of Jon Snow at the end of season 5 of Game of Thrones.
Against the advice of my doctors, I attended my mom's funeral and again tried to regain some sense of normalcy. We discussed a transplant at this point but, believe it or not, there is such a scarcity of organs I was not yet "sick enough" to get enough priority to receive a heart. I had more surgery to supercharge my ICD so it would be more likely to save my life the next time -- and there would be a next time, I knew.
As a transplant surgeon, I have been involved in some important innovations to expand the number of organs available for transplantation.
Months later in Matera, Italy, where I was attending a medical meeting, I developed what is referred to as ventricular tachycardia storm. I had 4 cardiac arrests over a 3-hour period. With the first one, I fell on to a stone floor and split my forehead open. When I arrived at the small hospital it seemed like Patagonia all over again. One of the first people I met was a Catholic priest who gave me the Last Rights.
I knew now was the moment and so with the help of one of my colleagues who was at the meeting with me and the compassion of the Italian doctors who supplied my friend with resuscitation medications and left my IV in place, I signed out of the hospital against medical advice and boarded a commercial flight back to New York. I was admitted to the NYU intensive care unit and received a heart transplant 3 weeks later.
Now, what I haven't said is that as a transplant surgeon, I have been involved in some important innovations to expand the number of organs available for transplantation. I came to NYU in 2016 to start a new Transplant Institute which included inaugurating a heart transplant program. We hired heart transplant surgeons, cardiologists, and put together a team that unbeknownst to me at the time, would save my life a year later.
It gets even more interesting. One of the innovations that I had been involved in from its inception in the 1990s was using organs from donors at risk for transmitting viruses like HIV and Hepatitis C (Hep C). We popularized new ways to detect these viruses in donors and ensure that the risk was minimized as much as possible so patients in need of a life-saving transplant could utilize these organs.
When the opioid crisis hit hard about four years ago, there were suddenly a lot of potential donors who were IV drug users and 25 percent of them were known to be infected with Hep C (which is spread by needles). In 2018, 49,000 people died in the U.S. from drug overdoses. There were many more donors with Hep C than potential recipients who had previously been exposed to Hep C, and so more than half of these otherwise perfectly good organs were being discarded. At the same time, a new class of drugs was being tested that could cure Hep C.
I was at Johns Hopkins at the time and our team developed a protocol for using these Hep C positive organs for Hep C negative recipients who were willing to take them, even knowing that they were likely to become infected with the virus. We would then treat them after the transplant with this new class of drugs and in all likelihood, cure them. I brought this protocol with me to NYU.
When my own time came, I accepted a Hep C heart from a donor who overdosed on heroin. I became infected with Hep C and it was then eliminated from my body with 2 months of anti-viral therapy. All along this unlikely journey, I was seemingly making decisions that would converge upon that moment in time when I would arise to catch the heart that was meant for me.
Dr. Montgomery with his wife Denyce Graves, September 2019.
(Courtesy Montgomery)
Today, I am almost exactly one year post-transplant, back to work, operating, traveling, enjoying the outdoors, and giving lectures. My heart disease is gone; gone when my heart was removed. Gone also is my ICD. I am no longer at risk for a sudden cardiac death. I traded all that for the life of a transplant patient, which has its own set of challenges, but I clearly traded up. It is cliché, I know, but I enjoy every moment of every day. It is a miracle I am still here.