Right now, there are more than 100,000 people in the United States on the waiting list for a lifesaving kidney transplant. Only a fraction of them will get one this year — in 2015, only 11,216 people received a kidney from a deceased donor, according to the Organ Procurement and Transplantation Network. Another 5,075 people received a kidney from a living donor. But even for those fortunate patients who got the kidney they needed, the journey to good health is far from over.

To prevent their immune system from rejecting the donated organ, all transplant recipients must take a mixture of toxic immunosuppressive drugs every day for the rest of their lives. These drugs come with serious side effects — including increased risk for infection, high blood pressure, diabetes, heart disease and even cancer — and sometimes they don’t even work. (About 20 percent of kidney transplants will fail within three years.) But these drugs may not always be a necessity thanks to research spearheaded at Northwestern Medicine’s Comprehensive Transplant Center.

“We’re trying to reduce or eliminate entirely the need for drug-based immunosuppression, which is imperfect, costly and not without side effects,” says Joseph Leventhal, MD, PhD, ’97 GME, the center’s surgical director of kidney and pancreas transplantation.

Stem Cells Trick Immune System

Leventhal and colleagues have pioneered two innovative cell-based approaches to induce immune tolerance in transplant recipients. Their objective: to wean patients off immunosuppressive medication a year after surgery. The first approach involves transplanting a batch of the living donor’s stem cells along with the organ. The cells trick the recipient’s immune system into accepting the organ as its own, instead of fighting it off as it would other foreign invaders, like a virus or bacteria.

“The goal of this work is to induce a state called chimerism, where donor and recipient stem cells peacefully coexist within the recipient and establish a dual immune system that tolerates the kidney,” explains Leventhal, who is also Fowler McCormick Professor in Surgery at Feinberg and a transplant surgeon in the Kovler Organ Transplantation Center at Northwestern Memorial Hospital.

Joseph Leventhal, MD, PhD, '97 GME

Joseph Leventhal, MD, PhD, ’97 GME

Investigators have enrolled 40 patients in an ongoing phase II clinical trial at Northwestern that began in 2009 to test this stem cell protocol. So far, they’ve treated 31 patients and successfully withdrawn all immunosuppressive drugs in 20 of them. Remarkably, the study is the first to achieve this feat in mismatched, unrelated donor-recipient pairs.

Ideally, an organ donor and recipient should match on multiple levels to avoid rejection and achieve a long-lasting transplant. In addition to being blood type compatible, they should have the same human leukocyte antigens (HLAs), protein markers on cells that help regulate the immune response. Only identical twins are a perfect match, though siblings can match partially. Northwestern’s stem cell-based strategy for inducing tolerance works for HLA mismatches, improving the odds that transplants from unrelated donor-recipient pairs will thrive in the long term.

The process begins about a month before transplantation. Bone marrow derived stem cells are collected from the donor’s blood through a minimally-invasive process called pheresis. The cells are sent to the lab of collaborator Suzanne Ildstad, MD, director of the Institute for Cellular Therapeutics at the University of Louisville in Kentucky. Manipulated to facilitate safe transplantation, the cells are then cryopreserved. A week before scheduled surgery, the recipient undergoes conditioning — low doses of radiation and chemotherapy — to prepare the immune system to receive the donor stem cell infusion, which happens a day after the organ is transplanted.

“It’s all very carefully choreographed and planned,” says Leventhal, acknowledging a major caveat to this approach: currently, it only works for living donor transplants. “Two-thirds of kidney transplants done every year are not from living donors. When a kidney suddenly becomes available from a deceased donor, we don’t have a week’s time to enrich the donor stem cells and condition the recipient.”

Leventhal says that Northwestern, currently the only active clinical site for this research, will be the lead center for a phase III trial testing the stem cell protocol. He anticipates the trial to launch in 2017, with the support of a $12 million grant from pharmaceutical company Novartis.

No Fire Drill Required

The larger population of deceased donor organ recipients may benefit from a second strategy under investigation at Northwestern Medicine. Rather than relying on a transfusion of donor-derived stem cells, this approach involves expanding the recipient’s own regulatory T-cells. These cells, called T-regs for short, suppress the immune system so it doesn’t attack the body’s own healthy tissue and have been shown to prevent transplant rejection.

The process involves collecting blood from a patient months or years before he or she receives a kidney transplant. From this sample, white blood cells including T-regs are separated out and sent to Northwestern Medicine’s Mathews Center for Cellular Therapy, where a few million cells are multiplied into a few billion cells to be re-infused into the patient after transplantation. Leventhal named the strategy TRACT (T-regs for adoptive cell transfer).

“Instead of suppressing the immune system with drugs, we’re trying to rebalance it with more regulation,” he explains. “As we envision it, the moment a patient is told he or she will need a transplant, we can collect these T-regs and freeze them. Then when it’s time to do the transplant, we can thaw them out for expansion and infusion. There’s not a fire drill aspect that exists with other cell-based approaches.”

Boosting a recipient's regulatory T-cells can prevent the immune system from attacking healthy kidney tissue.

Boosting a recipient’s regulatory T-cells can prevent the immune system from attacking healthy kidney tissue.

In 2014, Leventhal and principal investigator Anton Skaro, MD, PhD, ’07 GME, received a $500,000 grant from the Woman’s Board of Northwestern Memorial Hospital to conduct the first ever clinical trial testing the safety of expanded T-regs in kidney transplant patients. This June, they will present the positive results from the nine patients who participated in the study. They hope to initiate a phase II trial with 120 patients later this year to explore both safety and efficacy but first must secure funding for such an ambitious study.

“It is extremely costly to manufacture the cells for cell-based therapies. A dose of T-regs costs $40,000 to $50,000,” acknowledges Leventhal. He recently formed a company called TRACT Therapeutics to develop the technology for kidneys and other solid organ transplants, as well as to pursue applications for treating autoimmune diseases like inflammatory bowel disease and rheumatoid arthritis.

Feeling Normal

The benefits of withdrawing a patient from immunosuppression are twofold: It can potentially make a transplant last longer and it can improve a patient’s quality of life. Currently, a successful kidney transplant lasts 15 to 20 years at best. Realistically, about half of all recipients will need a second or third transplant in their lives.

“We want it to be one organ transplant for life,” says Leventhal. “We hope to make this possible by eliminating kidney transplant failure due to poor control of the immune system or the side effects of immunosuppressive drugs. Every time this works, we’ll have one less person coming back onto the waiting list for an organ.”

Last fall, Northwestern Medicine hosted an international workshop sponsored by the National Institutes of Health on immune tolerance in organ transplantation. The event highlighted the academic medical center’s leadership in a burgeoning field of medicine.

“Immune tolerance following transplantation has been the holy grail for several decades, but only in the last few years have we made the types of discoveries that make it a reality,” says Michael Abecassis, MD, MBA, director of the Comprehensive Transplant Center.

Abecassis is also chief of Organ Transplantation in Feinberg’s Department of Surgery and division chief of the Kovler Organ Transplantation Center, where surgeons transplant more than 400 organs each year.

“Six years ago, we made a strategic decision that it was time to make immune tolerance happen clinically,” he says. “We were extremely fortunate to be the first to achieve this elusive goal in mismatched kidney transplant recipients, and we believe that we have cracked the door open to broader applications of this approach.”

As for the quality of life benefits that immune tolerance brings, Leventhal points to a poignant case involving two sisters with the same genetic kidney disease. Both needed a transplant. One sister participated in the stem cell trial and has now been off immunosuppression for years. The other, ineligible for the trial, continues to take the drugs.

“My patient says she feels normal. Although the initial process was arduous, she now doesn’t feel like she’s had a transplant,” says Leventhal. “Her sister, meanwhile, has to worry about being in the sun, what’s in the water when she goes to the beach or who she’s sitting around during cold and flu season because her immune system is suppressed. These sisters live very different lives.”