Pinning their hopes on a Penn gene therapy

Still groggy from painkillers, Maddie Major, 7, clutched her stuffed Pooh Bear and laid her head on her father's shoulder as he carried her to the hospital cafeteria.

Maddie, dad Tim, mom Robyn, and big sister Candace spent that February morning at Children's Hospital of Philadelphia, where a doctor extracted samples of the child's spinal fluid and bone marrow.

In a few days, the biopsies would reveal whether Maddie's leukemia had been wiped out by an experimental gene therapy made from her own white blood cells - crucial disease fighters called T cells.

Medical science has been trying for 40 years to harness the immune system to cure cancer, or at least turn it into a docile chronic disease. Excitement has invariably been followed by disappointment.

But after 30 months of testing in more than a dozen adults and children - patients with no conventional options left - worldwide excitement over the T cell therapy's unprecedented power continues to build. The treatment, developed at the University of Pennsylvania, has eradicated advanced blood cancers in mere weeks, and is being adapted to attack solid tumors including prostate, pancreatic, ovarian, and breast cancer.

Maddie's parents, who live in La Plata, Md., marveled that the unique therapy was a cakewalk compared with what she has been through since her diagnosis at age 3.

She has had thousands of doses of toxic chemotherapy. Head-to-toe radiation. Hundreds of blood transfusions. Life-threatening infections in her kidneys, liver, and brain. Months on life support in intensive care. An experimental cell therapy at the National Institutes of Health.

And still, "the beast," as her parents call Maddie's acute lymphoblastic leukemia, would not stay away.

During lunch in the cafeteria, Robyn Major said she was optimistic about the T cell therapy. She did not elaborate because Maddie - perked up and chowing down on pizza, spaghetti, and Fritos - knows more than a 7-year-old should about the limits of modern medicine.

"We've been to Children's National Medical Center in D.C., the NIH, and now here," Maddie said. "This is definitely the best."

She meant the food.

Acute lymphoblastic leukemia was a death sentence in the 1960s. Today, with potent chemotherapies and aggressive treatment of the cerebrospinal fluid, about 80 percent of the 3,000 children diagnosed annually in the United States are cured.

That still leaves many other kids like Madison Grace Major.

At birth, she became the darling hub in a blended family of five much older children. "She was our surprise," Robyn said.

One July day when Maddie was 3, a bruise appeared on her hip, no bigger than a pencil eraser. Within days, it spread until, Robyn recalled, "she looked like she'd been beaten with a broom handle."

Immature, wildly proliferating B cells were crowding out Maddie's normal blood cells, reducing her ability to form clots and fight infection.

Almost overnight, she went from talkative tot to intensive-care patient, battling organ failure, a bloodstream infection, and internal bleeding, plus cancer.

When she got off the ventilator, a valve was put on her tracheostomy hole so she could speak.

"She is curious about all the new things on her body," Robyn wrote in an online journal in September 2008, "so [a therapist] made her a Cabbage Patch doll that has a trach, a feeding tube, and a port, just like hers."

Maddie went home in November 2008 and began physical therapy to relearn to walk.

"She struggles so much to be like she used to be," Robyn wrote. "She says, 'Remember when I did fill-in-the-blank, before I had my tube?' "

That first year threatened to use up the $2 million lifetime cap on Robyn's health insurance through her job as an accounting manager.

Tim, meanwhile, lost his job as a mechanic because of the endless vigils at Children's National. He trained as a patient-care technician and got a job with health benefits - at that hospital.

In February 2010, four months after finishing 18 months of chemotherapy, Maddie relapsed.

Her doctors recommended a stem-cell transplant. They would destroy her immune system, then rebuild it using a donor's cells. The drastic option posed many risks, some fatal. But it was her best chance to beat the beast.

It worked.

Over the next year, Maddie and her family reveled in near-normalcy - her new hair, first grade, soccer, dance lessons, clothes shopping.

Then, in August 2012, she relapsed for the second time.

Producing the novel T cell therapy takes months. It involves siphoning the patient's T cells, tricking them to multiply outside the body, then slipping a gene into them so they recognize and kill B cells - the component that turns malignant in certain blood cancers.

This feat is the culmination of 20 years of research led by Penn gene-therapy pioneers Carl H. June and Bruce Levine.

From the start, the therapy has shown startling effectiveness. Normally, the goal of early trials is to see if a therapy is safe enough to keep testing.

But the results from the first three adult leukemia patients, published in August 2011, were so impressive that the drug giant Novartis rushed to partner with Penn in commercializing the technology. Two of those initial patients have been cancer-free for 21/2 years.

Three months ago, results from the first dozen patients were presented at a conference. Five became cancer-free; four had partial remissions. Only three did not get better.

"The use of genetically engineered T cells to treat cancer has been a holy grail of sorts in oncology," Cleveland Clinic blood cancer specialist Mikkael Sekeres told Oncology Times. "It is incredibly exciting that Dr. June and colleagues have demonstrated, at the very least, proof of [the concept]. This type of response rate is impressive."

The first pediatric patient, Emily Whitehead, 7, of Philipsburg, Pa., was riddled with leukemia in her brain, liver, spleen, kidneys, and bone marrow. Seventeen days after the T cell infusion, her cancer was gone.

Media coverage led desperate families around the world to contact Children's Hospital of Philadelphia. Nora Situm, 5, who came from Croatia last month, is now waiting for her T cells to be grown and modified.

"Five children have been treated," said Stephan Grupp, the lead pediatric oncologist. "At least 10 more are in some stage of evaluation for this treatment. We continue to be very encouraged by the results."

Maddie, Grupp acknowledged, was the fifth child.

Ironically, Robyn Major dismissed the T cell therapy as quackery when Facebook friends e-mailed her stories about Emily Whitehead in December. Maddie's options by then were grim to none.

Days later, Anne Angiolillo, Maddie's oncologist, called with exciting news: Maddie might qualify for an experimental gene therapy at Children's in Philadelphia.

Robyn was stunned: "I said, 'You mean that's real?' "

Chemotherapy and radiation damage cells, particularly fast-growing cells, malignant or healthy. It's an indiscriminate, one-size-fits-all approach.

The T cell therapy, in contrast, is individualized, and tricks the patient's immune system to do something it is not supposed to do: Launch a self-attack. Cancer, after all, is the patient's own tissue gone rogue.

This manipulation is risky - another reason cancer immunotherapy has proved so hard.

Emily was the first to have a catastrophically bad reaction to the therapy. She was in a coma, near death, when researchers gave her a new rheumatoid arthritis drug, hoping it would act as an antidote. Luckily, it did.

Maddie got a lower dose of T cells and had a more typical reaction - several days of pain, severe flulike symptoms, tremors, hallucinations.

"Exciting news," Robyn wrote Feb. 6. "Half of the cells in today's lab [results] were T cells! Those little cancer-killers are growing! And Dr. Grupp said that as sick as Maddie is, there is nothing critical."

Two days after Maddie's biopsy samples underwent ultrasensitive molecular analysis to search for cancer, Grupp texted Robyn: "Stone cold negative."

She promptly posted the news on Facebook with a photo of Maddie: "Guess who's cancer free??? This girl!!!"

Will the remission last, or be just another poignant respite? The doctors don't know.

However, they have identified a hallmark of early success: The bioengineered cells transform from killers into "memory" T cells, permanently programmed to go after their target.

"When we don't see B cells and still see a small number of T cells, that's good," Grupp said, "because they're still patrolling."

Tests show Maddie's T cells are on patrol.

or mmccullough@phillynews.com.