Inside CAR-T Cell Glioblastoma Surgery
January 4, 2017 | by Stephanie Smith
This piece is a vivid account of a brain surgery performed at City of Hope. The details may be disturbing for some readers.
Surgery for a patient in a brain cancer CAR-T cell therapy trial begins with a blur of activity. At the center is B., a 36-year-old man with glioblastoma, an often-fatal type of brain tumor. Lines are checked and secured. Overhead lights are positioned. B.’s eyes are taped shut. The flurry soon gives way to calm, and a more deliberate air settles in the OR.
On a white board is scrawled, in clipped medical terms, what will happen during the next hour and a half: “Craniotomy. Image stealth-guided for tumor. Resection left. Insertion catheter. Rickham reservoir.”
In short, a section of the protective layer of bone around the patient’s brain will be removed; a tumor on the left side of it will be excised with the help of a computer-generated brain mapping system; and a thin tube, attached to a tiny well, will be nestled in his brain tissue.
In two weeks, through these instruments will flow genetically modified T cells, called chimeric antigen receptors (CARs) — a type of immunotherapy designed to dampen the progression of microscopic tumor cells peppering B.’s brain.
B. is one of several participants in a breakthrough clinical trial for brain cancer at City of Hope. Early results of the trial — describing promising results using CAR-T cells for a 50-year-old patient with an aggressive brain cancer called glioblastoma multiforme — were published recently in the New England Journal of Medicine.
These are sketches of the surgery performed on B. in early November:
B.’s head lolls as Behnam Badie, M.D. director of the Brain Tumor Program at City of Hope, and a neurosurgery resident named Analiz Rodriguez, M.D., carefully position it in a vise. Badie, who will lead the surgery, stalks the operating room floor, first helping to position B.’s head, then glancing at a terminal transmitting images from a large, knobbed probe — resembling an old-fashioned TV antenna — being used by Rodriguez to map the patient’s brain. “It works like a GPS system,” explains Badie. “When we move the probe, it’ll show us where we are in the brain.”
He points to a small, glowing mass on the computer screen, viewable from various angles. It is a tumor in B.’s brain, pressing up against regions responsible for his ability to move the right side of his body, including his arm and leg. “He has been rapidly losing function the last two weeks,” said Badie, chief of the Division of Neurosurgery. “He could barely walk and he was falling frequently.”
Badie and Rodriguez begin numbing the area where they will enter the brain. Badie shaves B.’s head, then a nurse dabs antiseptic solution on a section of his scalp. A trickle of red-orange liquid drips down his head and onto the floor, and the acrid smell of alcohol fills the OR.
The surgeons gently cut and peel back a flap of skin covering B.’s head. The effect on the rest of his scalp is similar to how sheets gather and wrinkle on an unkempt bed. The sound of suction fills the room as metal clamps are positioned to prop open B.’s scalp.
A jagged section of bone, about the size of a trifolded dollar bill, is gently lifted from B.’s cranium. The process is relatively easy — the bone comes right out — since B. has had three previous operations. His brain is exposed. It is the dull color of clay. It pulsates rhythmically under the dura, a thin layer of tissue that acts as a buffer between the cranium and the brain (and the last thing separating the surgeons from B.’s brain tissue). They begin the meticulous process of cutting through the dura.
The surgeons gently lift and move aside the dura, then stuff small swatches of gauze into the small opening in B.’s head. They slide a thin probe into B.’s brain tissue. Badie, who up to this point has been murmuring instructions to staff around him, suddenly calls out in a loud voice, “Ready? We’re going to stimulate.”
What follows is a staccato back-and-forth between Badie and Dormel Abea, a neurodiagnostic technician responsible for administering an electrical current to the patient’s brain. This exchange helps determine the location of the “eloquent cortex,” an important area of the brain that controls motor, sensory and speech functions; and the surgical margin — how much tissue the surgeon can safely remove while avoiding damaging that critical area.
“We pass electric current down from the brain to B.’s hand and leg, which confirms the location of those fibers, which is really important,” said Badie. “So that gives me an idea of how far I can go after the tumor is removed.”
Badie places a pearl-colored wand on top of B.s’ exposed brain tissue. It is an ultrasound used to assign borders to B.’s tumor. Badie then removes a sliver of tumor tissue and hands it to a nurse, who calls out her intention to have it examined by a pathologist: “This is a frozen section. Left parietal glioma versus inflammation.” The room lights are dimmed as B. is slowly awakened out of his anesthesia-induced slumber. “B. we’re waking you up. How are you feeling,” asks the anesthesiologist. “Can you move your finger for me, your right hand?”
Badie calls out to Abea, “I’m going to stimulate the arm area again.” “On?” questions Abea. “Right side,” answers Badie. The exchange continues, with Badie calling out the various regions being stimulated: “Bilateral. Upper extremities.” The anesthesiologist continues to ask B. to move various parts of his body: “Just move your arm, your right arm,” he says. “Wiggle your toes. Perfect.”
Badie then joins the conversation with B. “Can you move your leg, B.? Your arm?” Then he asks a curious question: “Do you want to sing?” B., whose answers to questions up to this point had been tentative, begins to sing with surprising gusto. He belts out “Glory, Glory Hallelujah,” before moving on to Bill Withers’ “Ain’t No Sunshine.” His voice trails off a bit as he sings, “I know, I know, I know, I know…” and the mood lightens among the staff in the OR.
“B. mentioned that he wanted to sing during surgery and so I said, 'Let’s sing,'” said Badie. “We have fun with the patients, too. Sometimes they remember what happened in the operating room, sometimes they don’t.”
The anesthesiologist asks B. to move some more before playing music to accompany his singing. B.’s response to the soundtrack is an anesthesia-soaked “Oh yeah.” The juxtaposition is fascinating: As he sings, B. is unaware that the tumor that has been compromising his movement is poking out of his brain, and that surgeons are gently tugging at the mass, about the size of a dime. Rodriguez trims a piece of the tumor mass before asking a nurse, “Do you have the flask that goes to the lab?”
Music rings through the OR and B. continues to sing, albeit with less gusto: “La, la, la, la,” as he and the anesthesiologist continue their exchange. At this point, the tumor removal is nearly complete. Once removed, the mass of malignant cells —dangling from a pair of surgical tweezers — wiggles like a glob of pinkish jelly. Considering how much damage they can do, tumors look innocuous when outside the body. Badie instructs Rodriguez to cut the tumor in half.
The phone rings and the nurse who answers calls out, “Pathology is on the phone.” Rodriguez takes the call and announces to her colleagues, “High grade” to describe pathology’s findings on the tumor that was removed: prone to grow and spread quickly.
Badie tells the patient that they are done — “It looks good” — and that he will soon go back under anesthesia. B. responds by expressing his gratitude to Badie: “I love you, man,” he says, and then adds, “Are you sure you’re done?” “Yeah, we’re done,” Badie answers. “You sure? How much tumor is left?” Badie says, “I don’t see anything obvious left.” B. is grateful: “Dr. Badie if you need a Snickers bar, I’ll buy it.” Badie and others in the OR laugh. Two minutes later, B. is back under and Badie instructs a nurse to call the patient’s wife.
Rodriguez is stitching together B.’s dura while Badie prepares the tiny plastic catheter and small chamber that will later usher in his CAR-T cells. Badie then turns to the section of bone (craniotomy) that earlier covered B.’s brain, which has been soaking in a sterile bath, and begins drilling into it. He later positions the catheter and the craniotomy back into the open section on B.’s skull and screws it back into place. Nearby, two nurses count gauze and surgical instruments.
Badie and Rodriguez pull out the metal clamps that have been holding open B.’s scalp, then stitch together the skin they had been propping open.
After surgery, Badie stands outside the OR to report that the surgery was successful.
“We found the tumor and removed as much of what was abnormal as possible,” he said. “We’re going to take a sample of it and grow some of the cancer cells in the laboratory, then we’ll test them to see how well the CARs attack the tumor cells.”
If the CARs perform well, they will be multiplied until they number into the billions, and be infused into B.’s brain.
In the meantime, B. will be able to walk and move his arm normally again soon.
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