When Lekha Mikkilineni's patients come in for their checkups at Stanford these days, many of the appointments feel less like medical visits and more like catching up. She hears from patients that have taken up competitive tennis again or finally took a trip they had written off as impossible. Many are spending time with family without needing to schedule it around their infusion treatments.
Her patients have multiple myeloma, a cancer of the blood that for most of medical history left patients with little more than borrowed time.
Mikkilineni, an assistant professor in Stanford Medicine's Division of Blood and Marrow Transplantation and Cellular Therapy, has spent her career working to change that. "The outlook has changed dramatically," she says, "in large part due to immune-based therapies, including CAR T-cell therapy, which uses a patient's own immune cells to attack their cancer."
A disease of the marrow
Our bone marrow is essentially an antibody factory. Every day, specialized white blood cells called plasma cells churn out trillions of antibodies, which are proteins tuned to fight specific infections. Some are built to attack strep throat. Others go after Salmonella.
In patients with multiple myeloma, certain plasma cells grow out of control and crowd out the healthy cells around them. The name literally means a tumor of the bone marrow. These rogue cells multiply in different sites throughout the body, hence "multiple," and release abnormal proteins into the bloodstream that can damage the kidneys, weaken bones, cause anemia and drive up blood calcium to dangerous levels. Patients often live with chronic, intense pain.
If you were diagnosed with multiple myeloma in 2001, you had roughly a 50-50 chance of surviving three years. Today, half of all patients live eight to ten years after diagnosis, with younger patients often exceeding that.
Combining the body's own cells to attack cancer
CAR T-cell therapy, the approach at the center of Mikkilineni's research, does something unusual: it recruits the patient's own immune system to do the job.
Here is how it works. A patient's T-cells, the immune system's frontline fighters, are collected from the blood and sent to a lab. Scientists modify them to recognize and target myeloma cells by adding an antibody component. The result is what researchers call a chimeric antigen receptor, or CAR: an engineered cell that can do both the job of an antibody and a T-cell. Those cells are grown by the millions and infused back into the patient, where they hunt down the disease.
CAR T-cell therapy was first approved by the FDA in 2017 as a leukemia treatment. It has only been approved for multiple myeloma in the last five years.
Before coming to Stanford, Mikkilineni worked at the National Cancer Institute, where she designed and ran two first-in-human CAR T-cell trials.
"During this time, CAR T-cell therapy was still in its infancy," she says. "I saw firsthand how patients who were hospice-bound were given an extension of life, from months to sometimes years. What makes this approach so important is that it can produce deep responses in patients who have run out of other options, and it does so as a single treatment rather than continuous, indefinite therapy."
A new design with all-human components
CAR T-cell therapy works — but earlier versions had a glitch that researchers spent years trying to fix.
The original designs included antibody components derived from mice or held together with artificial protein linkers. Because the patient's body could recognize these as foreign, it might attack the engineered cells before they had time to work, potentially shortening the treatment's effectiveness.
At the National Cancer Institute, James N. Kochenderfer, MD, developed a fully human version of the therapy that eliminates both the mouse-derived material and the artificial linker. Mikkilineni led the first-in-human clinical trial of this new design, with the goal of producing engineered T-cells that would be more potent, more durable, and better at keeping myeloma in remission.
The results were incredible. Twenty-three out of 25 patients — 92 percent — showed either a complete response, meaning no detectable sign of cancer, or a significant partial response.
More remarkable still was how long those responses lasted.
"A subset of these patients have now remained in remission for more than five years after a single infusion," Mikkilineni says. "Six reached the five-year mark and came off study still in remission. For patients who had exhausted standard options, some having gone through up to 10 lines of treatment, the fact that one treatment can produce remissions measured in years raises a question that would have been almost unthinkable a decade ago: whether a single cellular therapy can hold myeloma at bay for the long term."
Managing side effects
Like any powerful treatment, CAR T-cell therapy carries risks. One of the most common is cytokine release syndrome, an inflammatory reaction the body can mount shortly after infusion. Most oncologists who use this therapy are now well-versed in recognizing and managing it.
But some complications emerge later and are harder to identify. When one of Mikkilineni's Stanford patients developed a severe inflammation of the intestines two months after receiving a different CAR T-cell therapy for myeloma, she suspected the treatment was the cause.
"CAR T-cells travel to the gut and exert gastrointestinal damage," she says. "Enterocolitis arrives late, can be mistaken for infection or other causes of diarrhea, and requires a different management approach."
Mikkilineni assembled a team at Stanford to determine a course of treatment, which proved effective. She now co-leads a multi-institutional working group focused on diagnosing and treating this delayed side effect, which researchers have named immune effector cell-associated enterocolitis.
A return to life
"When we started, the goal was to control disease and buy time," Mikkilineni says. "Watching a subset of patients remain free of myeloma for this long, off all therapy, after a single infusion, changes the conversation."
After years of cycling through treatments and organizing their lives around medical appointments, many of her patients have returned to work, travel, and the relationships that their illness had put on hold.
“The success of the therapy is meaningful in ways that are hard to convey in clinical terms. The quality of life that was gained was everything to the patients. Watching patients on this trial thrive is a large reason I have dedicated my research to immune therapies in myeloma."
A vision for what comes next
Mikkilineni's goal now is to make this therapy safer, faster, and available to more people.
She envisions CAR T-cell therapy moving into earlier lines of treatment, so patients don't have to exhaust every other option first. She also sees next-generation technology allowing T-cells to be reprogrammed inside the patient's own body rather than in a laboratory, which could drastically reduce the time to treatment. And she is focused on expanding access for patients who have historically been excluded — older or frailer individuals, or those who live far from the academic medical centers where this therapy is currently available.
The language is still careful. But it is shifting.
"I am cautious about the word cure, because we are still learning whether the disease is truly gone or simply held in check," Mikkilineni says. "But for these individuals, a functional cure — meaning years of disease-free, treatment-free, normal life — is a reasonable way to describe what they are experiencing."
