Emily Whitehead was diagnosed with standard-risk pre-b acute lymphoblastic leukemia when she was only five years old. After two rounds of chemotherapy, an infection that almost cost her both legs and a full relapse, she became Patient 1 in a Phase 1 trial of T-cell therapy.
In the opening sessions of the 2020 Virtual PDA Annual Meeting (Jul. 20 – 22), Tom G. Whitehead shared the moving story about how T-cell therapy saved his daughter’s life, and Elliot C. Norry, MD, Chief Medical Officer of Adaptimmune, described how these life-saving therapies work.
In his presentation, “Delivering T-Cells to Patients: Challenges and Successes,” Norry explained the Autologous Specific Peptide Enhanced Affinity Receptor (SPEAR) T-cell therapies his company develops for the treatment of cancer. T-cells, a group of white blood cells that help find and fight things foreign to the body like bacteria and viruses, attack and clear them using an inflammatory response. Adaptimmune has developed SPEAR T-cells that specifically recognize certain cancer cells as foreign and target them.
“Behind every bag of SPEAR T-cells manufactured,” Norry stressed, “is an individual living with cancer.” And the individual is usually a patient with an advanced form that has not responded to other treatments.
He illustrated the patient’s journey from leukapheresis to infusion and the process of engineering the SPEAR T-cells. Adaptimmune ships the modified T-cells back to a patient’s treatment center; the whole process usually takes 22-25 days. Before being infused with their SPEAR T-cells, the patient undergoes lymphodepleting chemotherapy to “make space” for the incoming cells and improve the efficacy of the treatment.
Several factors present a challenge to the process, Norry noted, starting with the fact that each product batch is unique to the patient.
The apheresis starting material and the cell dose range will vary depending on the patient’s age, health and prior treatments, meaning no two products ever look the same. As such, a strict chain of custody must be maintained, location and temperature of the cells monitored at all times, and special measures taken to ensure that patients receive only their own cells.
Aligning patient scheduling with manufacturing capability creates a need for flexible capacity, requiring Adaptimmune to maintain control of the entire process. The growing success of the treatment in several different advanced cancers is why the company continues to pursue SPEAR T-cell studies, to improve the process and increase the availability of the treatment across a broader population.
Putting T-Cells to the Test
Whitehead enthusiastically supported T-cell therapies in his presentation, “Journey to Car-T Cell Therapy,” where he detailed the steps his family took to save their daughter Emily.
Following Emily’s diagnoses, Whitehead consulted with oncologists from Pennsylvania’s Hershey Medical Center and Children’s Hospital of Philadelphia (CHOP). They started Emily on outpatient chemotherapy at Hershey as it was “only a two-hour drive instead of four.” Soon after, she awoke one night with severe pain in her legs; she had developed infection in both legs, necrotizing fasciitis. The ER doctor said they may have to amputate both legs to save her. Whitehead remarked, “We had started with hope. Now we were really scared.” Fortunately, the infection was not in the muscle, but around it, so amputation wasn’t necessary, and Emily went back to chemo.
The majority of children with ALL are cured after a two-year treatment with standard chemotherapy and, initially, that worked. But 16 months later, Emily “felt the cancer in [her] bones again.” Despite the two rounds of chemo, a bone marrow test confirmed it. Because Emily went into full relapse, she was no longer considered a “standard risk” and a bone marrow transplant was not an option. All Hershey could offer was another round of more intense chemo.
Whitehead got a second opinion from Susan Rheingold, MD, at the CHOP Cancer Center, but received the same answer, so they continued treatment at Hershey, seeking a donor for an allogeneic stem cell transplant. One was found and the transplant was scheduled for February 2012, but before then, Emily relapsed again.
Her leukemia was so aggressive this time, doctors recommended Whitehead take Emily home for hospice care. Not giving up, Whitehead applied for an experimental clinical study of CAR T-cell therapy at CHOP. The study was underway, but the therapy had never been used on children. In the meantime, Emily underwent a new chemo they knew “wouldn’t cure her but would give her some time.”
It proved to be just enough, as soon the T-cell therapy clinical trial was approved, and in April 2012, Emily became Patient 1 in the Phase 1 pediatric trial.
As the doctor explained the process to Emily, they would use her T-cells to “build an army that would fight the cancer,” and took her T-cells “off to boot camp.” With no immune system, Emily remained in isolation for six weeks. When it was time to return her strengthened army of cells, they infused her in a stepped process—10% one day, 30% the next, 60% the last—to determine what was effective and to evaluate her reaction, especially since they had no existing protocol for dosing a child. Emily withstood the first two doses well, not even showing the flu-like symptoms the family had expected, but the final dose knocked her out.
After receiving the 60% dose, Emily experienced cytokine release syndrome, a “cytokine storm” that brought on a raging fever (106 °F at one point), chills, hallucinations, labored breathing and a sudden drop in blood pressure. She was put on a ventilator and induced into a coma to relieve the pain; the steroids they pumped into her to reduce pain and inflammation, instead swelled her body beyond recognition.
The doctors gave Emily a one in one-thousand chance of surviving the night, but Whitehead asked her to try to get through it, held her hand throughout the ordeal and told the doctors, “just don’t give up on her.” Emily kept fighting throughout her 14-day coma.
Whitehead said, one test revealed her interleukin-6 level was “higher than anyone alive,” 1000 times above normal. By chance, Carl H. June, MD, who led the clinical team at the University of Pennsylvania, recognized the IL-6 protein as one involved in rheumatoid arthritis, a disease that afflicted his daughter. He determined that Emily be treated with tocilizumab, the drug his daughter takes, though it had never been used in cancer patients. The results were dramatic! Within hours, her fever was down, her breathing came easier and her blood pressure normalized. She woke a week later on her seventh birthday. Twenty-three days after that, she texted her family “no cancer cells, T cells worked!!” Eight years later, Emily is still cancer-free, thanks to the T-cell therapy that turned her life around.
In the Q&A that followed his presentation, Whitehead replied that Emily is now a typical 15-year-old girl who, while hanging out with her family in isolation during the pandemic, spends lots of time texting friends. As a strong supporter of T-cell therapy, Whitehead and his wife, Kari, started the Emily Whitehead Foundation to help other families navigate childhood cancer and advocate for pediatric cancer research so others can have the same positive outcome as Emily.
Asked about the future of cell therapies, Norry said, “Harnessing a patient’s own immune system to help fight cancer makes sense. I don’t know what the future looks like, but I hope it expands to help more patients even earlier in their course of therapy.”