This year, ASCO named adoptive cell immunotherapy as the clinical cancer Advance of the Year. After decades of research, this powerful and decidedly unique way of treating cancer has become available to certain patients with an otherwise incurable blood cancer.
What Is Adoptive Cell Immunotherapy?
Immune cells navigate the body looking for anything that does not belong—bacteria, viruses, and even cancer cells. They do so by using their molecular feelers, or receptors, to scan for foreign molecules that intruder cells display on their surface. Once an intruder is detected, a class of immune cells, known as cytotoxic T cells, move in to eliminate it.
Unfortunately, cancers have a number of ways to hide from immune cells and avoid their attack. The recently successful immunotherapy approaches aim to remedy this by taking the brakes off the immune system with the use of targeted drugs, known as immune checkpoint inhibitors.
Whereas adoptive cell immunotherapy also boosts the body’s immune defenses against cancer, it does so in a completely different way—by genetically re-engineering a patient’s own immune T cells. In the late 1980s, an immunologist was the first to experiment with genetically reprogramming T cells, now known as CAR T cells.
CAR T cells are custom made to work against the cancer in each individual patient. To create these cells, researchers collect immune T cells from the patient and insert an artificial gene into the cells. The gene is designed to endow T cells with chimeric antigen receptors that can detect unique molecules on cancer cells after CAR T cells are multiplied in the laboratory and injected back into the patient. In essence, CAR T-cell therapy is both a gene therapy and an immunotherapy.
When the CAR T-cell receptor attaches to a molecule on a cancer cell, it sends a signal to turn on the destruction machinery of the T cell. Unlike traditional cancer treatments, this living therapy needs to be given to the patient only once, because CAR T cells continue to multiply in the patient’s body. As a result, the anticancer effects of CAR T cells can persist and even increase over time.
CAR T-Cell Therapy Is Poised to Transform Childhood ALL Treatment
In 2017, researchers demonstrated that a CAR T-cell therapy known as tisagenlecleucel can eradicate relapsed ALL in children. This represents one of the most remarkable advances in the treatment of childhood cancer in the last decade and could dramatically change treatment paradigms for this disease. Tisagenlecleucel targets a protein, known as CD19, on malignant and normal B cells.
In the United States, ALL will recur in approximately 600 children and young adults per year, despite achieving a response to initial therapy. After a relapse, ALL is difficult to treat, and survival is usually measured in weeks to months. Remission rates with current standard therapies in prior clinical trials have been only 20% with chemotherapy and 33% with targeted therapy.10,11
In a clinical trial of children and young adults with relapsed or refractory ALL, cancer went into remission within 3 months of receiving tisagenlecleucel in 52 (82%) of 63 patients, and 75% of patients remained relapse free at 6 months.12,13 On the basis of these findings, the FDA approved tisagenlecleucel for the treatment of children and young adults with B-cell ALL in August 2017.14
This global clinical trial confirmed the high efficacy that was demonstrated in prior, single-institution trials; however, the rate of immune-related adverse effects was high with tisagenlecleucel. Nearly 50% of patients experienced severe cytokine release syndrome (CRS), a complication during which CAR T cells produce a storm of inflammatory molecules. CRS can cause prolonged fever, low blood pressure, difficulty breathing, and problems with multiple organs. If severe, CRS may require intensive medical care, such as the use of a ventilator or medications known as pressors to increase blood pressure, and seizure medication. Although CRS can be serious and even life-threatening, doctors now have an effective medicine (tocilizumab) with which to curb and, in most cases, fully reverse the symptoms.
In addition, neurologic complications occurred in 15% of patients in the study. A broad range of neurologic problems, including word recall issues, difficulty speaking, reduction of alertness, delirium, hallucinations, seizures, and coma, have been reported in prior clinical trials with CAR T-cell therapies. In most patients, such symptoms resolved on their own within a few days without long-term consequences, but several deaths have occurred, with severe neurologic complications in other CAR T-cell trials. In this ALL trial, there were no deaths related to either CRS or neurologic complications.
The global ALL trial also helped to prove that patient access to this novel treatment could be broadened. It was the first time CAR T cells were produced from patient blood cells in an industrial manufacturing facility and distributed to patients via a global supply chain that included 25 centers in the United States, Canada, Europe, Australia, and Japan. Until then, the production of CAR T cells was limited to few academic laboratories, without the ability to ship the cell product to patients around the world.
CAR T-Cell Therapy Is Effective Against Hard-to-Treat Lymphoma in Adults
CAR T cells that target CD19 have also been proven to be promising against another hard-to-treat cancer, diffuse large B-cell lymphoma (DLBCL), which is the most common type of non-Hodgkin lymphoma.
In a multicenter clinical trial of patients with DLBCL that worsened after at least two prior therapies, the cancer responded to tisagenlecleucel in 59% of 51 patients and went into remission in 43% of patients.15 At 6 months, 79% of patients had not had a recurrence of lymphoma. Severe CRS occurred in 25% of patients, and neurologic complications in 13%.
In a different clinical trial, patients with relapsed or refractory DLBCL, refractory primary mediastinal B-cell lymphoma, or transformed follicular lymphoma, received another CAR T-cell product called axicabtagene ciloleucel that also targets CD19.16 Among the first 92 patients who were treated, the response rate was 82%, with complete remissions occurring in 54% of patients. At a median follow-up of 8.7 months, 39% of patients were still in complete remission. Severe CRS occurred in 13% of patients; neurologic adverse effects occurred in 28% of patients. In late 2017, the FDA approved axicabtagene ciloleucel to treat adults with DLBCL that has not responded to or has recurred after at least two prior therapies.17
CAR T-Cell Therapy Sends Multiple Myeloma Into Remission
The studies described above all included CAR T cells that were targeted to the B-cell biomarker CD19. A different type of CAR T-cell therapy that targets a biomarker known as B-cell maturation antigen seems to be effective against multiple myeloma. Despite recent advances in treatment, multiple myeloma—a cancer of plasma cells that make antibodies to fight infections—remains an incurable disease, with only approximately one-half of patients living 5 years after diagnosis.
In an early clinical trial, the cancer responded to B-cell maturation antigen CAR T cells in 33 (94%) of 35 patients and went into complete remission in 14 patients18 (Updated data presented at the 2017 ASCO Annual Meeting in Chicago, IL). Only two patients experienced severe CRS, and none experienced neurologic complications from CAR T-cell therapy.
Voices of Cancer Research: Melinda Bachini
At 41 years old, Melinda Bachini received a diagnosis of a rare cancer: cholangiocarcinoma, also known as bile duct cancer. Currently, there are very few treatments available for this disease. Melinda had five surgeries and several rounds of chemotherapy before eventually running out of options.
Then, Melinda joined a clinical trial at the National Institutes of Health. The study investigated a type of adoptive cell immunotherapy using immune cells from around the tumor (tumor infiltrating lymphocytes). This and another type of immunotherapy she received later on helped shrink the tumors for several years. Melinda has not needed cancer treatment for almost a year, and she calls her quality of life “amazing.”
“Cancer research has saved my life and I couldn’t be happier,” Melinda says, five years after beginning the trial. “It has allowed me to continue to be a wife, mother, and patient advocate.” She hopes that clinical trials will continue to lead to new and better treatment options for patients like her.
Melinda Bachini is a volunteer with The Cholangiocarcinoma Foundation, NCI Hepatobiliary Task Force, and NCI Patient Advocacy Steering Committee (PASC).