Ian W. Flinn, MD, PhD
Patients with advanced lymphoid malignancies have had few treatment options, particularly those with extensive, refractory disease. Allogeneic or autologous hematopoietic stem cell transplantation (HSCT) has been one life-prolonging and potentially curative option for these patients, but these procedures are associated with various toxicities and are not appropriate for all patients, with older adults and those with great- er disease burden often excluded as candidates.
Moreover, once intensive chemotherapy or HSCT fails, there are often no options left, which has spurred researchers to find new cellular strategies to target advanced hematologic malignancies.
One such novel strategy currently in development on the immunotherapy front is the use of chimeric antigen receptor (CAR) T cells, which has enabled some patients to move from hospice candidate to remission.
During a recent OncLive
Peer Exchange panel titled “Immunotherapy Use in Advanced Lymphoid Malignancies,” experts in the field provided a comprehensive overview of CAR T-cell therapies, including how they work, their toxicities, key clinical trial results, and their role in clinical practice.
Although CAR T-cell therapies have been in development for decades, recent advancements in how these treatments are designed have enabled them to become more efficacious and are bringing them closer to FDA approval, generating considerable excitement.
Moderator Ian W. Flinn, MD, PhD, said he is impressed about the progress being made. “It is not just the clinical results which are fantastic but also just the logistical advancement that we’ve had in terms of taking these out of a single academic center and being able to do it in large trials across the United States,” he said.
CAR T-Cell Therapy Overview
CAR T-cell therapies use reengineered T cells to target antigens on the surface of cancerous cells. The T cells are collected via apheresis and then sent to a facility where they are genetically engineered to produce CARs on their surface.
The reengineered cells are then expanded in the laboratory until they reach sufficient numbers, then frozen, and sent back to the treatment center for infusion. In many cases, patients receive a brief course of 1 or more lymphodepleting chemotherapeutic agents before the CAR T cells are infused. “The lymphodepleting chemotherapy drives down the existing lymphocytes that are within the body and creates space for those transferred T cells,” explained Frederick L. Locke, MD.
The CAR design is where CAR T-cell therapies differ. Although all CAR designs contain an antigen-recognition domain and a signaling domain that cause the T cells to activate, the first-generation CARs have only 1 signaling domain, whereas second-generation CARs have a costimulatory signaling domain, and third-generation CARs have 2 costimulatory signaling domains, providing additional signals to activate T cells.
Additionally, while all CARs use the CD3-zeta intracellular signaling domain, the costimulatory domains among the second- and third-generation treatments vary. “Several different costimulatory domains are in use today,” said Locke. “There’s a CD28 and a 4-1BB costimulatory domain.”
The costimulatory domains in use are not foreign to T cells. “[CD28 and 4-1BB] normally would be a receptor on the T cell that would receive a second signal through a unique ligand, but in the context of the CAR, they’re basically artificially delivered through the same genetic construct,” said Krishna V. Komanduri, MD.
“So, theoretically, the kinetics of engagement of the second signal through these receptors can vary and, therefore, when you deliver it artificially, the cell can react differently,” he noted.
He indicated that ongoing studies will provide better insights on how these costimulatory signals affect response in different patients and what effects they have on the cellular level in different hematologic malignancies.
CAR T-Cell Therapy Toxicities
Although CAR T-cell therapies are generally well tolerated the first few days following injection of the reengineered T cells, many patients develop cytokine release syndrome (CRS), which can be life-threatening but also serves as an indicator of efficacy. CRS generally manifests as high fevers, chills, hypotension, and hypoxia.
“This can be a very toxic treatment,” said Locke. “You need a specialized team that’s familiar with those toxicities.” He noted that his institution created a team with hematologic malignancy and transplant physicians for these toxicities, which are reversible if handled correctly.