Currently, axicabtagene ciloleucel and tisagenlecleucel are two commercially available CAR-T treatment products approved by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Based on clinical trial results, these cell therapies have demonstrated durable overall response and complete remission rate in one-third of relapse/refractory lymphoma patients.1
“For CAR-T cells, the overall response rate, PFS, and overall survival (of real-life data) are the same as those in clinical trials, which is sometimes not the case with other treatments,” said Professor Catherine Thieblemont, head of the Hemato-Oncology Department at Saint-Louis Hospital, University of Paris, France.1 She pointed out that many cases of relapse/refractory diffuse large B-cell lymphoma progressions were reported within the first three months after CAR-T cell transplant, especially among patients with high total metabolic tumor volume (TMTV) at preconditioning lymphodepletion and high baseline age-adjusted international prognostic index (aaIPI).1 These newly identified risk factors could help enhance patient selection algorithm for CAR-T therapy.
For adverse events, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) and neutropenia were most associated with CAR-T cell therapy. Real-life data showed that neutropenia and febrile neutropenia were frequent in the first month of treatment, highlighting the importance of monitoring and treatment. The use of granulocyte-colony-stimulating factor (G-CSF) after CAR-T cell transplant did not affect CAR-T cell expansion, toxicity prevalence and severity, while the reduction in hospitalization duration was seen.1
Dr. Michel Sadelain, director of the Center for Cell Engineering, the Memorial Sloan-Kettering Cancer Center, New York, highlighted other toxicities and unmet needs of current CAR therapies. CD28-expressing CAR-T cells were superior in effector function and tumor elimination, while 4-1BB-expressing CAR-T cells were more persistent in maintaining response. Yet, the dilemma of developing future CAR therapy lay in the balance between persistence and effector function, to avoid relapse, overloading and exhaustion of the T cells.2
Recent advance in the immunoreceptor tyrosine-based activation motifs (ITAMs) illustrated the potential of such calibration in directing the fate and differentiation of T cell to modulate signal strength. Gene editing which targets the integration site was also shown to optimize signaling and postpone T cell exhaustion, though the barriers of high translocation frequency and off-target activities need to be overcome. New CARs and structures are anticipated to gain better sensitivity to the low antigen density as compared to the classic CARs, particularly in the process of T cell activation and relapse risk reduction.2
Low-dose radiation as a conditioning regimen for CAR-T cell therapy was demonstrated to elicit death receptor expression in tumor cells and increase sensitivity to CAR-T action, highlighting the potential of combination therapy in addressing tumor heterogeneity. The future development of CARs might consist of combination therapy, target selection, cellular substrates, and expansion of cell sources. These would enable the inhibition of negative regulation and counteract microenvironmental suppression and antigen escape.
“One of the arms to control and direct T cell is synthetic immunity, for which the CAR-T cell provides a foundation and a paradigm, so my hope is that synthetic receptors will instruct immunity. For patients who do not have T cell response for whatever reasons, we can provide that to them,” stated Dr. Sadelain.