Liposomes hold great potential as gene and drug delivery vehicles due to their biocompatibility and modular properties, coupled with the major advantage of attenuating the risk of systemic toxicity from the encapsulated therapeutic agent. Decades of research have been dedicated to studying and optimizing liposomal formulations for a variety of medical applications, ranging from cancer therapeutics to analgesics. Some effort has also been made to elucidate the toxicities and immune responses that these drug formulations may elicit. Notably, intravenously injected liposomes can interact with plasma proteins, leading to opsonization, thereby altering the healthy cells they come into contact with during circulation and removal. Additionally, due to the pharmacokinetics of liposomes in circulation, drugs can end up sequestered in organs of the mononuclear phagocyte system, affecting liver and spleen function. Importantly, liposomal agents can also stimulate or suppress the immune system depending on their physiochemical properties, such as size, lipid composition, pegylation, and surface charge. Despite the surge in the clinical use of liposomal agents since 1995, there are still several drawbacks that limit their range of applications. This review presents a focused analysis of these limitations, with an emphasis on toxicity to healthy tissues and unfavorable immune responses, to shed light on key considerations that should be factored into the design and clinical use of liposomal formulations.

Background CD19-directed CAR T-cell therapy (CAR-T) has emerged as an effective therapy for relapsed/refractory large B-cell lymphoma (R/R LBCL). The neurologic toxicity seen with CAR-T, referred to as Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), is poorly understood. To better elucidate the clinical characteristics, treatment outcomes, and correlative biomarkers of ICANS, we review here a single-center analysis of ICANS after CAR-T therapy in R/R LBCL. Methods Patients (n=45) with R/R LBCL treated with axicabtagene ciloleucel (axi-cel) were identified. Data regarding treatment course, clinical outcomes, and correlative studies were collected. Patients were monitored and graded for ICANS via CARTOX-10 scoring and CTCAE v4.03 criteria, respectively. Results Twenty-five (56%) patients developed ICANS, eighteen (72%) of which had severe (grade 3-4) ICANS. Median time to development of ICANS of 5 days (range 3-11). Elevated pre-infusion (D0) fibrinogen (517 vs. 403 mg/dL, ULN 438mg/dL, p=0.01) and D0 LDH (618 vs. 506 units/L, ULN 618 units/L, p=0.04) were associated with ICANS. A larger drop in fibrinogen was associated with ICANS (393 vs 200, p<0.01). Development of ICANS of any grade had no effect on complete remission (CR), progression-free survival (PFS) or overall survival (OS). Duration and total dose of steroid treatment administered for ICANS did not influence CR, PFS, or OS. Conclusions ICANS after CAR-T with axi-cel for R/R LBCL was seen in about half of patients, majority of which was high grade. Contrary to previous reports, neither development of ICANS nor its treatment were associated with inferior CR, PFS, or OS. The novel finding of high D0 fibrinogen level can identify patients at higher risk for ICANS.

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