Summary: Cell and immune therapies have transformed the outcomes of patients with lymphoma, but the majority of patients do not have durable benefit. Here, we provide our perspective on key challenges in personalizing cell and immune therapy approaches for lymphoma through discovery, validation, and clinical deployment of microenvironment classification.
Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) affect most patients receiving axicabtagene ciloleucel (axi-cel) for relapsed or refractory large B-cell lymphoma (LBCL). Based on pre-clinical data, we hypothesized that prophylactic IFN-γ blockade could prevent toxicity without impairing efficacy. We initiated an open-label phase 2 trial (NCT06550141) evaluating single-dose emapalumab one day before axi-cel. Here, we report the first two patients to caution against the pre-emptive emapalumab use prior axi-cel: Both developed treatment-refractory toxicities including high-grade ICANS and overlapping CRS-IEC-HS requiring multiple immunomodulatory agents. CAR T-cell expansion exceeded levels reported in ZUMA-1 and a standard-of-care axi-cel cohort at our institution. Despite therapeutic emapalumab and suppressed free IFN-γ, IL-2 and sIL-2R were markedly elevated, suggesting CRS was driven independent of IFN-γ. Both patients achieved complete responses, suggesting preserved efficacy. Given the unanticipated severity and refractoriness of toxicities, recruitment with this design was discontinued and the protocol was amended.
Summary: In this issue of Blood Cancer Discovery, Corona, Gillmor, and colleagues show that quantitative CD19 density measured before chimeric antigen receptor (CAR) T-cell infusion stratifies progression-free survival in large B-cell lymphoma, yet low antigen density rarely reflects a genetic lesion at the CD19 locus itself, suggesting that other mechanisms of CD19 downregulation may promote CAR T-cell escape. Moreover, Newsam and colleagues offer one explanation—recurrent del(3p21.31)/RHOA loss that results in decreased CD19 in trans and impairs CAR T-cell efficacy. See related article by Corona, Gillmor, and colleagues, p. XX . See related article by Newsam and colleagues, p. XX .
Abstract In vivo chimeric antigen receptor (CAR) T-cell therapy generates engineered lymphocytes inside the patient, bypassing leukapheresis, ex vivo manufacturing, and, in many programs, lymphodepletion. Studies in relapsed or refractory multiple myeloma report deep responses with measurable residual disease negativity after BCMA-directed treatment. Because the administered product is a delivery system, cells are shaped by the host environment, which may complicate interpretation of efficacy and safety. This review summarizes clinical data and defines determinants of response that could be optimized for durable translation. It focuses on multiple myeloma, where clinical experience is most mature, while drawing on autoimmune applications. Significance: In vivo CAR T-cell therapy is appealing because it removes many of the cumbersome steps of conventional cellular therapy. Yet, because treatment administers a delivery system and the CAR T-cell product is generated within the patient, clinical activity depends on interactions among the delivery system, disease context, and host immune state. Trials would benefit from determining how much of the early benefit reflects CAR T-cell activity itself and how much is shaped by the biological conditions that enable, amplify, or constrain it.
Abstract Relapsed and/or refractory disease remains the leading cause of death in acute myeloid leukemia (AML), highlighting the need for broadly applicable, high-sensitivity approaches to measurable residual disease (MRD) detection. We developed AML-Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq), a personalized hybrid-capture assay that tracks both canonical AML drivers and patient-specific variants identified by whole-exome sequencing. In 56 patients with longitudinal plasma and matched peripheral blood and bone marrow samples, AML-CAPP-Seq enabled universal MRD assessment and resolution of clonal dynamics using a median of 30.5 variants per patient. Plasma circulating tumor DNA (ctDNA) outperformed cellular compartments for MRD detection and more strongly predicted relapse-free survival [hazard ratio (HR), 17.8; P < 0.0001] and overall survival (HR, 17; P < 0.0001) than standard-of-care (SOC) MRD methods. Among 29 allogeneic transplant recipients, peritransplant ctDNA-MRD dynamics markedly improved relapse risk stratification (HR, 36; P = 0.0009). Together, these results establish personalized ctDNA profiling as a minimally invasive, highly sensitive, and generalizable platform for enhanced clinical MRD detection and clonal surveillance in AML. Significance: We present a personalized blood test for AML that tracks patient-specific ctDNA, enabling sensitive, universal, and noninvasive detection of residual disease. It outperforms SOC marrow- and cell-based methods for predicting relapse and survival, including after transplant, reveals clonal dynamics, and supports individualized disease monitoring and risk-adapted treatment.
