In 2 complementary Letters to Blood, Karschnia et al and Graham et al provide new insights into the neurological toxicities that are observed with B-cell maturation antigen–directed chimeric antigen receptor T-cell treatment for multiple myeloma, identifying a frequency of immune effector cell–associated neurotoxicity syndrome (ICANS) that exceeds 40%. Severe ICANS is identified in 8% of patients in this real-world series. Outcomes were generally favorable, although the authors describe rare, late Parkinsonism-like hypokinetic movement disorders (also known as movement and neurocognitive toxicities) post-ICANS in 2 patients.

CD70 has emerged as a promising target in acute myeloid leukemia (AML), and we have previously demonstrated the potency of an optimized CD70-targeted ligand-based chimeric antigen receptor (CAR). However, here, we identify in vivo CD70 antigen escape as a limitation of single-antigen targeting. Combination targeting of CD70 and CD33 may overcome AML antigen heterogeneity. We hypothesized that modifying our CD70 CAR platform to secrete a bispecific T-cell engaging antibody molecule (TEAM) targeting CD33 (7033) would create a therapeutic window whereby AML heterogeneity could be addressed without increasing tissue toxicity. We found that CD33 TEAMs mediated specific cytotoxicity across AML cell lines, including CD33 or CD70 single-antigen knockout tumors. 7033 CAR T cells eradicated tumor in an in vivo mixed tumor model of CD70 antigen escape and outperformed the previously optimized CD70 CAR in a patient-derived xenograft. In vivo gene expression profiling of CAR T cells revealed enhanced 7033 CAR T-cell pathway scoring for persistence, activation, and T-cell receptor signaling. Additionally, CD33 TEAMs successfully redirected T cells isolated from patients with AML to activate, secrete cytokines, and kill tumor targets despite exposure to substantial prior cytotoxic therapies. In summary, our findings demonstrate the feasibility of our 7033 CAR to overcome AML heterogeneity and leverage the bystander T cells of patients; this approach warrants further study in patients with this dire clinical need.

Interferon-γ (IFN-γ) plays complex and, sometimes, contradictory roles in cancer, which can affect patient responses to treatments such as immunotherapies. We recently demonstrated that IFN-γ production by chimeric antigen receptor (CAR) T cells is not required for efficacy in hematologic tumor models, whereas IFN-γ receptor (IFN-γR) signaling in solid tumor cells facilitates CAR T cell adhesion and antigen-specific cytotoxicity. Here, we show that IFN-γ induces apoptosis of CAR T cells bearing a CD28 intracellular signaling domain, which can be reduced through targeting of IFN-γ or IFN-γR. In hematologic malignancies, knockout of IFN-γR (IFN-γRKO) in CAR T cells increased their persistence without compromising efficacy. In xenograft and syngeneic solid tumor models, IFN-γR knockout CAR T cells displayed more potent tumor control, prolonged survival, and improved T cell memory that conferred protection from tumor rechallenge. RNA sequencing of tumor-infiltrating IFN-γRKO CAR T cells derived from tumor-bearing mice revealed increased cell death in tumor cells. Collectively, these data show that inhibition of IFN-γ signaling can increase the expansion and antitumor activity of CD28-based CAR T cells in liquid and solid tumors.

NK cells play a critical role in anticancer immunity through their direct cytotoxicity and production of cytokines, such as FMS-like tyrosine kinase 3 ligand (Flt3L). NK cell production of Flt3L controls conventional type I dendritic cell (cDC1) abundance in the tumor and promotes protective immune responses. In this study, we show that NK cell production of Flt3l in the tumor is regulated by activation and that activation by IL2 and IL15 uniquely induced Flt3L expression in NK cells. In melanoma, IL2 signaling in NK cells led to increased Flt3L production, which boosted cDC1 abundance in the tumor and improved anti–PD-1 immunotherapy response. Furthermore, NK cell subsets differentially regulated Flt3l in the tumor, with CD11b−CD27+ NK cells in mouse tumors enriched for IL2 family signaling and upregulating Flt3l upon activation. Consistently, human CD56brightCD16− NK cells more strongly correlated with cDC1 and FLT3LG expression than other NK cell subsets across multiple human melanoma datasets and cancer indications. This mechanistic study of NK cell regulation of FLT3LG and control of the NK cell–cDC1 axis provides insights and strategies for the development of more effective cancer immunotherapies.

Supplementary Figure 12 from Secretion of a VEGF-Blocking scFv Enhances CAR T-cell Potency