In the clinic, chimeric antigen receptor-modified T (CAR T) cell therapy is frequently associated with life-threatening cytokine-release syndrome (CRS) and neurotoxicity. Understanding the nature of these pathologies and developing treatments for them are hampered by the lack of appropriate animal models. Herein, we describe a mouse model recapitulating key features of CRS and neurotoxicity. In humanized mice with high leukemia burden, CAR T cell-mediated clearance of cancer triggered high fever and elevated IL-6 levels, which are hallmarks of CRS. Human monocytes were the major source of IL-1 and IL-6 during CRS. Accordingly, the syndrome was prevented by monocyte depletion or by blocking IL-6 receptor with tocilizumab. Nonetheless, tocilizumab failed to protect mice from delayed lethal neurotoxicity, characterized by meningeal inflammation. Instead, the IL-1 receptor antagonist anakinra abolished both CRS and neurotoxicity, resulting in substantially extended leukemia-free survival. These findings offer a therapeutic strategy to tackle neurotoxicity and open new avenues to safer CAR T cell therapies.

After transplantation of haploidentical hematopoietic stem cells and infusion of donor T cells, leukemic cells can escape from the donor's antileukemic T cells through the loss of the mismatched HLA haplotype. This event leads to relapse.

Key Points T cells genetically targeted to the tumor-promoting antigen CD44v6 are effective against AML and MM. CD44v6-targeted T cells do not recognize hematopoietic stem cells and keratinocytes but cause reversible monocytopenia.

T cell memory relies on the generation of antigen-specific progenitors with stem-like properties.However, the identity of these progenitors has remained unclear, precluding a full understanding of the differentiation trajectories that underpin the heterogeneity of antigen-experienced T cells.We used a systematic approach guided by single-cell RNA sequencing data to map the organizational structure of the human CD8 + memory T cell pool under physiological conditions. We identified two previously unrecognized subsets of clonally, epigenetically, functionally, phenotypically, and transcriptionally distinct stem-like CD8 + memory T cells. Progenitors lacking the inhibitory receptors programmed death-1 (PD-1) and T cell immunoreceptor with Ig and ITIM domains (TIGIT) were committed to a functional lineage, whereas progenitors expressing PD-1 and TIGIT were committed to a dysfunctional, exhausted-like lineage.Collectively, these data revealed the existence of parallel differentiation programs in the human CD8 + memory T cell pool, with potentially broad implications for the development of immunotherapies and vaccines. 3 MAIN TEXTAntigen recognition by CD8 + naive T cells initiates a program of clonal expansion and effector differentiation that leads to the clearance of infected or malignant cells and the subsequent formation of heterogeneous memory populations that confer durable immunity 1 . These memory populations are thought to be organized in a developmental hierarchy, according to which stem cell memory T (TSCM) cells self-renew and generate long-lived central memory T (TCM) cells and short-lived effector memory T (TEM) cells 2-6 . However, the mechanisms that underlie the enhanced multipotency of TSCM cells relative to TCM cells have not been clearly defined in molecular terms 7 .Memory T cell differentiation can become corrupted under conditions of persistent antigenic stimulation, as observed during chronic viral infections and progressive malignancies, which promote a state of T cell exhaustion, characterized by an orderly loss of effector functions, impaired proliferation, and the upregulation of inhibitory receptors 8 . This dynamic process occurs over a period of weeks after the initial priming event 9,10 and involves the genome-wide accumulation of epigenetic modifications 11,12 . Recent studies have shown that exhausted T (TEX) cell populations are developmentally and functionally heterogeneous, incorporating stem-like progenitors that express T cell factor 1 (TCF1) which give rise to highly differentiated TEX cells that are constitutively dysfunctional and lack TCF1 [13][14][15][16] . Importantly, the therapeutic benefits of immune checkpoint blockade in the context of chronic viral infections and various cancers are thought to operate via these TCF1 + progenitors, which appear susceptible to interventions that specifically target the inhibitory receptor programmed death-1 (PD-1) 13,15,17-20 .