NKG2D ligands are widely expressed in solid and hematologic malignancies but absent or poorly expressed on healthy tissues. We conducted a phase I dose-escalation study to evaluate the safety and feasibility of a single infusion of NKG2D-chimeric antigen receptor (CAR) T cells, without lymphodepleting conditioning in subjects with acute myeloid leukemia/myelodysplastic syndrome or relapsed/refractory multiple myeloma. Autologous T cells were transfected with a g-retroviral vector encoding a CAR fusing human NKG2D with the CD3z signaling domain. Four dose levels (1 Â 10 6-3 Â 10 7 total viable T cells) were evaluated. Twelve subjects were infused [7 acute myeloid leukemia (AML) and 5 multiple myeloma]. NKG2D-CAR products demonstrated a median 75% vector-driven NKG2D expression on CD3 þ T cells. No dose-limiting toxicities, cytokine release syndrome, or CAR T cell-related neurotox-icity was observed. No significant autoimmune reactions were noted, and none of the ! grade 3 adverse events were attributable to NKG2D-CAR T cells. At the single injection of low cell doses used in this trial, no objective tumor responses were observed. However, hematologic parameters transiently improved in one subject with AML at the highest dose, and cases of disease stability without further therapy or on subsequent treatments were noted. At 24 hours, the cytokine RANTES increased a median of 1.9-fold among all subjects and 5.8-fold among six AML patients. Consistent with preclinical studies, NKG2D-CAR T cell-expansion and persistence were limited. Manufactured NKG2D-CAR T cells exhibited functional activity against autologous tumor cells in vitro, but modifications to enhance CAR T-cell expansion and target density may be needed to boost clinical activity.

NKG7 is a cytolytic granule-associated protein. The authors show that NKG7 is critical for cytotoxic CD8 + T-cell antitumor activity and that NKG7 mRNA transfection improves cytotoxic CD8 + T-cell tumor-cell killing, identifying NKG7 as a potential therapeutic target.

CAR T cell approaches to effectively target AML and T-ALL without off-tumor effects on healthy myeloid or T cell compartments respectively are an unmet medical need. NKG2D-ligands are a promising target given their absence on healthy cells and surface expression in a wide range of malignancies. NKG2D-ligand expression has been reported in a substantial group of patients with AML along with evidence for prognostic significance. However, reports regarding the prevalence and density of NKG2D-ligand expression in AML vary and detailed studies to define whether low level expression is sufficient to trigger NKG2D-ligand directed CART cell responses are lacking. NKG2D ligand expression in T-ALL has not previously been interrogated. Here we report that NKG2D-ligands are expressed in T-ALL cell lines and primary T-ALL. We confirm that NKG2D-ligands are frequently surface expressed in primary AML, albeit at relatively low levels. Utilizing CAR T cells incorporating the natural immune receptor NKG2D as the antigen binding domain, we demonstrate striking in vitro activity of CAR T cells targeting NKG2D-ligands against AML and T-ALL cell lines and show that even low-level ligand expression in primary AML targets results in robust NKG2D-CAR activity. We found that NKG2D-ligand expression can be selectively enhanced in low-expressing AML cell lines and primary AML blasts via pharmacologic HDAC inhibition. Such pharmacologic NKG2D-ligand induction results in enhanced NKG2D-CAR anti-leukemic activity without affecting healthy PBMC, thereby providing rationale for the combination of HDAC-inhibitors with NKG2D-CAR T cell therapy as a potential strategy to achieve clinical NKG2D-CAR T cell efficacy in AML.

The wrongful murders of Black individuals during 2020 (including George Floyd, Breonna Taylor, Ahmaud Aubery, and others), compounded by a long history of similar incidents, inspired protests around the world against racism and police brutality. The growing anti-racism movement sparked conversations within science, technology, engineering, mathematics, and medicine (STEMM) surrounding ways to combat racial bias in our respective fields. A spotlight was placed on the discriminatory history of scientific research and medical practice, as well as the problematic modern-day policies that perpetuate the lack of racial diversity and equity in STEMM.While observing and participating in recent discussions about the racism that pervades institutions, departments, and scientific discourse, we have noticed a set of standard arguments against anti-racism action within STEMM. Ten of these arguments are laid out in this manuscript and paired with evidence-based counterarguments. Notably, while this manuscript is primarily centered around a United States perspective, most of our arguments and suggested actions remain applicable to other countries as well. It is crucial for a STEMM anti-racism movement to extend beyond national borders, reflecting the international nature of scientific research and collaboration.This team of authors represents a collaboration between scientists from historically marginalized groups and their allies. By compiling published academic literature, we hope to directly

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