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Despite advances in treatment, most patients with multiple myeloma (MM) will relapse, and long-term survival remains poor. B-cell maturation antigen (BCMA) is an ideal therapeutic target as it is expressed throughout the disease course with normal tissue expression limited to plasma and some B-cell lineages. This phase 1, multicenter, first-in-human study evaluated the safety and efficacy of KITE-585, an autologous anti-BCMA chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed/refractory MM (RRMM). Key eligibility criteria included measurable MM and progression, defined by the International Myeloma Working Group Consensus Criteria within 60 days of the last treatment. Patients underwent leukapheresis and subsequently received a 3-day conditioning therapy regimen (cyclophosphamide [300 mg/m 2 /day] and fludarabine [30 mg/m 2 /day]). Patients then received a flat dose of 3 × 10 7 to 1 × 10 9 KITE-585 CAR T cells in a 3+3 dose-escalation design. The primary endpoint was incidence of adverse events (AEs) defined as dose-limiting toxicities (DLTs). Key secondary and exploratory endpoints included efficacy outcomes, incidence of AEs, levels of KITE-585 in blood, serum cytokines, and incidence of anti-BCMA CAR antibodies. Seventeen patients were enrolled, and 14 received KITE-585 with a median follow-up of 12.0 months. The median age of patients was 56 years, 41.2% had an Eastern Cooperative Oncology Group performance status of 1, 92.9% had baseline BCMA expression on plasma cells, and median number of prior therapies was 5.5. No patients experienced a DLT, all patients experienced ≥ 1 grade ≥ 3 treatment-emergent AE (TEAE), and no grade 5 TEAEs were observed. There were no grade ≥ 3 events of cytokine release syndrome, neurologic events, or infections; all were grade 1 or 2, and each occurred in 21.4% of patients. Among all patients infused with KITE-585, 1 patient who received 3 × 10 7 anti-BCMA CAR T cells experienced a partial response. Median peak CAR T-cell expansion was low (0.98 cells/μL), as were median peak serum levels of CAR-associated cytokines, including interferon-γ (61.45 pg/mL) and interleukin-2 (0.9 pg/mL). KITE-585 demonstrated a manageable safety profile; however, the limited CAR T-cell expansion and associated lack of anti-tumor response in patients with RRMM treated with KITE-585 is consistent with the minimal CAR T-cell activity observed., Competing Interests: R.F.C. has employment with AbbVie; honoraria from Karyopharm, Takeda, and GlaxoSmithKline; and consultancy or advisory role for Karyopharm, Takeda, and GlaxoSmithKline. M.R.B: honoraria from Kite, a Gilead Company, Incyte, Celgene, Sanofi, Novartis, Bristol Myers Squibb, and Agios; consultancy or advisory role for Novartis, Kite, a Gilead Company, CRISPR Therapeutics, Agios, Iovance, Bluebird Bio, WindMIL Therapeutics, and Arcellx; speakers’ bureau participation for Kite, a Gilead Company, Agios, Incyte, Sanofi, and Bristol Myers Squibb; research funding from Kite, a Gilead Company, Novartis, CRISPR Therapeutics, Arcellx, Autolus, Immatics, Triumvira, and Tmunity; and travel support from Kite, a Gilead Company, Novartis, Bristol Myers Squibb, Agios, and Incyte. S.K. has a consulting or advisory role for AbbVie, Celgene, Janssen, Takeda, Adaptive Biotechnologies, Kite, a Gilead Company, and Medimmune/AstraZeneca; research funding from AbbVie, Celgene, Janssen, Takeda, Adaptive Biotechnologies, Kite, a Gilead Company, Medimmune/AstraZeneca, Merck, Novartis, Roche, and Sanofi; other relationship with Oncopeptides Independent Review Committee. S.A.G. has a consulting or advisory role with Kite, a Gilead Company, Novartis, Amgen, Celgene, Sanofi, Pfizer, Miltenyi, Bristol Myers Squibb, GlaxoSmithKline, and Actinium; and research funding from Amgen, Celgene, Sanofi, Pfizer, Actinium, Bristol Myers Squibb, and Miltenyi. A.K.N. has a consulting or advisory role with Takeda, Amgen, Janssen, Bristol Myers Squibb, GlaxoSmithKline, Sanofi, Karyopharm, Adaptive, and Oncopeptides. S.M.L. has a consulting or advisory role for Bristol Myers Squibb; speakers’ bureau participation for Takeda; research funding from Bristol Myers Squibb, Takeda, Janssen, BioLineRx, and Novartis; and travel support from Bristol Myers Squibb. F.L.L. has a consulting or advisory role for Kite, a Gilead Company, Novartis, Amgen, Celgene/Bristol Myers Squibb, GammaDelta Therapeutics, Iovance, Bluebird Bio, Wugen Inc., Calibr, Cellular Biomedicine Group Inc., and Allogen; and research support from Kite, a Gilead Company. N.S.R. has a consulting or advisory role for Bristol Myers Squibb, Bluebird Bio, Takeda, and Amgen; and research funding from Bluebird Bio. L.L. has employment with Lei Lei LLC; leadership role with Lei Lei LLC, stock or other ownership in Amgen; and consulting or advisory role with Kite, a Gilead Company, and BeiGene. J.D. has employment with Kite, a Gilead Company; consultancy or advisory role for GliaCure/Tufts; and patents, royalties, or other intellectual property from Patent US8598141 (Dec 03, 2013). J.B.L. has employment with Kite, a Gilead Company, and stock or other ownership in Gilead and Allogene. J.M.R. has employment with Kite, a Gilead Company. R.Z.O. has stock or other ownership in Asylia Therapeutics; patents, royalties, other intellectual property from MD Anderson and Asylia Therapeutics; research funding from BioTheryX, CARsgen Therapeutics, Celgene, Exelixis, Janssen, Sanofi, and Takeda; advisory board membership for Amgen, Bristol Myers Squibb, Celgene, EcoR1 Capital, Forma, Genzyme, GlaxoSmithKline Biologicals, Ionis Pharmaceuticals, Janssen, Juno, Kite, a Gilead Company, Legend, Molecular Partners, Regeneron, Sanofi, Servier, and Takeda; and consultancy or advisory role for STATinMED Research., (AJCR Copyright © 2021.)

T cell senescence and exhaustion are major barriers to successful cancer immunotherapy. Here we show that miR-155 increases CD8 + T cell antitumor function by restraining T cell senescence and functional exhaustion through epigenetic silencing of drivers of terminal differentiation. miR-155 enhances Polycomb repressor complex 2 (PRC2) activity indirectly by promoting the expression of the PRC2-associated factor Phf19 through downregulation of the Akt inhibitor, Ship1. Phf19 orchestrates a transcriptional program extensively shared with miR-155 to restrain T cell senescence and sustain CD8 + T cell antitumor responses. These effects rely on Phf19 histone-binding capacity, which is critical for the recruitment of PRC2 to the target chromatin. These findings establish the miR-155-Phf19-PRC2 as a pivotal axis regulating CD8 + T cell differentiation, thereby paving new ways for potentiating cancer immunotherapy through epigenetic reprogramming of CD8 + T cell fate.

Intravenous BU divided four times daily (q6 h) has been shown to be safe and effective in pediatric allo-SCT recipients. Though less frequent dosing is desirable, pharmacokinetic (PK) data on twice daily (q12 h) i.v. BU administration in pediatric allo-SCT recipients is limited. We prospectively examined the PK results in a cohort of pediatric allo-SCT recipients receiving i.v. BU q12 h as part of conditioning before allo-SCT. BU levels were obtained after the first dose of conditioning. PK parameter analysis (n=49) yielded the following 95% confidence intervals (CI₉₅): weight-normalized volume of distribution: 0.65-0.73 L/kg; t(1/2): 122-147 min; weight-normalized clearance (CL(n)): 3.4-4.3 mL/min/kg; and area under the curve: 1835-2180 mmol × min/L. From these results, a steady state concentration was calculated with CI₉₅ between 628-746 ng/mL. Comparison between recipients ≤4 vs >4 years old revealed significant differences in t(1/2) (mean: 115 vs 146 min, P=0.008) and CL(n) (mean: 4.4 vs 3.5 mL/min/kg, P=0.038). Intravenous BU q12 h had a comparable PK to i.v. BU q6 h PK seen in the literature, and in pediatric allo-SCT recipients, is a feasible, attractive alternative to i.v. q6h dosing.