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We designed a CD19-targeted CAR comprising a calibrated signaling module, termed 1XX, that differs from that of conventional CD28/CD3z and 4-1BB/CD3z CARs. Here we report the first-in-human, phase 1 clinical trial of 19(T2)28z-1XX CAR T cells in relapsed/refractory large B-cell lymphoma. We hypothesized that 1XX CAR T cells may be effective at low doses and investigated 4 doubling dose levels starting from 25×10 6 CAR T cells. The overall response rate (ORR) was 82% and complete response (CR) rate 71% in the entire cohort (n=28) and 88% ORR and 75% CR in 16 patients treated at 25×10 6 . With the median follow-up of 24 months, the 1-year EFS was 61% (95% CI: 45-82%). Overall, grade ≥3 CRS and ICANS rates were low at 4% and 7%. The calibrated potency of the 1XX CAR affords excellent efficacy at low cell doses and may benefit the treatment of other hematological malignancies, solid tumors and autoimmunity., Competing Interests: Competing Interests J.H.P. received consulting fees from Affyimmune Therapeutics, Amgen, Autolus, Be Biopharma, Beigene, Bright Pharmaceutical Services, Inc., Caribou Biosciences, Curocell, Galapagos, In8Bio, Kite, Medpace, Minerva Biotechnologies, Pfizer, Servier, Sobi, and Takeda; received honoraria from OncLive, Physician Education Resource, and MJH Life Sciences; serves on scientific advisory board of Allogene Therapeutics, Artiva Biotherapeutics and Green Cross Biopharma; and received institutional research funding from Autolus, Genentech, Fate Therapeutics, InCyte, Servier, and Takeda. M.L.P. received consulting fees from BMS, Cellectis, Kite, Mustang Bio and Synthekine. G.Sh. received research funding to the institution from Amgen, BMS, Beyond Spring, Janssen, and GPCR, and serves on DSMB for Arcellx. P.D. received consulting fees from Kite. M.Sc. served as a paid consultant for McKinsey & Company, Angiocrine Bioscience, Inc., Kite, and Omeros Corporation; received research funding from Angiocrine Bioscience, Inc., Omeros Corporation, and Amgen, Inc.; served on ad hoc advisory boards for Kite-A Gilead company; and received honoraria from i3Health, Medscape and CancerNetwork for CME-related activity. G.Sa. has received financial compensations for participating in advisory boards or consulting for Abbvie, Atbtherapeutics, Beigene, BMS, Debiopharm Genentech/Roche, Genmab, Incyte, Ipsen, Janssen, Kite/Gilead, Loxo/Lilly, Merck, Molecular Partners, Nordic Nanovector, Novartis, Nurix and Orna. He is also a shareholder of: Owkin; he received Research Support managed by his institution from Genentech, Janssen, Ipsen, Nurix. Y.K.V. received one time consulting fee from EastRx. J.M.S. is an inventor on 1XX related IP. I.R. reports grants from Takeda Pharmaceuticals and Atara, personal fees from Mnemo Therapeutics, Akron, the Centre for Commercialization of Cancer, and Oribiotech, and other support from Bristol Myers Squibb outside the submitted work. M. S. reports grants from Atara Biotherapeutics outside the submitted work, as well as patent 8389282 issued and licensed to Juno Therapeutics, patent 11242375 issued and licensed to Atara Biotherapeutics, patent 10370452 issued, licensed, and with royalties paid from Fate Therapeutics, patent 11377637 issued and licensed to Takeda Pharmaceuticals, patent 11377637 issued and licensed to Mnemo Therapeutics, and patent 11377637 issued and licensed to Minerva Biotechnologies. MSK has licensed 1XX technology to Atara Biotherapy, Fate Therapeutics, Minerva Therapeutics, and Takeda Pharmaceuticals.

Background CD37 is expressed on B-cell lymphoid malignancies, thus making it an attractive candidate for targeted therapy in non-Hodgkin lymphoma (NHL). IMGN529 is an antibody-drug conjugate comprising a CD37-binding antibody linked to the maytansinoid DM1, a potent anti-mitotic agent. Methods This first-in-human, phase 1 trial recruited adult patients with relapsed or refractory B-cell NHL. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose. Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary clinical activity. IMGN529 was administered intravenously once every 3 weeks, and dosed using a conventional 3 + 3 dose-escalation design. Results Forty-nine patients were treated at doses escalating from 0.1 to 1.8 mg/kg. Dose limiting toxicities occurred in eight patients and included peripheral neuropathy, febrile neutropenia, neutropenia, and thrombocytopenia. The most frequent treatment-emergent adverse events were fatigue (39%), neutropenia, pyrexia, and thrombocytopenia (each 37%). Adverse events led to treatment discontinuation in 10 patients (20%). Eight patients (16%) had treatment-related serious adverse events, the most common being grade 3 febrile neutropenia. The MTD (with growth factor support) was 1.4 mg/kg every 3 weeks. IMGN529 plasma exposure increased monotonically with dose and was consistent with target-mediated drug disposition. Five (13%) of 39 response-evaluable patients achieved an objective response (one complete response and four partial responses), four of which occurred in the subgroup of patients with diffuse large B-cell lymphoma. Conclusions The manageable safety profile of IMGN529 and preliminary evidence of activity, particularly in DLBCL patients, support the continued development of this novel CD37-targeting agent.

CXCR4(WHIM) somatic mutations are distinctive to Waldenström Macroglobulinaemia (WM), and impact disease presentation and treatment outcome. The clonal architecture of CXCR4(WHIM) mutations remains to be delineated. We developed highly sensitive allele-specific polymerase chain reaction (AS-PCR) assays for detecting the most common CXCR4(WHIM) mutations (CXCR4(S338X C>A and C>G) ) in WM. The AS-PCR assays detected CXCR4(S338X) mutations in WM and IgM monoclonal gammopathy of unknown significance (MGUS) patients not revealed by Sanger sequencing. By combined AS-PCR and Sanger sequencing, CXCR4(WHIM) mutations were identified in 44/102 (43%), 21/62 (34%), 2/12 (17%) and 1/20 (5%) untreated WM, previously treated WM, IgM MGUS and marginal zone lymphoma patients, respectively, but no chronic lymphocytic leukaemia, multiple myeloma, non-IgM MGUS patients or healthy donors. Cancer cell fraction analysis in WM and IgM MGUS patients showed CXCR4(S338X) mutations were primarily subclonal, with highly variable clonal distribution (median 35·1%, range 1·2-97·5%). Combined AS-PCR and Sanger sequencing revealed multiple CXCR4(WHIM) mutations in many individual WM patients, including homozygous and compound heterozygous mutations validated by deep RNA sequencing. The findings show that CXCR4(WHIM) mutations are more common in WM than previously revealed, and are primarily subclonal, supporting their acquisition after MYD88(L265P) in WM oncogenesis. The presence of multiple CXCR4(WHIM) mutations within individual WM patients may be indicative of targeted CXCR4 genomic instability., (© 2015 John Wiley & Sons Ltd.)

The standard treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL) in frail elderly patients has not been established. A variation was made on rituximab (R), cyclophosphamide (C), etoposide (E), procarbazine and prednisone (P), substituting vorinostat (V) for procarbazine. Patients ≥aged 60 years with relapsed/refractory DLBCL, not candidates for autologous stem cell transplantation, were treated R-CVEP [R 375 mg/m(2) intravenously (IV), day 1; C 600 mg/m(2) IV days 1, 8: E 70 mg/m(2) IV day 1, 140 mg/m(2) days 2, 3 orally (PO); V (300 vs. 400 mg) PO and P 60 mg/m(2) PO days 1-10] every 28 d for six cycles. Quality of life (QoL) was assessed in addition to response. Thirty patients (median age 76 years, 69-88) were enrolled (one died before treatment). Maximum tolerated dose (MTD) for V was 300 mg. For 23 patients at MTD (six phase I + 17 phase II), two were discontinued for toxicity, one withdrew consent, eight achieved complete response (35%), five achieved partial response (22%) and seven progressed (25%). Median overall survival was 17·5 months. Median progression-free survival was 9·2 months. Nine patients are alive. QoL declined during treatment but improved above baseline for patients who completed treatment. In conclusion, R-CVEP was tolerated at MTD and produced durable responses with improved QoL., (© 2014 John Wiley & Sons Ltd.)