Citations

Abstract Background: Disease relapse is common with peripheral T-cell lymphomas (PTCL) or cutaneous T-cell lymphomas (CTCL). Adoptive immunotherapy with CD19 directed CAR-T cells is a standard option for B cell lymphoid malignancies in the relapsed setting. This study assesses the safety and preliminary efficacy of CD4 targeting autologous CAR-T, LB1901, in patients (pts) with CD4+ relapsed or refractory (R/R) TCL. A pre-clinical study showed LB1901 exhibited potent anti-tumor activity without off-target effects (Zeng 2021). Methods: This is a phase 1, open-label, multicenter, multicohort study of LB1901 (NCT04712864; currently enrolling). Eligible pts are ≥18 years with histologically confirmed CD4+ PTCL-NOS (not otherwise specified); or CD4+ AITL (angioimmunoblastic T-cell lymphoma); or CD4+ CTCL (either MF [mycosis fungoides] or SS [Sézary syndrome]). In Part A (dose escalation), pts with SS must have ≤2,000 circulating Sézary cells/µL to ensure safety of pts with higher disease burden. In Part B, pts with >2,000 Sézary cells/µL is allowed. CD4 expressed on tumor cells must be confirmed within 3 months prior to apheresis. Other inclusion criteria include: R/R disease with ≥2 prior lines of systemic antineoplastic therapy; for pts with PTCL-NOS or AITL, ≥1 measurable lesion according to IWG Response Criteria (Cheson 2014) and for pts with CTCL, ≥stage IIB on TNMB-ISLC/EORTC staging system; identified HSCT donor available prior to enrollment (in the event of severe recurrent infections and prolonged lymphopenia for which pt may need an allogeneic HSCT as a safety rescue); and ECOG status of 0 or 1. Response will be evaluated based on IWG response criteria for PTCL and Global Composite Response for CTCL (Olsen 2007). The study will be conducted in 2 parts (Part A: dose escalation and Part B: dose expansion). Three dose levels (0.3 X 106, 1.0 X 106, and 3.0 X 106 CAR+ viable T cells/kg) will be evaluated (N=3-6 for each dose level) with an optional dose level minus 1 (0.1 X 106 CAR+ viable T cells/kg). Part B will include 2 cohorts, PTCL and CTCL (N=12-20 for each), after the recommended dose for expansion (RDE) has been identified in Part A. Enrolled pts will undergo apheresis for PBMC collection. LB1901 will be manufactured from autologous CD8+ T cells. Pts may receive optional bridging therapy and receive lymphodepleting chemotherapy with fludarabine 30mg/m2/day and cyclophosphamide 300mg/m2/day (Flu-Cy), for 3 days followed by LB1901. Primary endpoints are incidence, duration, and severity of AEs and laboratory abnormalities (Parts A and B) and DLT at each dose level (Part A). Secondary endpoints include overall response rate; duration of response; CAR-positive T cell counts and CAR transgene level in blood; and presence of anti-CAR antibody response. Exploratory endpoints include preliminary efficacy, pharmacokinetics, and CD4+ T cell counts. Citation Format: Swaminathan P. lyer, David G. Maloney, Nora Bennani, Auris Huen, Muhammad Akram, Soo Kim, Chuan Wang, Zhiyin Liang, Henry Castro, Lida Pacaud, Mehdi Hamadani. LB1901: A phase 1, open-label, multicenter, multicohort study of CD4-targeted chimeric antigen receptor T cells (CD4-CAR-T) in relapsed or refractory T-cell lymphoma (TCL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT215.

Abstract This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas’ original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300–600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75–150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175–300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100–200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250–400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150–300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300–600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

Abstract Rationale: Given recent success in delivering interferon-beta (IFNβ) using replication incompetent adenovirus in patients with malignant pleural effusions, we hypothesized that vectors that could replicate (inducing oncolysis) and express IFNβ at high level would be more effective. Both vaccinia virus (VV) and vesicular stomatitis (VSV) expressing mouse IFNβ have been constructed in a manner to improve their safety and efficacy as oncolytic vectors. In this study, we evaluated these two oncolytic vectors in different murine thoracic cancer models for clinical translation. Experimental procedures: We compared the efficacy of VVIFNβ and VSVIFNβ to kill 3 mouse lung cancer and 4 mouse mesothelioma lines in vitro over a 5 day-period assessing cell viability by MTT assay. The amount of IFNβ produced by these two vectors were measured with ELISA. The viral replication in infected mice was assessed by measuring viral titers in both immunocompetent and immunodeficient mice bearing an IFN-non-responsive AB12 tumor, following intratumoral injection of either vector at 108 pfu/mouse. To assess their anti-tumor activity, the two vectors were also given at 108 pfu/mouse intratumorally in mice bearing two lung cancer tumors on their flanks. Results: The replication of VSVIFNβ and its killing ability was limited in some of the tumor lines. This appeared to be due to an intact IFN response pathway. In contrast, VVIFNβ was able to kill all of the tumor lines. In culture, VSV replicates faster than VV, which resulted in faster cell killing (in susceptible cell lines), but with less IFNβ production. The amount of IFNβ production by VVIFNβ was comparable with AdIFNβ over a 5 day period. VVIFNβ-infected immunodeficient mice showed minimal or no toxicity when given virus intravenously, while all 5 mice infected with VSVIFNβ developed neurotoxicity within a week. In the TC-1 lung cancer model, VVIFNβ caused tumor regression, while VSVIFNβ and AdIFNβ were completely ineffective. In a second model using LKRM2, all 3 viral vectors were equivalent. The anti-tumor effect of VVIFNβ was shown to be mainly CD8 dependant, as depletion of CD8 with antibody dampened the tumor growth inhibition from 48% to 20%. Conclusions: Overall, VVIFNβ appears to be a better oncolytic vector than VSVIFNβ for a number of reasons: 1) it is safer, 2) it is able to replicate in vitro and in vivo in almost every cell line tested, 3) it induces longer and larger IFNβ production, and 4) it can potentially be given intravenously. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1513.