Axicabtagene ciloleucel in vivo expansion and treatment outcome in aggressive B-cell lymphoma in a real-world setting

Data on the association between chimeric antigen receptor (CAR)-T-cell kinetics and patient outcome in the nontrial setting are missing, mainly due to the lack of broadly available CAR-T-cell diagnostic quantification tools. We performed prospective quantification of axicabtagene ciloleucel (axi-cel) in 21 patients treated for aggressive B-cell lymphoma at our clinic. Median peak CAR-T-cell count was 16.14 CAR-T cells/µL. Patients with 16.14/μL or higher peak CAR-T cells (strong expanders) had more day-30 objective responses (91% vs 40%, P = .02). In univariate analysis, peak CAR-T cell ≥ 16.14 (P < .001), normal platelet counts at start of lymphodepletion (P < .001), no prior stem cell transplant (P = .04), and peak CAR-T cells as continuous variable (P = .03) were associated with better progression-free survival (PFS). After adjusting for platelet counts and prior stem cell transplantation, peak CAR-T cells below median was still associated with shorter PFS (relative risk, 0.15, 95% confidence interval, 0.04-0.59, P = .007). Low platelet counts also maintained significant impact on PFS. Our data demonstrate association of axi-cel levels and outcome in a nontrial setting and for the first time use a cutoff to segregate weak and strong expanders with respective outcomes.

Maladaptive Planning and the Pro-Innovation Bias: Considering the Case of Automated Vehicles

This article argues that a more critical approach to innovation policy within planning is needed and offers recommendations for achieving this. These recommendations entail rethinking the values, focus, speed, and legitimacy of innovations. It takes a critical perspective on how contemporary societies treat rapid innovation as having necessarily positive results in the achievement of objectives such as sustainability and justice. This critical perspective is needed because innovation can both contribute to and drive a form of maladaptive planning: a collective approach to reality that imposes constant and rapid changes to societal configurations due to an obsession with the new and with too little rapport with the problems in place or that it creates. A maladaptive direction for transport planning is used as a sectorial illustration of the broader conceptual ideas presented: for both sustainability and social justice reasons, it would be desirable to see peak car occurring. However, the car industry is presenting driving automation as an innovation with the potential to restore the vitality of the private vehicles market while creating effective means to dismiss alternatives to car dominance.

Automated Manufacture of Matched Donor-Derived Allogeneic CD19 CAR T-Cells for Relapsed/Refractory B-ALL Following Allogeneic Stem Cell Transplantation: Toxicity, Efficacy and the Important Role of Lymphodepletion

Introduction: 2nd generation CD19 CAR T cells show unprecedented efficacy in B-ALL, but several challenges remain: (1) scaling manufacture to meet patient need and (2) feasibility of generating products from lymphopenic patients post allogeneic stem cell transplant (allo-SCT). To overcome these issues we propose: (1) use of the CliniMACS Prodigy (Miltenyi Biotec), a semi-automated cGMP platform that simplifies CAR T cell manufacture and (2) the use of matched donor T cells to overcome the challenge posed by patient lymphopenia, albeit this may come with a heightened risk of graft versus host disease (GvHD). CARD (NCT02893189) is a Phase I study of matched donor derived CD19 CAR T cells generated on the CliniMACS Prodigy in 14 adult patients with relapsed/refractory (r/r) B ALL following allo-SCT. We additionally explore the requirement for lymphodepletion (LD) in the allogeneic CAR T cell setting and report on the incidence of GvHD with this therapy. Methods: Manufacturing: CARD utilises non-mobilised matched donor leucapheresate to manufacture 2nd generation CD19CAR T cells using a closed CliniMACS® Prodigy/ TransACTTM process. Study design: Eligible subjects are aged 16-70y with r/r B ALL following allo SCT. Study endpoints include feasibility of CD19CAR T cell manufacture from allo-SCT donors on the CliniMACS Prodigy and assessments of engraftment and safety including GvHD. To assess the requirement for LD prior to CD19CAR T cells in lymphopenic post-allo-SCT patients, the study is split into Cohort 1 (no LD) and Cohort 2 (fludarabine (30 mg/m2 x3) and cyclophosphamide (300mg/m2 x3)). To mitigate for the potential GvHD risk, cell dosing on study mirrors conventional donor lymphocyte infusion (DLI) schedules and is based on total CD3+ (not CAR T) cell numbers: Dose 1=1x106/kg CD3+ T cells; Dose 2= 3x106/kg CD3+ T cells; Dose 3= 1x107/kg CD3+ T cells. Results: As of 26 July 2019, 17 matched allo SCT donors were leukapheresed and 16 products were successfully manufactured and QP released. Patient demographics are as follows: (1) median patient age was 43y (range 19-64y); (2) 4/17 had prior blinatumomab and 5/17 prior inotuzumab ozogamicin; (3) 7/17 had myeloablative allo SCT and 10/17 reduced intensity allo SCT of which 6/17 were sibling donors and 12/17 were matched unrelated donors. No patients with haploidentical transplant were enrolled. To date, 12/16 patients have received at least 1 dose of CD19CAR T cells: 7/16 on Cohort 1 and 5/16 on Cohort 2 (2/16 are pending infusion on Cohort 2 and 2/16 died of fungal infection prior to infusion). Median follow-up for all 12 patients is 22.9 months (IQR 2.9-25.9; range 0.7 - 25.9). At the time of CAR T cell infusion, 7/12 patients were in morphological relapse with >5% leukemic blasts. Despite this, CD19CAR T cells were administered safely: only 2/12 patients experienced Grade 3 CRS (UPenn criteria), both in Cohort 1, which fully resolved with Tocilizumab and corticosteroids. No patients experienced ≥Grade 3 neurotoxicity and importantly, no patients experienced clinically significant GvHD. In Cohort 1 (7 patients), median peak CAR expansion by flow was 87 CD19CAR/uL blood whereas in Cohort 2 (5 patients to date), median peak CAR expansion was 1309 CD19CAR/uL blood. This difference is likely to reflect the use of LD in Cohort 2. CAR T cell persistence by qPCR in Cohort 1 is short, with demonstrable CAR in only 2/7 treated patients at Month 2. Data for Cohort 2 is immature, but this will also be reported at the meeting in addition to potential mechanisms underlying the short persistence observed in Cohort 1. Of the 10 response evaluable patients (2/12 pending marrow assessment), 9/10 (90%) achieved flow/molecular MRD negative CR at 6 weeks. 2/9 responders experienced CD19 negative relapse (one at M3, one at M5) and 3/9 responders experienced CD19+ relapse (one at M3, one at M9, one at M12). 4/10 (40%) response evaluable patients remain on study and continue in flow/molecular MRD negative remission at a median follow up of 11.9 months (range 2.9-25.9). Conclusions: Donor-derived matched allogeneic CD19 CAR T cells are straightforward to manufacture using the CliniMACS Prodigy and deliver excellent early remission rates, with 90% MRD negative CR observed at Week 6 in the absence of severe CAR associated toxicity or GvHD. Peak CAR expansion appears to be compromised by the absence of LD and this may lead to a higher relapse rate. Updated results from Cohorts 1 and 2 will be presented. Disclosures Roddie: Novartis: Consultancy; Gilead: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. O'Reilly:Kite Gilead: Honoraria. Farzaneh:Autolus Ltd: Equity Ownership, Research Funding. Qasim:Autolus: Equity Ownership; Orchard Therapeutics: Equity Ownership; UCLB: Other: revenue share eligibility; Servier: Research Funding; Bellicum: Research Funding; CellMedica: Research Funding. Linch:Autolus: Membership on an entity's Board of Directors or advisory committees. Pule:Autolus: Membership on an entity's Board of Directors or advisory committees. Peggs:Gilead: Consultancy, Speakers Bureau; Autolus: Membership on an entity's Board of Directors or advisory committees.

Peak-Car Phenomenon Revisited for Urban Areas: Microdata Analysis of Household Travel Surveys from Five European Capital Cities

This study investigates the peak-car phenomenon for the five European capital regions of Berlin, Copenhagen, London, Paris, and Vienna. Household travel survey (HTS) microdata was harmonized for the five regions and transferred to one consistent database; all time-series date back at least 20 years. Developments in car use were found to be surprisingly similar despite the substantial differences between the regions in terms of size, governance structures, built environments, transport systems, and societal framework conditions. Car use peaked earliest in Paris in the early 1990s; followed by Berlin, London, and Vienna in the late 1990s; and lastly in Copenhagen in the late 2000s. Working persons and mandatory trips were found to be the most relevant person group and trip purpose for the observed peak-car developments, both with declining overall trip numbers and a modal shift toward non-car modes. Young working persons had the most significant decline with substantial cohort effects. People seem to carry forward their behavior adopted in early life-cycle stages as they age. The person groups of seniors and women both damped the peak-car effect. Shopping trips were the second most relevant trip purpose for car use: car use for this purpose was high and stable over time. This study has elaborated potentials for reducing car use in relation to person groups and trip purposes. Findings from this retrospective analysis could be used for purposefully shaping future transport systems.

Phase 1 Study of CD19/CD22 Bispecific Chimeric Antigen Receptor (CAR) Therapy in Children and Young Adults with B Cell Acute Lymphoblastic Leukemia (ALL)

Chimeric Antigen Receptor (CAR) therapy targeting CD19 achieves complete remission (CR) rates of 70%-90% in relapsed/refractory B-ALL. Relapse due to loss of the CD19 targeted epitope presents a therapeutic challenge as evidenced by the largest global pediatric CD19-CAR experience which showed 15 of 16 relapses to be explained by CD19 downregulation (Maude et al, NEJM 2018). Alternatively targeting CD22 using CD22-CAR therapy has demonstrated a CR rate of approximately 70% in both CD19+ and CD19- B-ALL, however relapse due to CD22 downregulation limits the curative potential of singularly-targeting CD22 (Fry et al, Nat Med. 2018). We hypothesized that simultaneous targeting of CD19 and CD22 via a bispecific CAR-T cell would be a safe and tolerable treatment strategy in relapsed/refractory B-cell ALL and address immune evasion. Here, we report the first clinical experience in pediatric patients using bispecific CD19-CD22 CAR T cells. We describe a single institution phase I dose escalation study in pediatric patients with relapsed or refractory B cell ALL. We utilized lentiviral transduction of a bivalent CAR construct incorporating the fmc63 CD19 and m971 CD22 single chain variable fragments (scFvs) used in clinically tested CAR constructs and a 41BB costimulatory endodomain (Fry et al, Nat Med. 2018). Our primary objectives are feasibility of production of this bivalent CAR and safety at 3 dose escalation levels (1x106, 3x106 and 1x107 CAR T cells/kg). Clinical response assessment is evaluated as a secondary aim. All patients described received lymphodepletion with fludarabine (25mg/m2 x 3 days) and cyclophosphamide (900mg/m2 x 1) followed by fresh or cryopreserved CAR T cell infusion after a 7-9 day production time. Patients were prospectively monitored at predefined intervals for disease response and correlative assessments. Four pediatric patients with precursor-B ALL, age 2-17, have been enrolled and treated with CD19/CD22 bispecific CAR T cells at dose level 1 (1x106) [Table 1]. Three patients entered CAR therapy with low disease burden detected by minimal residual disease (MRD) alone and 1 patient initiated therapy with 12% bone marrow blasts. All patients were CNS1 at time of treatment. The toxicity profile mirrored that of the singular CD19 and CD22 CAR experience with 3 patients experiencing reversible CRS (2 Grade I, 1 Grade II), onset day 3-8, and 2 patients experiencing grade I neurotoxicity, onset day 3-9. In our cohort, we experienced lower grade toxicities than previously reported, likely due to a mean lower disease burden. Only 1 patient with CRS met criteria for tocilizumab and this patient was the singular study patient treated with higher burden disease. Neurotoxicity was managed with supportive care and fully reversible. Peripheral blood flow cytometry analysis detects circulating CAR by day 6 in all patients and demonstrates peak CAR expansion between day 6-10. Peak CAR T expansion reached levels of 10-25% of total T cells with inter-patient variability in CD4 and CD8 predominance, favoring CD8 expansion in 3 of 4 patients. Clinical symptoms and inflammatory markers expectedly correlate with peak CAR expansion. Four of 4 patients achieved complete remission (CR) at day 28 post-CD19/CD22 bispecific CAR therapy. Three of 4 patients demonstrated MRD- remissions by flow cytometry and of these, next generation sequencing (NGS) was negative where available (N=2). Multi-parametric CyTOF studies permitting CAR T cell phenotyping in conjunction with single cell TCR tracking, proteomics, epigenomics and cytokine profiling are ongoing and will be used to further characterize persisting CAR T cells and define inter-product and inter-patient variability. In this phase I study, we demonstrate safety and tolerability of this bispecific CD19/CD22 CAR at a dose of 1x106 CAR T cells/kg in pediatric patients with relapsed/refractory B cell ALL. The CD19/22-bispecific CAR mediated antileukemic activity in 100% of patients studied thus far. Long-term follow up and further accrual will be required to inform the effect of bispecific CAR targeting on surface antigen remodeling. Disclosures Muffly: Adaptive Biotechnologies: Research Funding; Shire Pharmaceuticals: Research Funding. Miklos:Genentech: Research Funding; Kite - Gilead: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics - Abbot: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

Beijing’s Peak Car Transition: Hope for Emerging Cities in the 1.5 °C Agenda

Peak car has happened in most developed cities, but for the 1.5 °C agenda the world also needs emerging cities to go through this transition. Data on Beijing shows that it has reached peak car over the past decade. Evidence is provided for peak car in Beijing from traffic supply (freeway length per capita and parking bays per private car) and traffic demand (private car ownership, automobile modal split, and Vehicle Kilometres Travelled per capita). Most importantly the data show Beijing has reduced car use absolutely whilst its GDP has continued to grow. Significant growth in electric vehicles and bikes is also happening. Beijing’s transition is explained in terms of changing government policies and emerging cultural trends, with a focus on urban fabrics theory. The implications for other emerging cities are developed out of this case study. Beijing’s on-going issues with the car and oil will remain a challenge but the first important transition is well underway.

Understanding Outcomes of CD19-Targeted CAR T Cell Immunotherapy

CD19-specific chimeric antigen receptor (CAR)-modified T cells have antitumor activity in patients with relapsed and/or refractory B cell malignancies, but factors that impact toxicity and efficacy have been difficult to define because of heterogeneity of CAR-T cells administered to individual patients. We conducted a clinical trial in which CD19 CAR-T cells were manufactured from defined T cell subsets and administered in a 1:1 ratio of CD4+:CD8 + CAR-T cells to adults with CD19+ acute lymphoblastic leukemia (B-ALL), non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL) after lymphodepletion chemotherapy. The defined composition product was remarkably potent, with bone marrow CR rates exceeding 90% in B-ALL patients, and overall response rates of 70-80% in NHL and CLL patients. In vivo CAR-T cell expansion and persistence were enhanced by the combination of cyclophosphamide (Cy) and fludarabine (Flu) lymphodepletion compared to Cy-based regimens without Flu, and were associated with better response. The enhanced CAR-T cell expansion and persistence in NHL patients receiving Cy/Flu lymphodepletion was due in part to an increase in available homeostatic cytokines, such as IL-15, and in B-ALL and NHL patients abrogation of anti-CAR transgene immune responses, which promoted CAR-T cell rejection and early relapse in a subset of patients. The depth of response appeared important in CLL, in which we found that absence of the malignant IGH clone in marrow of patients who responded by IWCLL imaging criteria was associated with longer progression-free survival (PFS) after CAR-T cell infusion compared to those in whom the malignant IGH clone was detected. CD19 CAR-T cell immunotherapy can be complicated by cytokine release syndrome (CRS), neurotoxicity, and B cell depletion. Endothelial activation was observed in patients with severe CRS and neurotoxicity, which may account for clinical manifestations, including vascular instability, capillary leak, and blood-brain barrier permeability. In B-ALL, NHL and CLL patients, we found that more severe CRS and neurotoxicity were associated with factors that increase CAR-T cell expansion, resulting in higher concentrations of distinct cytokines in serum after infusion. In B-ALL, CAR-T cell expansion and the risk of toxicity were also higher in patients with high tumor burden. Probability curves defined the likelihood of CRS, neurotoxicity or response in each disease cohort according to in vivo peak CAR-T cell concentrations in blood. The data indicate that a therapeutic window between CR and CRS or neurotoxicity can be defined in B-ALL within a distinct range of peak CAR-T cell counts. Reduction of the infused CAR-T cell dose in those with high marrow burden minimized the risk of high peak CAR-T cell counts that were associated with an increased risk of toxicity. In NHL patients, probability curves indicated that CAR-T cell dose reduction to reduce toxicity could be associated with loss of anti-tumor efficacy, suggesting that CAR-T cell dosing at the maximum tolerated dose combined with early intervention strategies in patients at high risk of CRS or neurotoxicity might be a suitable strategy to minimize toxicity while maintaining efficacy. Using a classification-tree algorithm we identified clinical and serum biomarkers that allow testing of early intervention strategies in patients at the highest risk of toxicity. These data will inform strategies that facilitate safe and effective clinical application of CD19 CAR-T cell therapy. Disclosures Turtle: Juno Therapeutics: Other: Advisory board, Patents & Royalties, Research Funding; Celgene: Other: Advisory board; Precision Biosciences: Other: Advisory board; Adaptive Biotechnologies: Other: Advisory board; Bluebird Bio: Other: Advisory board; Gilead Sciences: Other: Advisory board.