We report on 16 patients with relapsed or refractory B cell acute lymphoblastic leukemia (B-ALL) that we treated with autologous T cells expressing the 19-28z chimeric antigen receptor (CAR) specific to the CD19 antigen. The overall complete response rate was 88%, which allowed us to transition most of these patients to a standard-of-care allogeneic hematopoietic stem cell transplant (allo-SCT). This therapy was as effective in high-risk patients with Philadelphia chromosome–positive (Ph+) disease as in those with relapsed disease after previous allo-SCT. Through systematic analysis of clinical data and serum cytokine levels over the first 21 days after T cell infusion, we have defined diagnostic criteria for a severe cytokine release syndrome (sCRS), with the goal of better identifying the subset of patients who will likely require therapeutic intervention with corticosteroids or interleukin-6 receptor blockade to curb the sCRS. Additionally, we found that serum C-reactive protein, a readily available laboratory study, can serve as a reliable indicator for the severity of the CRS. Together, our data provide strong support for conducting a multicenter phase 2 study to further evaluate 19-28z CAR T cells in B-ALL and a road map for patient management at centers now contemplating the use of CAR T cell therapy.

Adults with relapsed B-acute lymphoblastic leukemia (ALL) have a dismal prognosis. Only those patients able to achieve a second remission with no minimal residual disease (MRD−) have a hope for long-term survival in the context of a subsequent allogeneic hematopoietic stem cell transplantation (allo-HSCT). We have treated 5 relapsed B-ALL subjects with autologous T cells expressing a CD19-specific CD28/CD3ζ second generation dual-signaling chimeric antigen receptor (CAR) termed 19-28z. All patients with persistent morphological disease or MRD+ disease upon T cell infusion demonstrated rapid tumor eradication and achieved MRD-negative complete remissions as assessed by deep sequencing PCR. Therapy was well tolerated although significant cytokine elevations, specifically observed in those patients with morphologic evidence of disease at the time of treatment, required lymphotoxic steroid therapy to ameliorate cytokine-mediated toxicities. Significantly, cytokine elevations directly correlated to tumor burden at the time of CAR modified T cell infusions. Tumor cells from one patient with relapsed disease after CAR modified T cell therapy, ineligible for additional allo-HSCT therapy, exhibited persistent expression of CD19 and sensitivity to autologous 19-28z T cell mediated cytotoxicity suggesting potential clinical benefit of additional CAR modified T cell infusions. These results demonstrate the marked anti-tumor efficacy of 19-28z CAR modified T cells in patients with relapsed/refractory B-ALL and the reliability of this novel therapy to induce profound molecular remissions, an ideal bridge to potentially curative therapy with subsequent allo-HSCT.

We study bosonic atoms near a Feshbach resonance, and predict that in addition to a standard normal and atomic superfluid phases, this system generically exhibits a distinct phase of matter: a molecular superfluid, where molecules are superfluid while atoms are not. We explore zero-and finite-temperature properties of the molecular superfluid (a bosonic, strong-coupling analog of a BCS superconductor), and study quantum and classical phase transitions between the normal, molecular superfluid and atomic superfluid states.Experimental realizations and coherent manipulation of trapped degenerate gases [1, 2] is leading to exciting possibilities for studies of quantum liquids in previously unexplored (e.g., extremely coherent and nonequilibrium) regimes. Magnetic field-induced Feshbach resonance (FBR) in ultracold atom collisions allows fine tuning of interactions in these quantum fluids, and was recently used to create a degenerate mixture of coherentlycoupled alkali atoms and their diatomic molecules [3]. In this Letter we study phases and phase transitions that take place in bosonic atom-molecule mixtures. Our main contribution is the prediction of a thermodynamically distinct "molecular superfluid" (MSF) phase, that, as illustrated in Figs. 1, 2 ubiquitously intervenes between the "normal" (N) and "atomic superfluid" (ASF) phases. Molecular superfluidity [and accompanying offdiagonal long-range molecular order (ODLRO)] distinguishes MSF from the normal state, and the absence of atomic superfluidity from the ASF, in which both bosonic atoms and molecules display ODLRO. If atomic and molecular components can be imaged independently [4], in a harmonic trap MSF should be easily identifiable by a sharp Bose-Einstein condensation (BEC) peak in the molecular density profile and a broad, seemingly normal, thermal atomic cloud.As a conventional superfluid, MSF is characterized by a (molecular) acoustic second-sound mode. However, MSF also exhibits a gapped, Bogoliubov-like mode, derived from unpaired atom excitations. MSF ground state (bosonic analog of the BCS state) exhibits strong (atom and molecule) pairing correlations that in a trap should be observable in the atomic density-density correlation function. Experimentally, MSF should be accessible by tuning temperature, atomic density (or number), and detuning ν. The MSF-ASF transition is in the (d + 1)-and d-dimensional Ising universality classes for T = 0 and finite T , respectively, and is reentrant as a function of detuning ν and density n. The tricritical point, where N, MSF and ASF meet, exhibits nontrivial and, to our knowledge, unexplored quantum critical behavior for d < 4. We now sketch derivation of these results.Near a FBR a bosonic atom-molecule system is characterized by the grand-canonical HamiltonianĤ µ =Ĥ − µN [5]whereψ † σ (x),ψ σ (x) are bosonic field operators for atoms (σ = 1) and molecules (σ = 2),ĥ σ = −( 2 /2m σ )∇ 2 − µ σ are the corresponding single particle Hamiltonians (focusing for concreteness on the case of a homogeneous trap) with effec...

To increase the commercialization of fuel cell electric vehicles, it is imperative to improve the activity and performance of electrocatalysts through combined efforts focused on material characterization and device-level integration. Obtaining fundamental insights into the ongoing structural and compositional changes of electrocatalysts is crucial for not only transitioning an electrode from its as-prepared to functional state, also known as "conditioning", but also for establishing intrinsic electrochemical performances. Here, we investigated several oxygen reduction reaction (ORR) electrocatalysts via in situ and ex situ characterization techniques to provide fundamental insights into the interfacial phenomena that enable peak ORR mass activity and high current density performance. A mechanistic understanding of a fuel cell conditioning procedure is described, which encompasses voltage cycling and subsequent voltage recovery (VR) steps at low potential. In particular, ex situ membrane electrode assembly characterization using transmission electron microscopy and ultra-small angle X-ray scattering were performed to determine changes in carbon and Pt particle size and morphology, while in situ electrochemical diagnostics were performed either during or after specific points in the testing protocol to determine the electrochemical and interfacial changes occurring on the catalyst surface responsible for oxygen transport resistances through ionomer films. The results demonstrate that the voltage cycling (break-in) step aids in the removal of sulfate and fluoride and concomitantly reduces non-Fickian oxygen transport resistances, especially for catalysts where Pt is located within the pores of the carbon support. Subsequent low voltage holds at low temperature and oversaturated conditions, i.e., VR cycles, serve to improve mass activities by a factor of two to three, through a combined removal of contaminants, surface-blocking species (e.g., oxides), and rearrangement of the catalyst atomic structure (e.g., Pt−Pt and Pt−Co coordination).

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