Ceftaroline (active form of the prodrug ceftaroline fosamil) is a novel cephalosporin with activity against pathogens commonly associated with community-acquired pneumonia (CAP), including Streptococcus pneumoniae and Gram-negative pathogens. This randomized, double-blind, Phase III study evaluated the efficacy and safety of ceftaroline fosamil in treating patients with CAP. The primary objective was to determine non-inferiority [lower limit of 95% confidence interval (CI) ≥ -10%] of clinical cure rates achieved with ceftaroline fosamil compared with those achieved with ceftriaxone in the clinically evaluable (CE) and modified intent-to-treat efficacy (MITTE) populations.Patients hospitalized in a non-intensive care unit setting with CAP of Pneumonia Outcomes Research Team (PORT) risk class III or IV requiring intravenous (iv) therapy were randomized (1:1) to receive 600 mg of ceftaroline fosamil iv every 12 h or 1 g of ceftriaxone iv every 24 h. Clinical cure, microbiological response, adverse events (AEs) and laboratory tests were assessed. FOCUS 2 registration number NCT00509106 (http://clinicaltrials.gov/ct2/show/NCT00509106).The study enrolled 627 patients, 315 of whom received ceftaroline fosamil and 307 of whom received ceftriaxone. Patients in both treatment groups had comparable baseline characteristics. Clinical cure rates were as follows: CE population, 82.1% (193/235) for ceftaroline fosamil and 77.2% (166/215) for ceftriaxone [difference (95% CI), 4.9% (-2.5, 12.5)]; and MITTE population, 81.3% (235/289) for ceftaroline fosamil and 75.5% (206/273) for ceftriaxone [difference (95% CI), 5.9% (-1.0, 12.7)]. Clinical cure rates for CAP caused by S. pneumoniae in the microbiological MITTE (mMITTE) population were 83.3% (35/42) and 70.0% (28/40) for ceftaroline fosamil and ceftriaxone, respectively. Ceftaroline fosamil and ceftriaxone were well tolerated, with similar rates of AEs, serious AEs, deaths and discontinuations due to an AE. The most common AEs for ceftaroline fosamil-treated patients were diarrhoea, headache, hypokalaemia, insomnia and phlebitis, and the most common AEs for ceftriaxone-treated patients were diarrhoea, insomnia, phlebitis and hypertension.Ceftaroline fosamil achieved high clinical cure and microbiological response rates in patients hospitalized with CAP of PORT risk class III or IV. Ceftaroline fosamil was well tolerated, with a safety profile that is similar to that of ceftriaxone and other cephalosporins. Ceftaroline fosamil is a promising agent for the treatment of CAP.
Hispanics and non-Hispanic (NH)-Blacks continue to face numerous health disparities related to multiple myeloma (MM). We aimed to analyze trends of MM-related hospitalizations and incidence of in-hospital mortality with a 10-year cross-sectional analysis of inpatient hospitalizations. The prevalence of MM-related hospitalizations was higher in NH-Blacks compared to NH-Whites (476.0 vs. 305.6 per 100,000 hospitalizations, p < .001). MM-related in-hospital mortality was higher in Hispanics compared to NH-Whites and NH-Blacks (6.2 vs. 5.3%, p < .001). Using average annual percent change (AAPC), we found a statistically significant decline of in-hospital mortality among all MM patients except NH-Blacks (AAPC: −2.2, 95% confidence interval (CI) −4.7, 0.4, p = .47), who had the highest inpatient mortality in recent years. Multivariate analysis showed that NH-Blacks received fewer transplants, more blood product transfusions, fewer palliative care consults, less inpatient chemotherapy, and utilized more intensive care. Disparities in MM care for NH-Blacks and Hispanics continue to persist despite recent advancements in MM therapy.
Although 2nd-generation (2G) CD19-specific CARs containing CD28 or 4-1BB costimulatory endodomains show remarkable efficacy against B-NHL, the optimal choice of domains in these and other CARs remains controversial. Individual endodomains, such as CD28 (Long, Nat Med 2015), may be associated with deleterious ligand-independent tonic signaling in the transduced T cell, but it is unclear if tonic 4-1BB signaling may have such consequences as well, and if such effects can be reversed. We therefore modeled tonic CAR signaling in T cells by transducing them with gammaretroviral vectors expressing 2G CD19.CAR constructs containing CD3-ζ and either the CD28 or 4-1BB endodomains. 4-1BB CD19.CAR-T cells (CARTs) expanded 70% slower, which was coupled with a 4-fold increase in apoptosis and a gradual downregulation of CAR expression. This was a consequence of 4-1BB-associated tonic TRAF2- dependent signaling, leading to activation of NF-κB, upregulation of Fas and augmented Fas-dependent activation induced T cell death. Because of the toxicity of 4-1BB in our CAR construct, we could not directly compare the in vivo fate of 4-1BB CD19.CARTs with that of CD28 CD19.CARTs. We found, however, that the 4-1BB toxicity could be overcome in a 3rd-generation (3G) CD19.CAR vector containing both CD28 and 4-1BB. We thus compared the fate of that 3G vector with the 2G vector containing CD28 alone. Eight patients with refractory/ relapsed diffuse large B-cell lymphoma received 2 cell populations, one expressing 2G and one expressing 3G vectors. To determine whether CD28 alone was optimal (which would suggest 4-1BB is antagonistic) or whether 4-1BB had an additive or synergistic effect contributing to superior persistence and expansion of the CD28-41BB combination, patients were simultaneously infused with 1-20 × 106 of both 2G and 3G CARTs/m2 48-72 hours after lymphodepletion with cyclophosphamide (500 mg/m2/d) and fludarabine (30 mg/m2/d) × 3. Persistence of infused T cells was assessed in blood by qPCR assays specific for each CAR. Molecular signals peaked approximately 2 weeks post infusion, remaining detectable for up to 6 months. The 3G CARTs had a mean 23-fold (range 1.1 to 109-fold) higher expansion than 2G CARTs and correspondingly longer persistence. Two patients had grade 2 cytokine release syndrome, with elevation of proinflammatory cytokines at the time of peak expansion. Of the 6 patients evaluable for response, 2 entered complete remission (the longest ongoing for 1 year), 1 has had continued complete remission after ASCT, 1 had a partial response, and 2 progressed. In conclusion, our data indicate that infusion of T cells carrying a CD19.CAR containing CD28 and 4-1BB endodomains is safe and can have efficacy at every dose level tested. Additionally, in a side-by-side comparison, the 3G vector produced greater in vivo expansion and persistence than an otherwise identical CART population with CD28 alone.
2558 Background: Vaccines prevent HPV-associated Ca, but their benefits in established Ca are disappointing: although these tumors express viral E6 and E7 antigens (Ags) immune responses are limited even after vaccination, likely due to negative environmental cues that block tumor recognition and T cell (TC) activation in vivo. We postulated that ex vivo stimulation of TCs in an immunologically favorable milieu would allow us to reactivate tumor-directed CTLs from Ca patients and benefit the recipients on reinfusion. Methods: We studied 68 patients with HPV+ Ca. To detect HPV16 E6/E7-specific TCs (HPV-TCs) in blood, we measured the IFNγ ELISpot responses of TCs stimulated by monocyte-derived dendritic cells (DCs) loaded with pepmixes (peptide libraries of 15-mers overlapping by 11 aa) spanning E6/E7. Because HPV-TCs from these patients may be anergized by their tumors, potent Ag presenting strategies might be required for reactivation, and thus we stimulated these cells in the presence of IL-6, -7, -12 and -15, as we have shown that these can induce responses to poorly immunogenic Ags. Results: We successfully reactivated HPV-TCs from 8/16 cervical and 33/52 oropharyngeal Ca patients. We could expand these HPV-TCs to clinically useful numbers by using patient B-cell blasts (BBs) as APCs. Stimulation of DC-stimulated HPV-TCs by E6/E7 pepmix-loaded BBs further expanded (3.8 ± 1.5×/round) HPV-TC lines, which phenotypically are almost exclusively composed of TCs (98 ± 3% CD3+), with a variable proportion of mostly effector memory (CD45RA–, CD45RO+, CD62L– and CCR7–) CD4+ and CD8+ cells (37 ± 28% and 49 ± 27%, respectively). The viral/tumor associated epitopes recognized mapped to E6 aa 49-71, 77-91 and 125-143, and E7 aa 1-19 and 73-87. The expanded cells from patients killed E6/E7+ targets (specific lysis up to 45-61% vs. 0-8% in controls, 40:1 E:T ratio). Conclusions: We have developed a system that allows the robust generation of HPV-directed CTLs from patients with HPV16+ Ca, which recognize specific epitopes in tumor-associated Ags. Our lines have the potential to be used for adoptive cellular immunotherapy of HPV+ Ca.
Acute upper and lower respiratory tract infections (RTI) due to community-acquired respiratory viruses (CARV) including respiratory syncytial virus (RSV), influenza, parainfluenza virus (PIV) and human metapneumovirus (hMPV) are a major public health problem.1 For example, RSV-induced bronchiolitis is the most common reason for hospital admission in children under one year of age,2-4 while the Center for Disease Control (CDC) estimates that, annually, Influenza accounts for up to 35.6 million illnesses worldwide, between 140,000 and 710,000 hospitalizations, annual costs of approximately $87.1 billion in disease management in the US alone, and between 12,000 and 56,000 deaths.
Thus, CARV are a leading cause of morbidity and mortality worldwide, with individuals whose immune systems are naive (e.g. young children) or compromised being the most vulnerable. For example, in allogeneic hematopoietic stem cell transplant (HSCT) recipients, the incidence of CARV-related respiratory viral diseases is as high as 40%.5 While most patients initially present with rhinorrhea, cough and fever, in approximately 50% of cases, infections progress to the lower respiratory tract and are characterized by severe symptoms including pneumonia and bronchiolitis and mortality rates of 23-50%.6-9 There are neither approved preventative vaccines nor antiviral drugs for hMPV10 and PIV11 and for Influenza the preventative vaccine is not indicated unless patients are at least six months post-HSCT.12 Aerosolized ribavirin (RBV) has been approved by the US Food and Drug Administration (FDA) for the treatment of RSV, but it is extremely costly (5-day course = $149,756) and logistically difficult to administer, requiring a specialized nebulization device that connects to an aerosol tent surrounding the patient.13-16 Thus, the lack of approved antiviral agents for many clinically problematic CARV, and the high cost and complexity of administering aerosolized RBV, underscores the need for alternative treatment strategies.
Our group has previously demonstrated that the adoptive transfer of in vitro-expanded virus-specific T cells (VST) can safely and effectively prevent and treat infections associated with both latent [Epstein-Barr virus (EBV), cytomegalovirus (CMV), BK virus (BKV), human her-pesvirus 6 (HHV6)] and lytic [adenovirus (AdV)] viruses in allogeneic HSCT recipients.17,18 Given that susceptibility to CARV is associated with underlying cellular immune deficiency,1,5,6 in the current study, we explored the feasibility of extending the therapeutic range of VST therapy to include Influenza, RSV, hMPV and PIV-3.
We here describe a mechanism by which we can rapidly generate a single preparation of polyclonal (CD4+ and CD8+) VST with specificity for 12 immunodominant antigens derived from our four target viruses using Good Manufacturing Practices (GMP)-compliant manufacturing methodologies. The viral proteins used for stimulation were chosen on the basis of both their immunogenicity to T cells and their sequence conservation.19-21 The expanded cells are Th1-polarized, polyfunctional and selectively able to react to and kill, viral antigen-expressing target cells with no activity against non-infected autologous or allogeneic targets, attesting to both their selectivity for viral targets and their safety for clinical use. We anticipate such multi-respiratory virus-targeted cells (multi-R-VST) will provide broad spectrum benefit to immunocompromised individuals with uncontrolled CARV infections.
