Stimulation of Potent Humoral and Cellular Immunity via Synthetic Dual-Antigen MVA-Based COVID-19 Vaccine COH04S1 in Cancer Patients Post Hematopoietic Cell Transplantation and Cellular Therapy.

Hematopoietic cell transplantation (HCT) and chimeric antigen receptor (CAR)-T cell patients are immunocompromised, remain at high risk following SARS-CoV-2 infection, and are less likely than immunocompetent individuals to respond to vaccination. As part of the safety lead-in portion of a phase 2 clinical trial in patients post HCT/CAR-T for hematological malignancies (HM), we tested the immunogenicity of the synthetic modified vaccinia Ankara-based COVID-19 vaccine COH04S1 co-expressing spike (S) and nucleocapsid (N) antigens. Thirteen patients were vaccinated 3-12 months post HCT/CAR-T with two to four doses of COH04S1. SARS-CoV-2 antigen-specific humoral and cellular immune responses, including neutralizing antibodies to ancestral virus and variants of concern (VOC), were measured up to six months post vaccination and compared to immune responses in historical cohorts of naïve healthy volunteers (HV) vaccinated with COH04S1 and naïve healthcare workers (HCW) vaccinated with the FDA-approved mRNA vaccine Comirnaty® (Pfizer, New York, NY, USA). After one or two COH04S1 vaccine doses, HCT/CAR-T recipients showed a significant increase in S- and N-specific binding antibody titers and neutralizing antibodies with potent activity against SARS-CoV-2 ancestral virus and VOC, including the highly immune evasive Omicron XBB.1.5 variant. Furthermore, vaccination with COH04S1 resulted in a significant increase in S- and N-specific T cells, predominantly CD4+ T lymphocytes. Elevated S- and N-specific immune responses continued to persist at six months post vaccination. Furthermore, both humoral and cellular immune responses in COH04S1-vaccinated HCT/CAR-T patients were superior or comparable to those measured in COH04S1-vaccinated HV or Comirnaty®-vaccinated HCW. These results demonstrate robust stimulation of SARS-CoV-2 S- and N-specific immune responses including cross-reactive neutralizing antibodies by COH04S1 in HM patients post HCT/CAR-T, supporting further testing of COH04S1 in immunocompromised populations.

Letermovir and maribavir for pan-resistant cytomegalovirus infection in a patient with haematologic malignancy: Consideration for combination therapy.

WHAT IS KNOWN AND OBJECTIVE: Management of pan-resistant cytomegalovirus infection (CMVi) requires a multifaceted approach, including host defence optimization by reducing immunosuppression, and standard or experimental antiviral therapy. CASE DESCRIPTION: A 36-year-old man with anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma, who underwent allogeneic haematopoietic stem cell transplant (alloHCT) with resultant graft-versus-host disease treated with immunosuppressive therapy, developed pan-resistant CMVi. He was successfully treated with combination therapy of maribavir and letermovir. WHAT IS NEW AND CONCLUSION: Combination therapy, used for other infections to prevent cross-resistant, may apply for CMVi.

Infectious complications of immune checkpoint inhibitors in solid organ malignancies.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are targeted cancer therapies regarded to have less toxicity than chemotherapy. Immune-related adverse events (irAEs) of ICIs are well described in the literature but limited data exist on their infectious complications. The objective is to describe the spectrum and risk factors for developing serious infections in patients receiving ICIs. METHODS: Retrospective review of patients with melanoma, renal cell carcinoma, or nonsmall-cell lung cancer on nivolumab, pembrolizumab, and/or ipilimumab from January 1, 2017 to November 30, 2017. Exclusion: receipt of less than two ICI doses or history of other malignancy. Characteristics: age, sex, prior chemotherapy, steroid use, and temozolomide or infliximab use. Data identified from microbiology, radiography, serology, or physician note documentation. Serious infection is defined as infections requiring hospitalization and/or IV antibiotics from initiation of ICI until the end of the study period. RESULTS: One hundred and eleven pts received ICIs. Suspected or confirmed bacterial infections occurred in 24% (27/111) with 8% (9/111) confirmed bacterial cultures. The overall serious infection rate was 14% (16/111) with 25% (4/16) confirmed bacterial cultures. Suspected or confirmed infection sites: genitourinary 20% (22/111), pneumonia 5% (7/111), skin/soft tissue 7% (8/111). Noninfectious pneumonitis (NIP) occurred in 5% (5/111). No association regarding the risk of infection between the type of malignancy and ICI used. Steroid use was the only risk factor significantly associated with serious infection: 12/16 (75%) on steroids versus 27/95 (28.4%) without steroid use (p = 0.0003). CONCLUSION: The rate of serious infection with ICI was higher in our study compared with previous reports of pts treated with melanoma. Infectious complications are encountered with ICIs and correlate with steroid use.

Ibalizumab-uiyk as a bridge therapy for a patient with drug-resistant HIV-1 infection receiving chemotherapy: A case report.

WHAT IS KNOWN AND OBJECTIVE: Treatment for diffuse large B-cell lymphoma (DLBCL) in persons with AIDS consists of chemotherapy alongside antiretroviral therapy (ART). To determine optimal HIV treatment, drug-drug interactions, toxic effects and ART resistance must be considered. CASE DESCRIPTION: A 40-year-old man with drug-resistant HIV and DLBCL initiating chemotherapy which had drug interactions with his ART. During chemotherapy, darunavir/cobicistat was held and ibalizumab-uiyk was started to ensure he was on three active HIV medications. WHAT IS NEW AND CONCLUSION: Ibalizumab-uiyk has no known drug-drug interactions and may be used as bridge therapy for patients with drug-resistant HIV undergoing chemotherapy.

Practitioner Education and Feedback to Decrease Ciprofloxacin Prescriptions in Patients with Acute Uncomplicated Cystitis.

CONTEXT: Current guidelines recommend a nonfluoroquinolone agent as first-line treatment of acute uncomplicated cystitis (AUC) because of concerns of antimicrobial resistance and adverse effects. OBJECTIVE: To test whether a multifaceted intervention involving education and feedback reduced primary care practitioners' ciprofloxacin prescriptions for AUC therapy. DESIGN: Primary care practitioners at 3 medical offices participated: 65 in the intervention group and 51 in the control group. Intervention group participants received an educational lecture and emailed summary of antimicrobial guidelines, their AUC prescriptions were audited, and feedback was provided on inappropriate antibiotic choices. Prescriptions at AUC encounters were tracked during baseline, intervention, and postintervention periods. MAIN OUTCOME MEASURES: Proportion of AUC encounters at which ciprofloxacin was prescribed vs recommended first-line antibiotics. RESULTS: Intervention group participants had 5262 eligible AUC encounters, and control group participants had 5473. At baseline, ciprofloxacin was prescribed at 29.7% and 33.7% of eligible AUC encounters in the intervention and control groups, respectively (p = 0.003). After intervention, ciprofloxacin was prescribed at 10.8% of eligible AUC encounters in the intervention group and 34.3% in the control (p < 0.001). Adjusted odds ratios of ciprofloxacin prescription for AUC therapy were significantly lower in the intervention group during postintervention and intervention periods vs baseline (0.29, 95% confidence interval = 0.20-0.44, p < 0.001 and 0.80, 95% confidence interval = 0.66-0.97, p = 0.03). Adjusted odds ratios did not change over time in the controls. CONCLUSION: Educating primary care practitioners and conducting audit and feedback reduced their prescriptions of ciprofloxacin for AUC therapy.

Cost analysis of ganciclovir and foscarnet in recipients of allogeneic hematopoietic cell transplant with cytomegalovirus viremia.

BACKGROUND: Ganciclovir (GCV) and foscarnet (FOS) are the most commonly used antivirals for preemptive treatment of cytomegalovirus (CMV) viremia in recipients of allogeneic hematopoietic cell transplantation (alloHCT). The current literature indicates similar efficacy between these agents. Thus, the primary consideration for choice of initial anti-CMV treatment is the safety profile, time period after alloHCT, and concern of myelosuppression or renal dysfunction. METHODS: Herein, we retrospectively reviewed medical records of 124 alloHCT recipients who received GCV or FOS between April 27, 2014, and December 31, 2015, during the first year post-transplant. Healthcare resource use included drug, hospitalization, home health, dialysis, and growth factor costs. RESULTS: Total duration of therapy was longer in the GCV group (37 days vs 28 days, P = .21) but hospitalization days were similar (9 days) in both groups. The total treatment cost was significantly lower in the GCV group ($38 100 vs $59 400, P < .05). CONCLUSION: Preemptive anti-CMV therapy is associated with major healthcare resource costs, which were greater in patients who required FOS than those who were treated with GCV.

Endocarditis following Consumption of Cereal Associated with Salmonella enterica Subtype Mbandaka Outbreak.

A 69-year-old immunocompromised man developed mitral valve endocarditis due to Salmonella enterica serotype Mbandaka, contracted from the cereal outbreak. The patient had a history of HLA-matched related hematopoietic stem cell transplant with persistent graft-versus-host disease (GVHD). This case report discusses prior international outbreaks that occurred due to Salmonella enterica subtype Mbandaka, the risks of developing endovascular infections from salmonellosis, and persistent infections that may develop more frequently with S. enterica serotype Mbandaka. The patient received a six-week course of intravenous antibiotics and remains on oral suppressive antibiotics, with his length of therapy to be determined based on his GVHD treatment.

Histoplasmosis complicating tumor necrosis factor-α blocker therapy: a retrospective analysis of 98 cases.

BACKGROUND: Histoplasmosis may complicate tumor necrosis factor (TNF)-α blocker therapy. Published case series provide limited guidance on disease management. We sought to determine the need for long-term antifungal therapy and the safety of resuming TNF-α blocker therapy after successful treatment of histoplasmosis. METHODS: We conducted a multicenter retrospective review of 98 patients diagnosed with histoplasmosis between January 2000 and June 2011. Multivariate logistic regression was used to evaluate risk factors for severe disease. RESULTS: The most commonly used biologic agent was infliximab (67.3%). Concomitant corticosteroid use (odds ratio [OR], 3.94 [95% confidence interval {CI}, 1.06-14.60]) and higher urine Histoplasma antigen levels (OR, 1.14 [95% CI, 1.03-1.25]) were found to be independent predictors of severe disease. Forty-six (47.4%) patients were initially treated with an amphotericin B formulation for a median duration of 2 weeks. Azole treatment was given for a median of 12 months. TNF-α blocker therapy was initially discontinued in 95 of 98 (96.9%) patients and later resumed in 25 of 74 (33.8%) patients at a median of 12 months (range, 1-69 months). The recurrence rate was 3.2% at a median follow-up period of 32 months. Of the 3 patients with recurrence, 2 had restarted TNF-α blocker therapy, 1 of whom died. Mortality rate was 3.2%. CONCLUSIONS: In this study, disease outcomes were generally favorable. Discontinuation of antifungal treatment after clinical response and an appropriate duration of therapy, probably at least 12 months, appears safe if pharmacologic immunosuppression has been held. Resumption of TNF-α blocker therapy also appears safe, assuming that the initial antifungal therapy was administered for 12 months.