Outpatient treatment with concomitant vaccine-boosted convalescent plasma for patients with immunosuppression and COVID-19.

Although severe coronavirus disease 2019 (COVID-19) and hospitalization associated with COVID-19 are generally preventable among healthy vaccine recipients, patients with immunosuppression have poor immunogenic responses to COVID-19 vaccines and remain at high risk of infection with SARS-CoV-2 and hospitalization. In addition, monoclonal antibody therapy is limited by the emergence of novel SARS-CoV-2 variants that have serially escaped neutralization. In this context, there is interest in understanding the clinical benefit associated with COVID-19 convalescent plasma collected from persons who have been both naturally infected with SARS-CoV-2 and vaccinated against SARS-CoV-2 ("vax-plasma"). Thus, we report the clinical outcome of 386 immunocompromised outpatients who were diagnosed with COVID-19 and who received contemporary COVID-19-specific therapeutics (standard-of-care group) and a subgroup who also received concomitant treatment with very high titer COVID-19 convalescent plasma (vax-plasma group) with a specific focus on hospitalization rates. The overall hospitalization rate was 2.2% (5 of 225 patients) in the vax-plasma group and 6.2% (10 of 161 patients) in the standard-of-care group, which corresponded to a relative risk reduction of 65% (P = 0.046). Evidence of efficacy in nonvaccinated patients cannot be inferred from these data because 94% (361 of 386 patients) of patients were vaccinated. In vaccinated patients with immunosuppression and COVID-19, the addition of vax-plasma or very high titer COVID-19 convalescent plasma to COVID-19-specific therapies reduced the risk of disease progression leading to hospitalization.IMPORTANCEAs SARS-CoV-2 evolves, new variants of concern (VOCs) have emerged that evade available anti-spike monoclonal antibodies, particularly among immunosuppressed patients. However, high-titer COVID-19 convalescent plasma continues to be effective against VOCs because of its broad-spectrum immunomodulatory properties. Thus, we report clinical outcomes of 386 immunocompromised outpatients who were treated with COVID-19-specific therapeutics and a subgroup also treated with vaccine-boosted convalescent plasma. We found that the administration of vaccine-boosted convalescent plasma was associated with a significantly decreased incidence of hospitalization among immunocompromised COVID-19 outpatients. Our data add to the contemporary data providing evidence to support the clinical utility of high-titer convalescent plasma as antibody replacement therapy in immunocompromised patients.

Use of convalescent plasma in COVID-19 patients with immunosuppression.

In the absence of effective countermeasures, human convalescent plasma has been widely used to treat severe acute respiratory syndrome coronavirus 2, the causative agent of novel coronavirus disease 19 (COVID-19), including among patients with innate or acquired immunosuppression. However, the association between COVID-19-associated mortality in patients with immunosuppression and therapeutic use of convalescent plasma is unknown. We review 75 reports, including one large matched-control registry study of 143 COVID-19 patients with hematological malignancies, and 51 case reports and 23 case series representing 238 COVID-19 patients with immunosuppression. We review clinical features and treatment protocols of COVID-19 patients with immunosuppression after treatment with human convalescent plasma. We also discuss the time course and clinical features of recovery. The available data from case reports and case series provide evidence suggesting a mortality benefit and rapid clinical improvement in patients with several forms of immunosuppression following COVID-19 convalescent plasma transfusion. The utility of convalescent plasma or other forms of antibody therapy in immune-deficient and immune-suppressed patients with COVID-19 warrants further investigation.

Convalescent Plasma for Infectious Diseases: Historical Framework and Use in COVID-19.

Convalescent plasma has emerged as a promising therapeutic agent for patients with coronavirus disease 2019 (COVID-19), has received emergency use authorization, and is being widely used during the COVID-19 pandemic. Passive antibody therapy via plasma or serum has been successfully used to treat infectious diseases for more than a century. Passive antibody administration is based on the presumption that convalescent plasma or serum contains therapeutic antibodies that can be passively transferred to the plasma recipient. There are numerous examples in which convalescent plasma has been used successfully as post-exposure prophylaxis and treatment of infectious diseases, including previous coronavirus outbreaks. In the context of the COVID-19 pandemic, convalescent plasma was demonstrated to be safe and potentially effective among patients infected with COVID-19. This review provides an overview of the historical uses of convalescent plasma therapy, summarizes current evidence for convalescent plasma use for COVID-19, and highlights future antibody therapies.

The Role of Arrestin Domain-Containing 3 in Regulating Endocytic Recycling and Extracellular Vesicle Sorting of Integrin ß4 in Breast Cancer.

Despite the established role of integrin ß4 (ITG ß4) in breast cancer progression, the importance of endocytic recycling of ITG ß4 and its regulatory mechanism are poorly understood. Here, we found that a sub-population of ITG ß4 is sorted into early endosomes, recycled back to the plasma membrane, and secreted in the form of extracellular vesicles (EVs) upon EGF treatment in triple negative breast cancer (TNBC) cells. A metastasis suppressor, ARRDC3 (arrestin domain-containing 3) prevents EGF-driven endocytic recycling of ITG ß4 by inducing NEDD4-dependent ubiquitination of ITG ß4 and targeting endosomal ITG ß4 into lysosomes. Endocytic recycling of ITG ß4 is linked to sorting of ITG ß4 into EVs (ITG ß4+ EVs). ITG ß4+ EVs are mainly detectable from supernatants of TNBC cells and their production is inhibited by ARRDC3 expression. ARRDC3 reduces the metastatic potentials of breast cancer cell-derived EVs by reducing ITG ß4 levels in EVs. Overall, current studies provide novel mechanistic insights on the regulatory mechanism of ITG ß4 recycling, and its importance in invasive potentials of TNBC EVs, thus providing the basis for therapeutic targeting of the ARRDC3/ITG ß4 pathway in TNBC.

Exosomes in Cancer Diagnostics.

Exosomes are endosome derived extracellular vesicles of 30-120 nm size ranges. Exosomes have been identified as mediators of cell-to-cell communication by transferring bioactive molecules such as nucleic acids, proteins and lipids into recipient cells. While exosomes are secreted by multiple cell types, cancer derived exosomes not only influence the invasive potentials of proximally located cells, but also affect distantly located tissues. Based on their ability to alter tumor microenvironment by regulating immunity, angiogenesis and metastasis, there has been growing interest in defining the clinical relevance of exosomes in cancers. In particular, exosomes are valuable sources for biomarkers due to selective cargo loading and resemblance to their parental cells. In this review, we summarize the recent findings to utilize exosomes as cancer biomarkers for early detection, diagnosis and therapy selection.