Adamksi, Jill

Abstract Purpose: Naturally occurring tumor-specific T cells derived from peripheral blood (PB) offer a clinically accessible source for adoptive immunotherapy. However, the expansion of these T cells from patients with cancer remains a challenge. We hypothesized that mimicking innate immune activation could optimally stimulate antigen-driven T-cell expansion in vitro, unlocking the therapeutic potential of PB-derived T cells. Patients and Methods: We previously developed an ex vivo culture system that selectively expands tumor antigen–activated T cells from PB mononuclear cells (PBMC), generating multiclonal effector and central memory T cells. In this hypothesis-generating study, we evaluated the therapeutic potential of MUC1-activated T cells in patients with relapsed and/or refractory multiple myeloma (r/rMM) in a phase I clinical trial (NCT05411497). MUC1 is an oncoprotein overexpressed in r/rMM. We translated our small-scale culture into GMP-compliant, large-scale manufacturing, which achieved expansion of T cells from heavily pretreated patients’ PBMCs without exhaustion. Five patients were treated with escalating doses of up to 1 × 1010 T cells. Results: Although the cell infusions were well tolerated, no objective responses occurred. One patient, who received the highest dose, has had stable disease for 2 years after infusion. This patient exhibited transient dermatitis with localized MUC1 and CD3 staining, as potential evidence of on-target, off-tumor T-cell reactivity, perhaps contributing to disease stabilization. T-cell receptor sequencing revealed the T-cell product in four of the patients’ blood, which correlated with the product’s degree of polyfunctionality and MUC1 reactivity. Conclusions: These findings demonstrate the feasibility, safety, and biological activity of PB-derived, MUC1-specific T cells as adoptive immunotherapy. Significance: Expanding tumor antigen–specific T cells for clinical use from the blood of heavily pretreated patients with cancer remains a significant hurdle. We scale up a novel culture method that integrates innate immune signals to stimulate T-cell expansion and demonstrate safety, feasibility, and a case of long-term disease stabilization upon treatment of patients with multiple myeloma in a phase I clinical trial.

ABSTRACT We report a case of fulminant Clostridium perfringens septicemia complicated by massive intravascular hemolysis in a 19‐year‐old male with acute myelogenous leukemia. The patient presented with severe anemia and laboratory evidence of profound hemolysis. Despite the high mortality associated with this condition, the patient was successfully treated with broad‐spectrum antibiotics, including clindamycin, and three consecutive sessions of therapeutic plasma exchange (TPE). TPE was employed to remove circulating α‐toxin and cell‐free hemoglobin, thereby mitigating ongoing hemolysis and organ injury. This case highlights the potential role of TPE, in conjunction with appropriate antimicrobial therapy, as an intervention in C. perfringens septicemia with hemolysis.

The use of normothermic machine perfusion (NMP) over static cold storage in liver transplantation has been shown to reduce posttransplant risks of early allograft dysfunction, primary nonfunction, and ischemic cholangiopathy, and its increasing use has played a role in the expanded utilization of marginal livers. While studies have demonstrated improved clinical outcomes using NMP over static cold storage preservation, real-time intraoperative data reflecting the quality and viability of NMP livers is limited. This retrospective, single-center study compared NMP versus static cold storage livers in first-time recipients of liver transplants through the evaluation of synthetic coagulation function as measured by thromboelastography and conventional coagulation testing. Secondarily, transfusion utilization between the 2 cohorts was reviewed. One hundred eighty-six recipients of liver transplants receiving allografts from donors after circulatory death were included in the study, of which 99 (53%) allografts were preserved in static cold storage, and 87 (47%) allografts were placed on the TransMedics Organ Care System. Study findings showed NMP livers supported with the TransMedics Organ Care System were associated with increased synthetic coagulation function and less excess fibrinolysis in the postreperfusion period compared to static cold storage livers, and that these findings were better reflected in real-time with thromboelastography monitoring versus conventional coagulation testing. Following reperfusion, there was a significant decrease in the transfusion of blood products in the NMP group compared with that in the static cold storage group. Overall, we determined that the use of intraoperative thromboelastography can provide real-time data to assess one aspect of reperfusion liver quality and viability.

AbstractConvalescent plasma, collected from donors who have recovered from a pathogen of interest, has been used to treat infectious diseases, particularly in times of outbreak, when alternative therapies were unavailable. The COVID‐19 pandemic revived interest in the use of convalescent plasma. Large observational studies and clinical trials that were executed during the pandemic provided insight into how to use convalescent plasma, whereby high levels of antibodies against the pathogen of interest and administration early within the time course of the disease are critical for optimal therapeutic effect. Several studies have shown outpatient administration of COVID‐19 convalescent plasma (CCP) to be both safe and effective, preventing clinical progression in patients when administered within the first week of COVID‐19. The United States Food and Drug Administration expanded its emergency use authorization (EUA) to allow for the administration of CCP in an outpatient setting in December 2021, at least for immunocompromised patients or those on immunosuppressive therapy. Outpatient transfusion of CCP and infusion of monoclonal antibody therapies for a highly transmissible infectious disease introduces nuanced challenges related to infection prevention. Drawing on our experiences with the clinical and research use of CCP, we describe the logistical considerations and workflow spanning procurement of qualified products, infrastructure, staffing, transfusion, and associated management of adverse events. The purpose of this description is to facilitate the efforts of others intent on establishing outpatient transfusion programs for CCP and other antibody‐based therapies.

AbstractBackgroundImmunomodulatory strategies in heparin‐induced thrombocytopenia (HIT) include the use of intravenous immune globulin (IVIG) and therapeutic plasma exchange (TPE). The optimal application of these therapies is unknown and outcomes data are limited. We investigated treatment categories and laboratory and clinical outcomes of IVIG and/or TPE in HIT with a systematic literature review.Study Design and MethodsWe searched MEDLINE, Embase, and Web of Science through December 2019 for studies combining controlled vocabulary and keywords related to thrombocytopenia, heparin, TPE, and IVIG. The primary outcome was treatment indication. Secondary outcomes were platelet recovery, HIT laboratory parameters, heparin re‐exposure, and post‐treatment course. Case‐level data were analyzed by qualitative synthesis.ResultsAfter 4241 references were screened, we identified 60 studies with four main categories of IVIG and/or TPE use as follows: (a) treatment of refractory HIT (n = 35; 31%); (b) initial therapy (n = 45; 40%); (c) cardiopulmonary bypass surgery (CPB; n = 30; 27%); and (d) other (n = 2; 2%). IVIG was most commonly used for the treatment of refractory HIT while TPE was primarily used to facilitate heparin exposure during CPB. Both IVIG and TPE were equally used as initial therapy. Heparin re‐exposure occurred without thrombotic event in 29 TPE‐treated patients and three IVIG‐treated patients.ConclusionIn patients with HIT, both TPE and IVIG are used for initial therapy or treatment of refractory HIT. However, TPE is more commonly used in patients undergoing CPB. Prospective studies may help clarify which treatment is indicated in HIT population subsets.

BACKGROUNDPatients requiring chronic apheresis treatments typically lack sufficient peripheral venous access to support long‐term therapy. Historically, central venous tunneled catheters, septum‐bearing subcutaneous ports, and fistulas were used to obtain required blood flow rates for apheresis procedures. In 2017, the US Food and Drug Administration approved the first intravascular device specifically designed for apheresis therapy, the PowerFlow Implantable Apheresis IV Port.METHODSSeveral preimplementation meetings with key hospital stakeholders were held to determine the most efficient and safest strategy for integrating the PowerFlow device into our practice. Interventional radiologists implanted the apheresis port in patients meeting specified criteria. Performance metrics and adverse events were evaluated over a 2‐year period, July 2017 through June 2019.RESULTSEighteen patients underwent apheresis therapy using the PowerFlow port. The most common apheresis therapy provided was extracorporeal photopheresis, followed by therapeutic plasma exchange and low‐density lipoprotein apheresis. Flow rates up to 90 mL/min were obtained; the rates were limited by patient tolerance for the apheresis procedure. Complications included infection, obstruction due to fibroblastic sleeve, and migration of the vascular device. The estimated risk of PowerFlow‐associated bloodstream infection in the study population was 0.18 per 1000 intravascular device days.CONCLUSIONThe PowerFlow Implantable Apheresis IV Port can achieve flow rates necessary for all apheresis therapies and is a promising alternative vascular access device for patients undergoing apheresis.