Eltrombopag improves platelet engraftment after haploidentical bone marrow transplantation: Results of a Phase II study.

Slow platelet recovery frequently occurs after haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with bone marrow graft and post-transplant cyclophosphamide (PCy)-based graft-versus-host disease (GVHD) prophylaxis. Improved platelet recovery may reduce the need for transfusions and improve outcomes. We investigated the safety and efficacy of eltrombopag, a thrombopoietin receptor agonist, at enhancing platelet recovery post-haplo-HSCT. The prospective study included patients ≥18 years of age who received haplo-HSCT with bone marrow graft and PCy. Patients received eltrombopag 300 mg/day starting on Day +5. The primary objective was to estimate platelet engraftment (>50 000/µL by Day 60). In a post hoc analysis, they were compared to a contemporary matched control group who did not receive eltrombopag. One hundred ten patients were included in the analysis (30 eltrombopag and 80 control). Seventy-three percent and 50% of patients in the eltrombopag group and control group, respectively, attained >50 000/µL platelet count by Day 60 (p = .043). No eltrombopag-related grade ≥4 adverse events were observed. Median time to platelet recovery (>20 000/µL) was 29 days with eltrombopag and 31 days for controls (p = .022), while its cumulative incidence was 90% (95% confidence interval [CI]: 78%-100%) with eltrombopag versus 67.5% (95% CI: 57%-78%) for controls (p = .014). Number of platelet transfusions received, overall survival, progression-free survival, GVHD rate, relapse rate, and non-relapse mortality were similar between groups. Overall, eltrombopag is safe and improves platelet recovery in patients undergoing haplo-HSCT with bone marrow graft and PCy.

Efficient neutralization of daratumumab in pretransfusion samples using a novel recombinant monoclonal anti-idiotype antibody.

BACKGROUND: Anti-CD38 antibodies such as daratumumab (DARA) are critical therapies for multiple myeloma and other diseases. Unfortunately, anti-CD38 antibodies cause panreactivity in indirect antiglobulin tests (IATs), complicating blood compatibility testing. The anti-CD38 interference is most often mitigated by treating reagent red blood cells (RBCs) with dithiothreitol (DTT). However, when using the DTT method, not all RBC antibody specificities can be detected (e.g., anti-K), and the DTT method is impractical for some transfusion services. We evaluated the ability of a new anti-idiotype antibody to neutralize DARA in vitro and eliminate the anti-CD38 interference. STUDY DESIGN AND METHODS: A recombinant monoclonal rabbit anti-DARA idiotype antibody ("anti-DARA") was generated. The ratio of anti-DARA required to neutralize DARA in spiked samples was evaluated in IATs performed in gel. IATs performed in tube were used to demonstrate that anti-DARA allows alloantibody detection in the presence of DARA. Plasma samples from 29 patients receiving DARA were treated with a fixed quantity of anti-DARA (120 µg) before performing antibody detection tests (screens) in tube. RESULTS: Anti-DARA used at or above a 1:1 ratio with DARA eliminated the DARA interference with IATs. Anti-DARA allowed detection of both alloanti-E and alloanti-K in the presence of DARA. In 27/29 (93.1%) clinical samples, 120 µg anti-DARA was sufficient to neutralize the DARA in 100 µl patient plasma. DISCUSSION: An anti-DARA:DARA ratio as low as 1:1 is sufficient to neutralize DARA in solution. A fixed amount of anti-DARA eliminates the anti-CD38 interference in most patient samples.

Freeze-dried platelets are a promising alternative in bleeding thrombocytopenic patients with hematological malignancies.

Thrombosomes are trehalose-stabilized, freeze-dried group O platelets with a 3-year shelf life. They can be stockpiled, rapidly reconstituted, and infused regardless of the recipient's blood type. Thrombosomes thus represent a potential alternative platelet transfusion strategy. The present study assessed the safety and potential early signals of efficacy of Thrombosomes in bleeding thrombocytopenic patients. We performed an open-label, phase 1 study of single doses of allogeneic Thrombosomes at three dose levels in three cohorts, each consisting of eight patients who had hematologic malignancies, thrombocytopenia, and bleeding. Adverse events, dose-limiting toxicities (DLTs), World Health Organization (WHO) bleeding scores, and hematology values were assessed. No DLTs were reported. The median age was 59 years (24-71). Most patients had AML (58%) or ALL (29%), followed by MDS (8%) and myeloproliferative neoplasm (4%). The WHO scores of 22 patients who were actively bleeding at a total of 27 sites at baseline either improved (n = 17 [63%]) or stabilized (n = 10 [37%]) through day 6. Twenty-four hours after infusion, 12 patients (50%) had a clinically significant platelet count increase. Of eight patients who received no platelet transfusions for 6 days after Thrombosomes infusion, 5 had a clinically significant increase in platelet count of ≥5000 platelets/µL and 2 had platelet count normalization. Thrombosomes doses up to 3.78 × 108 particles/kg demonstrated safety in 24 bleeding, thrombocytopenic patients with hematological malignancies. Thrombosomes may represent an alternative to conventional platelets to treat bleeding. A phase 2 clinical trial in a similar patient population is underway.

The Role of Granulocyte Transfusions in Optimizing Candidacy for Chimeric Antigen Receptor T-cell Therapy in Patients With Treatment-refractory Infections.

While advancements in cellular therapy have improved outcomes for patients with refractory leukemia, severe infections may hinder access. Granulocyte transfusions, in combination with anti-microbial therapy, may be a safe option to facilitate candidacy for chimeric antigen receptor T-cell therapy in patients with leukemia and prolonged immune-compromised status.

Practice patterns and clinical outcomes of platelet alloimmunization in a comprehensive cancer center.

BACKGROUND: Platelet transfusion refractoriness (PTR) secondary to human leukocyte antigen (HLA) alloimmunization is a challenge in the treatment of hematology-oncologypatients and increases the risk of morbidity and mortality from bleeding events. Guidelines for treating PTR have not been clearly described in literature. We aim to describe the practice patterns for the management of PTR secondary to HLA alloimmunization, and to assess the mortality, thrombosis and bleeding-related clinical outcomes at 30 days from diagnosis. METHODS: A retrospective review of 51 cases of PTR secondary to HLA alloimmunization were analyzed. RESULTS: The majority of patients (98 %) had a diagnosis of hematological malignancy of which 88.2 % were undergoing active chemotherapy. Clinically relevant bleeding, by ISTH criteria, was observed in 33.3 %; hemorrhagic shock was diagnosed in 7%. The rate of bleeding-related mortality was estimated at 7.8 %. The use of antifibrinolytics and plasma products (including intravenous immunoglobulin) was more common in cases with major versus non-major bleeding. Grade A or B1U HLA matched products were available in less than half of cases. CONCLUSIONS: There is heterogeneity in the management of the bleeding risk and bleeding events during PTR, with antifibrinolytics more commonly used in patients who suffered severe bleeding. Grade A and B1U HLA-matched platelets are not always readily available, and HLA-typing and HLA-antibody testing are not always performed prior to PTR. Prospective randomized control trials may help to determine the safety and efficacy of antifibrinolytics and other supportive measures in the management of PTR.

Unrecognized fluid overload during induction therapy increases morbidity in patients with acute promyelocytic leukemia.

BACKGROUND: The combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has proven to be the most effective therapy for patients with acute promyelocytic leukemia (APL). The majority of the morbidity and mortality from APL therapy occur during the induction phase. The objective of the current study was to identify the risk factors associated with transfer to the intensive care unit (ICU) and endotracheal intubation during induction therapy in patients with APL. METHODS: The authors analyzed the clinical characteristics of 187 patients with newly diagnosed APL who were treated with ATRA and ATO with or without gemtuzumab ozogamicin. The authors documented the percentage change in body weight from baseline to the maximum recorded weight during induction or to the day of ICU transfer. RESULTS: A total of 18 patients (10%) who initiated therapy with ATRA and ATO on a regular hospital floor required transfer to the ICU after a median of 12 days of induction therapy. The median volume of transfusions was 4350 mL (range, 60-30,750 mL). The volume of transfusions was the main factor associated with the risk of ICU transfer (odds ratio, 4.1; P < .001). Of the 18 patients transferred to the ICU, 10 patients (5%) required intubation. An increase in the total volume of transfusions, increase in weight ≥10% during induction therapy, and a plasma albumin level ≤3.2 g/dL at the time of diagnosis were found to be associated with an increased risk of endotracheal intubation. CONCLUSIONS: Large volumes of blood product transfusions and unrecognized fluid overload during induction are associated with ICU transfer and endotracheal intubation in patients with APL. These can be prevented by limiting the amount of transfusions, careful monitoring for subtle signs of fluid overload, and early intervention with aggressive diuretic therapy.

Approaching treatment of transplant-associated thrombotic Microangiopathy from two directions with Eculizumab and transitioning from Tacrolimus to Sirolimus.

BACKGROUND: In the past, conventional treatment strategies for transplant-associated thrombotic microangiopathy (TA-TMA) have not proven to be very effective. Recently, eculizumab which is a humanized monoclonal antibody that works as a terminal complement inhibitor has demonstrated promise in the treatment landscape of TA-TMA. METHODS AND MATERIALS: This was a single-center retrospective analysis of 20 consecutive adult patients with TA-TMA: 10 patients who received conventional therapy and 10 patients who received eculizumab-based therapy. These patients had undergone allogeneic HSCT at MD Anderson Cancer Center between August 2011 and September 2016. RESULTS: When comparing the treatment outcomes in the two cohorts, none of the patients in the conventional therapy group obtained a hematologic or complete response according to our response criteria whereas seven patients in the eculizumab group achieved a hematologic response with one patient achieving a complete response with organ recovery. In addition, overall survival at the end of assessment was 60% in the eculizumab cohort and 30% in the conventional cohort. One major difference in practice at our institution versus previously published studies is the management of immunosuppression. In a majority of patients, tacrolimus was continued or transitioned to sirolimus for GVHD prophylaxis. CONCLUSION: Response rates and survival were improved for patients who were transitioned to sirolimus, so a two-pronged approach of inhibiting complement along with providing an alternative effective immunosuppressive agent may be beneficial in the treatment of early onset TA-TMA.

Eculizumab for transplant-associated thrombotic microangiopathy in adult allogeneic stem cell transplant recipients.

OBJECTIVE: To evaluate response rates and survival in adults with transplant-associated thrombotic microangiopathy (TA-TMA) after allogeneic hematopoietic stem cell transplantation (HSCT) who were treated with eculizumab (ECU). METHODS: Patients were identified retrospectively and data collected through HSCT and pharmacy databases. RESULTS: Ten patients with TA-TMA after allogeneic HSCT were treated with ECU between 2013 and 2016. TA-TMA was diagnosed at a median of 93 days post-HSCT. Organ-specific injury was documented in all ten patients at time of TA-TMA diagnosis, the most common being renal dysfunction (90%). Acute GVHD (70%) and active infection (80%) were common at time of diagnosis. The median time to ECU initiation from TA-TMA diagnosis was 4 days. Seven patients received ECU as first-line therapy in combination with other treatment modalities, while three patients were treated with ECU as second-line therapy. ECU was well tolerated with the exception of one case of severe skin rash leading to discontinuation. ECU achieved an overall hematologic response rate of 70% and an overall survival rate of 60%. One patient achieved a complete response with corresponding organ recovery. CONCLUSION: Early initiation of ECU may not alter the disease process enough to restore organ function, but it may prolong survival.

Prognosis of patients with intermediate risk IPSS-R myelodysplastic syndrome indicates variable outcomes and need for models beyond IPSS-R.

The International Prognostic Scoring System-Revised (IPSS-R) is one standard for myelodysplastic syndrome (MDS) risk stratification. It divides patients into five categories including an intermediate subset (IPSS-R int-risk). Outcomes and clinical interventions for patients with IPSS-R int-risk are not well defined. We performed an analysis of outcomes of this group of patients. Out of 3167 patients, a total of 298 were identified with IPSS-R int-risk MDS and retrospectively analyzed to assess characteristics affecting outcomes. Cox proportional hazard models for overall survival (OS) were performed to identify statistically significant clinical factors that influence survival. Age of 66 years or greater, peripheral blood blasts of 2% or more, and history of red blood cell (RBC) transfusion were significantly associated with inferior survival. Based on these features, MDS patients with IPSS-R int-risk were classified into two prognostic risk groups for analysis, an int-favorable group and an int-adverse group, and had significantly divergent outcomes. Sequential prognostication was validated using two independent datasets comprising over 700 IPSS-R int-risk patients. The difference in median survival between int-favorable and int-adverse patients was 3.7 years in the test cohort, and 1.8 and 2.0 years in the two validation cohorts. These results confirm significantly variable outcomes of patients with IPSS-R int-risk and need for different prognostic systems.

Comparative outcomes of thrombocytopenic acute leukemic patients with venous thromboembolism at a Comprehensive Cancer Center.

Patients with hematological malignancies often have severe thrombocytopenia, which poses problems when making thrombosis management decisions. A retrospective study was conducted to analyze the clinical outcomes associated with different management options in acute leukemic patients with thrombocytopenia (≤ 50 × 109/L) following an acute venous thromboembolic event. A total of 74 patients were divided into three treatment groups: observation only (n = 30); anticoagulation (n = 23); or inferior vena cava placement (n = 21). Multivariate analysis showed that anticoagulant administration was significantly associated with improved overall survival without an increased rate of clinical relevant bleeding events when compared to other thrombosis management modalities. This study notes that dose adjusted-anticoagulant therapy may offer a safe and clinical advantageous strategy for the treatment and secondary prevention of recurrent venous thrombosis in thrombocytopenic patients with hematologic malignancies.

A small amount of cyclooxygenase 2 (COX2) is constitutively expressed in platelets.

Cyclooxygenase (COX) is the rate-limiting enzyme in conversion of arachidonic acid to prostanoids, and has two isoforms, COX1 and COX2, which share ~65% amino acid homology. COX1 is universally expressed in many cell types including platelets; however, expression of COX2 is known to be more limited. We examined expression of COX2 mRNA and protein in platelets and platelet-derived microparticles (MPs); using quantitative RT-PCR, immunostaining, and Western blotting. We have detected a significant amount of COX2 in platelets, both at mRNA and protein levels. We found that COX1/COX2 mRNA and protein ratios in platelets were 370:1 and 17:1, respectively. Expression level of COX2 in platelets was less than COX1, but comparable to the expression of COX2 in malignant epithelial cells. Considering the important role of COX2 in tumorigenesis and thrombosis, and the large number of circulating platelets, we propose that platelet COX2 may play an important role in physiologic and pathologic conditions.

Pure Red Cell Aplasia in Major ABO-Mismatched Allogeneic Hematopoietic Stem Cell Transplantation Is Associated with Severe Pancytopenia.

In major ABO-mismatched allogeneic hematopoietic stem cell transplantation (HSCT) persistence of antidonor isohemagglutinins leads to pure red cell aplasia (PRCA). To investigate severe pancytopenia noted in a previous study of PRCA, we analyzed all major ABO-mismatched HSCT between January 2003 and December 2012. Of 83 PRCA patients, 13 (16%) had severe pancytopenia. Severe pancytopenia was defined as an absolute neutrophil count (ANC) < 1.5 K/µL or requiring granulocyte colony-stimulating factor, platelets < 50 K/µL or transfusion dependent, and PRCA with RBC transfusion dependence at post-transplant day 90. In 6 patients (46%) severe pancytopenia resolved after PRCA resolution. Two patients (15%) received a second transplant because of persistent pancytopenia/secondary graft failure, 1 (8%) died from secondary graft failure despite a stem cell boost, 1 (8%) did not recover his platelet counts despite RBC/ANC recovery, and 3 patients (23%) died from disease relapse. We found that severe pancytopenia is frequently associated with PRCA in 16% of major ABO-incompatible HSCT with a higher incidence in males and pancytopenia resolved with resolution of PRCA in 46% of patients.

Complement-Binding Donor-Specific Anti-HLA Antibodies and Risk of Primary Graft Failure in Hematopoietic Stem Cell Transplantation.

Detection of donor-specific anti-HLA antibodies (DSA) has been associated with graft rejection in all forms of transplantation. The mechanism by which DSA increase the risk of graft failure remains unclear. We hypothesized that complement-binding DSA are associated with engraftment failure in hematopoietic stem cell transplantation (HSCT) and analyzed 122 haploidentical transplant recipients tested prospectively for DSA. Retrospective analysis to detect C1q binding DSA (C1q+DSA) was performed on 22 allosensitized recipients. Twenty-two of 122 patients (18%) had DSA, 19 of which were women (86%). Seven patients with DSA (32%) rejected the graft. Median DSA level at transplant for patients who failed to engraft was 10,055 mean fluorescence intensity (MFI) versus 2065 MFI for those who engrafted (P = .007). Nine patients with DSA were C1q positive in the initial samples with median DSA levels of 15,279 MFI (range, 1554 to 28,615), compared with 7 C1q-negative patients with median DSA levels of 2471 MFI (range, 665 to 12,254) (P = .016). Of 9 patients who were C1q positive in the initial samples, 5 patients remained C1q positive at time of transplant (all with high DSA levels [median, 15,279; range, 6487 to 22,944]) and experienced engraftment failure, whereas 4 patients became C1q negative pretransplant and all engrafted the donor cells (P = .008). In conclusion, patients with high DSA levels (>5000 MFI) and complement-binding DSA antibodies (C1q positive) appear to be at much higher risk of primary graft failure. The presence of C1q+DSA should be assessed in allosensitized patients before HSCT. Reduction of C1q+DSA levels might prevent engraftment failure in HSCT.

Incidence and natural history of pure red cell aplasia in major ABO-mismatched haematopoietic cell transplantation.

Major ABO mismatching is not considered a contraindication to allogeneic haematopoietic stem cell transplantation (HSCT). Modern reduced-intensity conditioning and reduced-toxicity regimens cause much less myeloablation than conventional myeloablative regimens, such as cyclophosphamide with busulfan or total body irradiation, which may affect the incidence of pure red cell aplasia (PRCA). We estimated the incidence and described the natural history of PRCA in patients with major ABO-mismatched donor stem cells. Between 2007 and 2008, 161 (27% of all patients undergoing HSCT) underwent allogeneic HSCT with major ABO-mismatched stem cells and 12 (7·5%) of these patients developed PRCA. Thirty and ninety day T-cell and myeloid cell chimerism and neutrophil and platelet engraftment did not differ between patients who developed PRCA and those who did not. The only risk factor associated with PRCA was the use of a fludarabine/busulfan conditioning regimen. All patients with PRCA needed red cell transfusion for several months after HSCT resulting in significant iron overload. Pure red cell aplasia resolved spontaneously in the majority (seven patients) but only resolved after stopping tacrolimus in three patients. Hence, after major ABO-mismatched HSCT, the incidence of PRCA was 7·5% and it resolved spontaneously or after withdrawal of immunosuppression in the majority of patients.

Donor-specific anti-HLA Abs and graft failure in matched unrelated donor hematopoietic stem cell transplantation.

Anti-HLA donor-specific Abs (DSAs) have been reported to be associated with graft failure in mismatched hematopoietic stem cell transplantation; however, their role in the development of graft failure in matched unrelated donor (MUD) transplantation remains unclear. We hypothesize that DSAs against a mismatched HLA-DPB1 locus is associated with graft failure in this setting. The presence of anti-HLA Abs before transplantation was determined prospectively in 592 MUD transplantation recipients using mixed-screen beads in a solid-phase fluorescent assay. DSA identification was performed using single-Ag beads containing the corresponding donor's HLA-mismatched Ags. Anti-HLA Abs were detected in 116 patients (19.6%), including 20 patients (3.4%) with anti-DPB1 Abs. Overall, graft failure occurred in 19 of 592 patients (3.2%), including 16 of 584 (2.7%) patients without anti-HLA Abs compared with 3 of 8 (37.5%) patients with DSA (P = .0014). In multivariate analysis, DSAs were the only factor highly associated with graft failure (P = .0001; odds ratio = 21.3). Anti-HLA allosensitization was higher overall in women than in men (30.8% vs 12.1%; P < .0001) and higher in women with 1 (P = .008) and 2 or more pregnancies (P = .0003) than in men. We conclude that the presence of anti-DPB1 DSAs is associated with graft failure in MUD hematopoietic stem cell transplantation.

Outcomes of patients with myeloid malignancies treated with allogeneic hematopoietic stem cell transplantation from matched unrelated donors compared with one human leukocyte antigen mismatched related donors using HLA typing at 10 loci.

Most candidates for hematopoietic stem cell transplantation (HSCT) lack a human leukocyte antigen (HLA)-identical sibling donor. Some patients may have a related donor with whom they are mismatched at 1 antigen/allele. It is not known whether such a match is preferable to a matched unrelated donor (MUD). We evaluated the outcomes (survival, relapse, nonrelapse mortality [NRM]) of all 28 patients with a single HLA antigen/allele mismatch identified through high-resolution HLA typing at HLA-A, -B, -C, -DRB1, and -DQB1, and all 318 patients with myeloid malignancies who received transplants from a 10/10 MUD treated during the same period of time at a single institution. Overall, outcomes for patients treated from a 1-antigen/allele mismatch related donor were significantly worse than from a MUD, primarily because of increased NRM. Overall survival (OS) rates at 3 years for 1-antigen/allele mismatched related donor and MUD transplant recipients were 19% and 45% (P = .007), and NRM rates were 40% and 26% (P = .05), respectively. Patients with class I mismatches appeared to have poorer OS than did patients with class II mismatches. A higher incidence of graft rejection was identified in the mismatched related donor group (P = .02). These results indicate that transplant outcomes are better with a MUD than with a 1 antigen/allele-mismatched related donor.

Treatment of allosensitized patients receiving allogeneic transplantation.

Donor-specific anti-HLA antibodies (DSAs) are a major cause of engraftment failure in patients receiving haploidentical stem cell transplantation (HaploSCT). Effective treatments are needed for these patients, who often have no other donor options and/or are in need to proceed urgently to transplantation. We studied a multimodality treatment with alternate-day plasma exchange (PE), rituximab, intravenous γ globulin (IVIg) and an irradiated donor buffy coat for patients with DSAs at 2 institutions. Thirty-seven patients with a median age of 51 years were treated with this desensitization protocol. Treatment outcomes were compared with a control group of HaploSCT patients without DSAs (n = 345). The majority of patients in the DSA group were female (83.8% vs 37.1% in controls, P < .001) and received stem cells from a child as the donor (67.6% vs 44.1%, P = .002). Mean DSA level before and after desensitization was 10 198 and 5937 mean fluorescence intensity (MFI), respectively, with mean differences of 4030 MFI. Fourteen of 30 tested patients (46.7%) had C1q positivity, while 8 of 29 tested patients (27.6%) remained positive after desensitization. In multivariable analysis, patients with initial DSA > 20 000 MFI and persistent positive C1q after desensitization had a significantly lower engraftment rate, which resulted in significantly higher non-relapse mortality and worse overall survival (OS) than controls, whereas graft outcome and survival of patients with initial DSA < 20 000 MFI and those with negative C1q after treatment were comparable with controls. In conclusion, treatment with PE, rituximab, IVIg, and donor buffy coat is effective in promoting engraftment in patients with DSAs ≤20 000 MFI.

High levels of common cold coronavirus antibodies in convalescent plasma are associated with improved survival in COVID-19 patients.

BACKGROUND: COVID-19 Convalescent plasma (CCP) is safe and effective, particularly if given at an early stage of the disease. Our study aimed to identify an association between survival and specific antibodies found in CCP. PATIENTS AND METHODS: Patients ≥18 years of age who were hospitalized with moderate to severe COVID-19 infection and received CCP at the MD Anderson Cancer Center between 4/30/2020 and 8/20/2020 were included in the study. We quantified the levels of anti-SARS-CoV-2 antibodies, as well as antibodies against antigens of other coronavirus strains, in the CCP units and compared antibody levels with patient outcomes. For each antibody, a Bayesian exponential survival time regression model including prognostic variables was fit, and the posterior probability of a beneficial effect (PBE) of higher antibody level on survival time was computed. RESULTS: CCP was administered to 44 cancer patients. The median age was 60 years (range 37-84) and 19 (43%) were female. Twelve patients (27%) died of COVID-19-related complications. Higher levels of two non-SARS-CoV-2-specific antibodies, anti-HCoV-OC43 spike IgG and anti-HCoV-HKU1 spike IgG, had PBE = 1.00, and 4 SARS-CoV-2-specific antibodies had PBEs between 0.90 and 0.95. Other factors associated with better survival were shorter time to CCP administration, younger age, and female sex. CONCLUSIONS: Common cold coronavirus spike IgG antibodies anti-HCoV-OC43 and anti-HCoV-HKU1 may target a common domain for SARS-CoV-2 and other coronaviruses. They provide a promising therapeutic target for monoclonal antibody production.

High Levels of Common Cold Coronavirus Antibodies in Convalescent Plasma Are Associated With Improved Survival in COVID-19 Patients.

Background: COVID-19 Convalescent plasma (CCP) is safe and effective, particularly if given at an early stage of the disease. Our study aimed to identify an association between survival and specific antibodies found in CCP. Patients and Methods: Patients ≥18 years of age who were hospitalized with moderate to severe COVID-19 infection and received CCP at the MD Anderson Cancer Center between 4/30/2020 and 8/20/2020 were included in the study. We quantified the levels of anti-SARS-CoV-2 antibodies, as well as antibodies against antigens of other coronavirus strains, in the CCP units and compared antibody levels with patient outcomes. For each antibody, a Bayesian exponential survival time regression model including prognostic variables was fit, and the posterior probability of a beneficial effect (PBE) of higher antibody level on survival time was computed. Results: CCP was administered to 44 cancer patients. The median age was 60 years (range 37-84) and 19 (43%) were female. Twelve patients (27%) died of COVID-19-related complications. Higher levels of two non-SARS-CoV-2-specific antibodies, anti-HCoV-OC43 spike IgG and anti-HCoV-HKU1 spike IgG, had PBE = 1.00, and 4 SARS-CoV-2-specific antibodies had PBEs between 0.90 and 0.95. Other factors associated with better survival were shorter time to CCP administration, younger age, and female sex. Conclusions: Common cold coronavirus spike IgG antibodies anti-HCoV-OC43 and anti-HCoV-HKU1 may target a common domain for SARS-CoV-2 and other coronaviruses. They provide a promising therapeutic target for monoclonal antibody production.

Generation of glucocorticoid-resistant SARS-CoV-2 T cells for adoptive cell therapy.

Adoptive cell therapy with virus-specific T cells has been used successfully to treat life-threatening viral infections, supporting application of this approach to coronavirus disease 2019 (COVID-19). We expand severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) T cells from the peripheral blood of COVID-19-recovered donors and non-exposed controls using different culture conditions. We observe that the choice of cytokines modulates the expansion, phenotype, and hierarchy of antigenic recognition by SARS-CoV-2 T cells. Culture with interleukin (IL)-2/4/7, but not under other cytokine-driven conditions, results in more than 1,000-fold expansion in SARS-CoV-2 T cells with a retained phenotype, function, and hierarchy of antigenic recognition compared with baseline (pre-expansion) samples. Expanded cytotoxic T lymphocytes (CTLs) are directed against structural SARS-CoV-2 proteins, including the receptor-binding domain of Spike. SARS-CoV-2 T cells cannot be expanded efficiently from the peripheral blood of non-exposed controls. Because corticosteroids are used for management of severe COVID-19, we propose an efficient strategy to inactivate the glucocorticoid receptor gene (NR3C1) in SARS-CoV-2 CTLs using CRISPR-Cas9 gene editing.