scholarly journals Immunogenicity of Covid-19 Vaccination in Subjects with Myelodysplastic Syndromes

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3696-3696
Author(s):  
Jennifer Vidler ◽  
Thanussuyah Alaguthurai ◽  
Sultan Abdul-Jawad ◽  
Sivalekha Viramuthu ◽  
Richard Beatson ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Severe Disease ◽  
Booster Vaccination ◽  
Cellular Responses ◽  
Post Vaccination ◽  
Disease Modifying Therapy ◽  
Disease Modifying

Abstract Myelodysplastic syndromes (MDS) represent a spectrum of clonal bone marrow neoplasms from low risk disease through to those transforming into acute myeloid leukaemia. The COVID-19 pandemic has presented a great risk to those with hematological malignancies who are at higher risk of severe disease and death than the general population. Previous studies looking at the immune response to influenza vaccination in those with MDS had shown promising results, with immune responses not differing from those of healthy family members. Whilst some data exist to reassure the MDS community that majority of patients show seroconversion following Covid-19 vaccination, little data exists on their neutralizing capacity or post vaccination T-cell responses in this cohort. In addition, the majority of patients in these studies received BNT162b2 and there is little published data on vaccine response to the ChAdOx1 nCoV-19 vaccine. We have investigated the humoral and T-cell response of 39 patients with MDS two to four weeks following Covid-19 booster vaccination with BNT162b2 or ChAdOx1 nCoV-19 through the SOAP study (Sars-cov-2 fOr cAncer Patients, IRAS project ID:282337). Plasma and PBMCs from MDS cases and healthy controls have been collected, and are being assessed for both humoral and cellular responses to SARS_CoV_2, the alpha (B.1.1.7) and delta (B.1.617.2) variants. Humoral responses will be assessed using ELISA (peptide binding) and functional viral neutralization assays. Cellular responses will be assessed using IFNy ELISPOT and flow cytometry (CD25 and CD69 expression) after 24h peptide stimulation. All data at time point 1 (2 - 4 weeks following booster vaccination) have been collected and will subsequently be collected at 6 months and 12 months post-vaccination. We also report on the safety data for these vaccines within this patient population. Of this cohort 64% were male with a median age of 65 years (range 21-84). 54% received vaccination with ChAdOx1 nCoV-19 and 44% received BNT162b2 (2% unrecorded). The vaccines were well tolerated with no serious adverse events to date. The mean interval between doses was 70.7 days (range 50 - 90 days). 71% of the cohort were receiving no disease modifying therapy at the time of vaccination, half of whom were receiving supportive therapy and the other half no intervention for their MDS. Of those receiving disease modifying therapy; 5 were receiving azacitidine, (1 in conjunction with low-dose cytarabine) and 3 ciclosporin. We will report the largest study of the humoral and T-cell mediated response to the Covid-19 vaccine in MDS patients to date. This will include cellular response to the delta variant and immunogenicity of both the BNT162b2 and ChAdOx1 nCoV-19 vaccines. Given the vulnerability of these patients to severe disease, investigating the immune response to the vaccines begins to build an evidence base for advising MDS patients on their ongoing risk of infection during the pandemic and going forward. The SOAP study will reassess the immune response at 6 and 12 months post-vaccination to continue to investigate post-vaccine immunity in this cohort. Disclosures Kulasekararaj: F. Hoffmann-La Roche Ltd.: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy; Akari: Consultancy, Honoraria, Speakers Bureau; Biocryst: Consultancy, Honoraria, Speakers Bureau; Achilleon: Consultancy, Honoraria, Speakers Bureau; Alexion: Consultancy, Honoraria, Speakers Bureau; Ra Pharma: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Alexion, AstraZeneca Rare Disease Inc.: Consultancy, Honoraria, Other: Travel support. Patten: JANSSEN: Honoraria; NOVARTIS: Honoraria; GILEAD SCIENCES: Honoraria, Research Funding; ROCHE: Research Funding; ASTRA ZENECA: Honoraria; ABBVIE: Honoraria.

Induction Of In Vivo Oligoclonal T Cell Expansion and Specific In Vitro T Cell Responses Following K562/GM-CSF Vaccination Of MDS Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2811-2811
Author(s):  
Gabrielle Prince ◽  
Chris Thoburn ◽  
Erica D. Warlick ◽  
Allan D. Hess ◽  
B. Douglas Smith
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Clinical Response ◽  
Cytokine Production ◽  
Booster Vaccination ◽  
Post Vaccination ◽  
Gm Csf ◽  
Csf Production

Abstract Background Myelodysplatic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell malignancies, characterized by the ineffective hematopoiesis, and risk of progression to acute myeloid leukemia. Allogeneic stem cell transplant (SCT) remains the only potentially curative therapy, but toxicities limit its application in older adults. Vaccination strategies have been developed to modulate the immune system, ideally with less toxicity. We present results from a pilot study of single agent K562/GM-CSF whole cell vaccination in MDS patients (pts). Methods Poor-risk or transfusion-dependent MDS pts (n=5) were enrolled and received K562/GM-CSF whole cell vaccine (1 X 108 cells) every 3 weeks for 4 cycles followed by a booster vaccination 8 weeks later. Eligible pts could receive supportive care only for the 2 months preceding study entry, have no history of SCT, and not be on immunosuppressants. Blood, bone marrow, and skin biopsies were taken prior to vaccination, day 4 following first vaccine, and at 4 weeks after the booster vaccination. Diversity of the T cell compartment was assessed in the blood, marrow and skin using the TCRExpress Quantitative Analysis Kit (Biomed Immunotech, Tampa FL). Fragment length analysis was performed by the DNA Analysis Facility. In vitro stimulation studies for proliferation and cytokine production were performed using peripheral blood monocytes (PBMCs) for the pt with the best clinical response (>4 years). Proliferation of banked PBMCs, collected prior to every vaccination and stimulated with the vaccine, was assessed using 3H-Thymidine. The cytokines generated were measured using a multiplexed bead based immunoassay (Human 17-plex bioplex pro-panel) (Biorad, Hercules CA). Results All pts tolerated the vaccinations well with localized skin reactions being common. Clinically, 2 pts normalized their blood counts and became transfusion independent following the immunotherapy. One responding pt (CMML) remained stable without need for medical intervention for 4 yrs and only recently showed progression. T cell spectratyping indicated oligocolonal populations of T cells in post-vaccination skin, blood and marrow samples. T cells infiltrating the skin were tracked to the marrow. Interestingly, the best clinical responder demonstrated the most restricted skewed repertoire with a significant number of oligoclonal T cells tracking from skin to marrow (n=5). The marrow also had infiltrates of oligoclonal T cells not detected in the post-vaccination skin. Further, this skewed repertoire was absent when the pt relapsed. Proliferation assays measuring this pt’s T cell cytokine production in response to the vaccine cells in vitro, showed increased levels of IL-2, IL-13 and IL-5 that were suppressed or not produced by the time of the 4th vaccination. Inversely, IL-6, IL-10, IL-17, IL-1beta, MIP-1beta and TNF alpha levels increased throughout. The expected proliferative “boost” was seen with the initiation of the booster vaccine series at the time of progression, and co-culture of the pt’s lymphocytes with the vaccine cells suppressed the ability of the vaccine cells to produce GM-CSF in vitro. The ability to suppress GM-CSF production decreased during therapy and the pt’s lymphocytes had no effect on GM-CSF production by the vaccine at the end of the immunotherapy. Conclusions All pts showed T cell skewing by spectratyping analysis, suggesting that each had a change in T cell proliferation patterns in response to the vaccine. One pt had a significant clinical response and the most specific T cell response by spectratyping to the original vaccine, followed by the absence of these cells in the marrow at the time of progression. This suggests that an immune response may have stabilized his disease and progression was associated with loss of this T cell population. Proliferation studies suggest that the lymphocytes recognized the vaccine. Lastly, GM-CSF levels produced by the vaccine were decreased during the vaccination cycles suggesting that the pt’s lymphocytes and/or tumor had a suppressive effect on the vaccine cells. It is unclear if the GM-CSF suppression was essential, detrimental, or unrelated to the pt’s clinical response. Further study of the T cells patterns in these pts may elucidate details of the immune response that are integral to clinical responses. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Selection of patients with myelodysplastic syndromes from a large electronic medical records database and a study of the use of disease-modifying therapy in the United States

BMJ Open ◽  
2018 ◽  
Vol 8 (7) ◽  
pp. e019955 ◽  
Author(s):  
Xiaomei Ma ◽  
David P Steensma ◽  
Bart L Scott ◽  
Pavel Kiselev ◽  
Mary M Sugrue ◽  
...  
Keyword(s):  
Myelodysplastic Syndromes ◽  
Cox Regression ◽  
Patient Characteristics ◽  
The United States ◽  
Treatment Patterns ◽  
First Line ◽  
Disease Modifying Therapy ◽  
Disease Modifying Therapies ◽  
The Usa ◽  
Disease Modifying

ObjectivesTreatment patterns for patients with myelodysplastic syndromes (MDS) outside clinical trials are not well described. Our objective was to evaluate treatment patterns and patient characteristics that influence time to disease-modifying therapy in patients with MDS in the USA.Design, participants and outcome measuresPatients with MDS treated with erythropoiesis-stimulating agents (ESAs), iron chelation therapy, lenalidomide (LEN) and the hypomethylating agents (HMAs) azacitidine and decitabine, were retrospectively identified in the GE Centricity Electronic Medical Record database between January 2006 and February 2014; LEN and HMAs were defined as ‘disease-modifying’ therapies. Multivariable Cox regression models were used to ascertain patient characteristics associated with time to disease-modifying therapy.ResultsOf the 5162 patients with MDS, 35.7%, 40.3% and 4.6% received 1, ≥1 and ≥2 therapies, respectively. ESAs were the first-line (72.5%) and only (64.0%) treatment in the majority of patients who received ≥1 therapy. ESA-only patients were older and had more comorbidities, including isolated anaemia. LEN and HMAs were first-line treatment in 12.4% of patients each; 32.7% received LEN or HMAs at any time. The majority of del(5q) patients (77.6%) received ≥1 therapy, most commonly LEN, compared with 40% of patients without del(5q). A shorter time to disease-modifying therapy was significantly associated with absence of comorbidities, diagnosis after February 2008, lower baseline haemoglobin level, age <80 years and male gender (p<0.002 for all).ConclusionsA high proportion of patients diagnosed with MDS in the USA do not receive approved disease-modifying therapies. It is important to improve access to these therapies.

scholarly journals Expansion of myeloid-derived suppressor cells in patients with severe coronavirus disease (COVID-19)

2020 ◽  
Vol 27 (11) ◽  
pp. 3196-3207 ◽  
Author(s):  
Chiara Agrati ◽  
Alessandra Sacchi ◽  
Veronica Bordoni ◽  
Eleonora Cimini ◽  
Stefania Notari ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Mononuclear Cells ◽  
Severe Disease ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Cell Functions ◽  
Convalescent Phase

Abstract SARS-CoV-2 is associated with a 3.4% mortality rate in patients with severe disease. The pathogenesis of severe cases remains unknown. We performed an in-depth prospective analysis of immune and inflammation markers in two patients with severe COVID-19 disease from presentation to convalescence. Peripheral blood from 18 SARS-CoV-2-infected patients, 9 with severe and 9 with mild COVID-19 disease, was obtained at admission and analyzed for T-cell activation profile, myeloid-derived suppressor cells (MDSCs) and cytokine profiles. MDSC functionality was tested in vitro. In four severe and in four mild patients, a longitudinal analysis was performed daily from the day of admission to the early convalescent phase. Early after admission severe patients showed neutrophilia, lymphopenia, increase in effector T cells, a persisting higher expression of CD95 on T cells, higher serum concentration of IL-6 and TGF-β, and a cytotoxic profile of NK and T cells compared with mild patients, suggesting a highly engaged immune response. Massive expansion of MDSCs was observed, up to 90% of total circulating mononuclear cells in patients with severe disease, and up to 25% in the patients with mild disease; the frequency decreasing with recovery. MDSCs suppressed T-cell functions, dampening excessive immune response. MDSCs decline at convalescent phase was associated to a reduction in TGF-β and to an increase of inflammatory cytokines in plasma samples. Substantial expansion of suppressor cells is seen in patients with severe COVID-19. Further studies are required to define their roles in reducing the excessive activation/inflammation, protection, influencing disease progression, potential to serve as biomarkers of disease severity, and new targets for immune and host-directed therapeutic approaches.

A Phase II Prospective Feasibility Study of Clofarabine Cytoreduction Prior to Allogeneic Hematopoietic Cell Transplantation (HCT) for Patients with Relapsed or Refractory Acute Leukemias and Advanced Myelodysplastic Syndromes

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 496-496
Author(s):  
Rajiv Agarwal ◽  
Frederick L Locke ◽  
Rangesh Kunnavakkam ◽  
Koen van Besien ◽  
Richard A. Larson ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Acute Leukemias ◽  
T Cell Depletion ◽  
Kaplan Meier ◽  
One Year

Abstract Abstract 496 HCT may provide long-term disease control for patients (pts) with relapsed and/or refractory acute leukemias (AL) and advanced myelodysplastic syndromes (MDS). Active disease burden at HCT is associated with high relapse rates and poor long-term outcomes. We hypothesized tolerable intensification would be achieved safely by clofarabine cytoreduction followed by HCT conditioning at the nadir and would result in improved outcomes. We performed a prospective study (3/08 – 9/10) to examine the feasibility and efficacy of clofarabine (Clo) cytoreduction prior to HCT for relapsed or refractory AL and MDS with > 5% marrow blasts. Clo was administered at 30mg/m2/day IV over 2 hours for 5 consecutive days. On Day 12 post Clo initiation, a bone marrow (BM) biopsy determined cytoreduction, followed by HCT conditioning by day 21 post-Clo. Our primary endpoint was to assess the proportion of pts who achieved effective cytoreduction, defined as BM cellularity <20% and BM blasts<10% on Day 12 post Clo initiation. Our secondary endpoints included (a) the proportion of pts able to proceed to HCT within 21 days of initiating Clo bridge, (b) Clo-related toxicities, and (c) disease free (DFS) and overall survival (OS) on Day 100 post HCT. 29 pts were enrolled and evaluable; 11 AML, 7 MDS, 3 t-MN, 4 secondary AML, 2 CML, 2 ALL; median age was 51 years (range 23–69); sex: 16 M, 13 F. 16 pts had high risk and 13 had intermediate risk cytogenetic profiles. 3 of 12 pts evaluated showed a FLT3 ITD mutation. 18 of 23 evaluable pts had high C-reactive protein levels at study entry (>5mg/L). All pts had ECOG performance status of 0 to 1. The median Charlson co-morbidity index was 1 (range 0–8). Effective cytoreduction was achieved in 15/29 pts (52%). Clo bridge therapy was well tolerated with mild toxicities (CTCAE v.3) prior to HCT as follows: 7% with grade (gr.) 1 creatinine elevation; 46% gr.1–2 and 7% gr.3 bilirubin elevation; 50% gr.1–2 and 25% gr.3 SGOT elevation, which were reversible. There were no hand-foot syndrome, cardiac, or CNS toxicities. All 29 pts (100%) successfully proceeded to HCT conditioning after clofarabine bridge – one pt with refractory AML, who achieved cytoreduction and conditioning, died one day before HCT due to sepsis. Median time from Clo initiation to HCT was 21 days (range 18–77). Two pts were delayed due to infection and/or failure to cytoreduce; both received second bridge with HiDAC mitoxantrone and achieved cytoreduction followed by HCT. 25 of 29 underwent reduced intensity conditioning (flu-mel-campath-17, clo-mel-campath 3, flu-mel-atg 5) and 26 of 28 received T-cell depletion (campath 22, ATG 5). Among the 28 transplanted pts, graft sources included: 23 PBSC (11 matched related, 12 matched unrelated), and 5 haploidentical PBSC plus a cord blood unit. With a median follow up 343 days after HCT, the median PFS = 353 days (95% CI 229–573) and the median OS = 381 days (95% CI 229–649). One year PFS is 65% by Kaplan-Meier estimate for cytoreduced pts compared to 33% in non-cytoreduced pts. Of the 28 pts who received transplant, 3 pts died before Day 100 – one due to sepsis before Day 28 post HCT, and two due to disease progression. At Day 28 post HCT, 26/27 pts (96%) had BM biopsies showing no evidence of residual disease – one pt had residual AML. The cumulative incidence of gr.2–3 acute GVHD by Day 100 was 9/27 pts, and 2/25 pts developed mild or moderate chronic GVHD within the first year. The Kaplan Meier estimate for one year survival is 65% (95% CI 35–84%) for the cytoreduced pt group and 41% (95% CI 16–65%) for the non-cytoreduced pt group. In summary, clofarabine bridge achieved cytoreduction in 52% of very high risk pts with advanced hematologic malignancies with low toxicity. Cytoreduction was associated with prolonged PFS, but late relapse remains problematic. Despite RIC and T-cell depletion, most pts achieved remission post-HCT with low rates of acute and chronic GVHD. This bridging approach provides a platform for testing novel post-transplant interventions. Disclosures: Off Label Use: Clofarabine is being used for treatment of advanced leukemia for cytoreduction prior to HCT. Locke:Genzyme: Honoraria. van Besien:Genzyme: Research Funding. Odenike:Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stock:Genzyme: Research Funding.

Activity Of Single Agent Temsirolimus and Associated Impact On Bone Marrow Vascularization and T-Cell Composition In Patients With Myelodysplastic Syndromes – Result Of The Prospective Temds Trial Of The German MDS-SG

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2808-2808
Author(s):  
Martin Wermke ◽  
Claudia Schuster ◽  
Claudia Schönefeldt ◽  
Christiane Jakob ◽  
Malte von Bonin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Adverse Events ◽  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Single Agent ◽  
Infectious Complications ◽  
T Cell Subsets ◽  
Concentration Data ◽  
Cell Composition

Abstract Introduction Enhanced progenitor proliferation, bone marrow (BM) hypervascularization and disturbed immune regulation contribute to the pathogenesis of myelodysplastic syndromes (MDS). Inhibition of mammalian-target of rapamycin (mTor) by temsirolimus (TEM) might be a promising strategy to target these disease-specific cellular alterations. We report on the effects of single agent TEM on the clinical course as well as on immune composition and BM vascularization of MDS patients treated within the prospective, multicenter “TEMDS”-trial (NCT01111448). Patients, Materials and Methods Twenty patients being either IPSS low/int-1 MDS (n = 9) or IPSS int-2/high after azacitidine failure were treated with TEM at a dose of 25 mg/week in the absence of toxicity or disease progression. BM was reevaluated after 4 months of treatment with the option of TEM continuation for a maximum of 12 months in responding patients. Translational research within this study included flowcytometry-based measurement of changes in T-cell composition as well as determination of cytokine levels and BM-vascularization prior to and after TEM. Results Of 20 patients treated, 15 discontinued TEM treatment prematurely due to intolerable side effects (n = 11), infectious complications (n = 3), or progression to AML (n = 1). Fatigue, stomatitis and profound leukopenia were the most frequent adverse events. A total of 13 severe adverse events were encountered in 10 patients and 1 patient died of infectious complications during TEM treatment. Of the 5 patients who were treated for at least 4 months and underwent regular BM reevaluation, none showed signs of response according to IWG criteria. TEM treatment resulted in a remarkable, although non-significant, decrease in total number of lymphocytes in the pB (pre: 74.6%, post: 48.4%, p = 0,083) and BM (pre: 23.5% post: 20.1%, p = 0.123). Within the T-helper cell compartment a trend towards an increase in regulatory T-cell (Treg) frequency was observed (pB: pre: 6.0 %, post: 6.4 %, p = 0.083). Moreover, the balance between naive (CD45RA+/CD45RO-) and activated/memory (CD45RA-/CD45RO+) Treg shifted significantly in favor of the latter (p = 0.004). Plasma analysis in BM and pB revealed, that these changes were obviously not mediated by alterations in TGFβ plasma levels. In a total of 12 assessable patients, a significant (p = 0.006) decrease of BM vascularization was observed after treatment with TEM for a median of 5 weeks (Fig. 1). There were, however, no changes in the medullary or peripheral blood VEGF concentration (data not shown). Conclusions Selective inhibition of the mTOR signaling cascade in MDS patients results in specific alterations of the composition of T-cell subsets as well as BM vascularization. Given the absence of any hematological response we suggest that these drug-induced modifications cannot alter the natural course of the disease. Disclosures: Wermke: Pfizer: Research Funding. Off Label Use: Temsirolimus is licensend for the treatment of MCL and RCC but not MDS. Platzbecker:Pfizer: Research Funding.

Immunomodulatory Effects and Adaptive Immune Response to Daratumumab in Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3037-3037 ◽  
Author(s):  
Jakub Krejcik ◽  
Tineke Casneuf ◽  
Inger Nijhof ◽  
Bie Verbist ◽  
Jaime Bald ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Research Funding ◽  
Immune Cell ◽  
Adaptive Immune Response ◽  
Advisory Committees ◽  
Adaptive Immune ◽  
T Cell Clonality ◽  
Cell Clonality

Abstract Introduction: Daratumumab (DARA) is a novel human monoclonal antibody that targets CD38, a protein that is highly expressed on multiple myeloma (MM) cells. DARA acts through multiple immune effector-mediated mechanisms, including complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis. In two clinical studies (NCT00574288 [GEN501] and NCT01985126 [Sirius]) of DARA monotherapy in patients with relapsed and refractory MM, overall response rates were 36% and 29%, respectively. CD38 is highly expressed in myeloma cells but also expressed in lymphocytes and other immune cell populations. Therefore, the effects of DARA on immune cell populations and adaptive immune response pathways were investigated. Methods: The patient population investigated included treated subjects with MM that were relapsed after or were refractory to ≥2 prior therapies (GEN501) or had received ≥3 prior therapies, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or were refractory to both a PI and an IMiD (Sirius). Patients assessed in this analysis were treated with 16 mg/kg DARA. When both studies were combined, median age (range) was 64 (31-84) years and median time from diagnosis was 5.12 (0.77-23.77) years. Seventy-six percent of patients had received >3 prior therapies and 91% were refractory to their last treatment. Clinical response was evaluated using IMWG consensus recommendations. Peripheral blood (PB) samples and bone marrow (BM) biopsies/aspirates were taken at prespecified time points and immunophenotyped by flow cytometry to enumerate various T-cell sub-types. T-cell clonality was measured by TCR sequencing. Antiviral T-cell response and regulatory T-cell (Treg) activity were analysed by functional in vitro assays. T-cell subpopulation counts were modelled over time with linear mixed modelling. Two group comparisons were performed using non-parametric Wilcoxon rank sum tests. Results: Data from 148 patients receiving 16 mg/kg DARA in GEN501 (n = 42) and Sirius (n = 106) were analyzed for changes in immune response. In PB, robust mean increases in CD3+ (44%), CD4+ (32%) and CD8+ (62%) T-cell counts per 100 days were seen with DARA treatment. However, responding evaluable patients (n = 45) showed significantly greater increases from baseline than nonresponders (n = 93) in CD3+ (P = 0.00012), CD4+ (P = 0.00031), and CD8+ (P = 0.00018) T cells. In BM aspirates the number of CD3+, CD4+, and CD8+ T-cells increased during treatment compared to baseline (the median percent increases were 19.95%, 5.66%, and 26.99% [n = 58]). Additionally, CD8+: CD4+ T-cell ratios significantly increased compared to baseline in both PB (P = 0.00017), and BM (P = 0.00016). T cell clonality, assessed by TCR sequencing, increased after DARA treatment compared with pretreatment (P = 0.049), with greater sums of absolute expansion in the repertoire (P = 0.037), as well as greater maximum expansion of a single clone (P = 0.048) in responders compared to nonresponders. Increased antiviral T-cell responses were observed post-DARA treatment, particularly in responders. Interestingly, a novel subpopulation of regulatory T cells was identified that expressed high levels of CD38. These cells comprised ~10% of all Tregs and were depleted by one DARA infusion. In ex vivo analyses, CD38+ Tregs appeared to be highly immune suppressive compared to CD38-Tregs. Conclusions: Robust T cell increases, increased CD8+: CD4+ ratios, increased antiviral responses, and increased T cell clonality were all observed after DARA treatment in a heavily pretreated, relapsed, and refractory patient population not expected to have strong immune responses. Improved clinical responses were associated with changes in these parameters. In addition, a sub-population of regulatory T cells expressing high CD38 levels was determined to be extremely immune suppressive and sensitive to DARA treatment. These data suggest a previously unknown immune modulatory role of DARA that may contribute to its efficacy, and a potential role for CD38 immune targeted therapies. We postulate that there are several distinct and complementary mechanisms that contribute to DARA's efficacy including increased antigen presentation through phagocytosis, targeting of immune suppressive Tregs, and increased adaptive immune responses. JK and TC contributed equally to this work. Disclosures Casneuf: Janssen: Employment. Verbist:Janssen: Employment. Bald:Janssen: Employment. Plesner:Genmab: Membership on an entity's Board of Directors or advisory committees; Roche and Novartis: Research Funding; Janssen and Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Liu:Janssen: Employment. van de Donk:Janssen Pharmaceuticals: Research Funding; Amgen: Research Funding; Celgene: Research Funding. Weiss:Janssen and Onclave: Research Funding; Janssen and Millennium: Consultancy. Ahmadi:Janssen: Employment. Lokhorst:Genmab: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria. Mutis:Janssen: Research Funding; Genmab: Research Funding.

scholarly journals The Grndad Registry: Contemporary Natural History Data and an Analysis of Real-World Patterns of Use and Limitations of Disease Modifying Therapy in Adults with SCD

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 34-36
Author(s):  
Alexandra Boye-Doe ◽  
Elizabeth Brown ◽  
Charu Puri-Sharma ◽  
Anjulika Chawla ◽  
Joshua J Field ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Real World ◽  
Research Funding ◽  
Clinical Characteristics ◽  
Reticulocyte Count ◽  
Principal Investigator ◽  
Advisory Committees ◽  
Disease Modifying Therapy ◽  
Disease Modifying ◽  
The Impact

Incremental improvement in care for children with sickle cell disease (SCD), arising from government-funded research over the last 4 decades, resulted in a dramatically reduced childhood mortality. However, the impact of iterative research and disease modifying therapy (DMT) on adults with SCD has not been as strong. Until now, there has been no coordinated, longitudinal, generalizable, natural history study of SCD that allowed for an assessment of the contemporary adult population. Here, we describe demographics at enrollment and cross-sectional clinical characteristics of 570 adults with SCD (SCA, homozygous HbSS or HbSb0 N=387, 68%, and compound heterozygous SCD variant, HbSC or HbSb+ N=183, 32%, Table I) on whom we have evaluable data. These data are from the multi-site REDCap-based prospective Globin Research Network for Data and Discovery (GRNDaD) registry, comprising 11 centers with over 1100 consented adults and children. The objective of this work was to evaluate the cohort at year of entry, including the use and clinical associations with DMT, and to explore indicators of disease progression as patients age. 16% of adults with SCA and 9.6% with variant disease stroke; 60.9% of adults with SCA and 41% with variant disease had a history of acute chest syndrome. Albuminuria was prevalent in both SCA (39.5%) and variant disease (19.4%). 185 adults (185/387, 47.8%) with SCA, previously referred for symptoms in clinic, had recorded tricuspid regurgitant jet velocity measurements, with a significantly abnormal result (&gt;2.7 m/s), in 92 (92/185, 49.7%). At enrollment, 45% of adults with SCA (175/387) and 14% of adults with variant disease (25/183) were on hydroxyurea (HU); 20.4% of adults with SCA were on chronic transfusions (79/387) compared with 7% of adults with variant disease (13/183). One third of all adults with SCA were not on or were not consistently on DMT, and had laboratory evidence for increased hemolysis (Table 1). Adults with SCA who were on HU had a higher MCV and higher HbF than other treatment states (Table 1). However, only 34% (60/175) of adults with SCA on HU were at maximally tolerated dose (MTD), per guideline-based recommendations, i.e. ANC ≤4.0 x109/L. On HU, those in the lowest quartile for ANC (&lt;3.2 x109/L) were older (mean age 35.9 years (95% Confidence Limit (CL) 32.5-39.3) vs. 31.2 (95% CL 28.2 to 34.4) years, P=0.04), had a lower mean reticulocyte count (119 x109/L (95% CL 76-162) vs. 203 (95% CL 129-278), P=0.05), and a higher mean MCV (104.4 fL (95% CL 100.2-108.7) vs. 92.5 (95% CL 87.2-97.8), P=0.0007), compared to those in the highest quartile for ANC (&gt;5.7 x109/L, N=34), but did not otherwise differ (including mean HbF, which was not measured in a standardized way). In older adults with SCD (Table 2), fewer people with SCA than with variant disease were &gt;54 years old, (26/387 HbSS, 7%, vs. 34/183, 19%, respectively). The older adult with SCA had a depressed reticulocyte count and a trend towards a higher creatinine. 45% of adults with SCA were on HU, and only a minority were at MTD, highlighting the challenges to optimal long-term therapy in chronic illness. Those patients not stably on DMT had laboratory evidence for worse anemia and hemolysis, without an evident increase in hospital admissions, perhaps due to a hyper hemolytic phenotype. Despite a more intensive regimen, SCA patients on transfusions had a higher Hgb but did not have hemolysis labs that differed from SCA patients on HU. Further, there was no difference in hospitalizations amongst treatments for SCA, although a decrease in hospitalizations was detectable in variant disease (Table 1). Successful use of DMTs in SCA was challenging even in academic centers, and there was evidence for ongoing hemolysis in treated and untreated patients. These real world data provide useful information about adults (&gt;17 years) with SCD. These data highlight opportunities to improve adherence to therapy (patient-centered) and to prescribing guidelines (provider-centered), and to consider less-burdensome alternatives. Importantly, we found that a large proportion of people with SCA were not on DMT, and with HU often not at MTD. In future, the GRNDaD registry will enable prospective longitudinal real-world analyses of the impact of DMTs and/or newer therapies on clinical outcomes, will enhance quality improvement, and will allow us to more fully explore clinical characteristics, of SCA and variant disease, in the aging adult. Disclosures Puri-Sharma: Bluebird Bio: Current Employment. Chawla:Bluebird Bio: Current Employment. Field:Shires: Research Funding; Ironwood: Research Funding. Neumayr:Emmaus: Consultancy; Bayer: Consultancy; CTD Holdings: Consultancy; Pfizer: Consultancy; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Micelle: Other: Site principal investigator; GBT: Other: Site principal investigator; PCORI: Other: site principal investigator; Novartis: Other: co-investigator; Bluebird Bio: Other: co-investigator; Sangamo Therapeutics: Other; Silarus: Other; Celgene: Other; La Jolla Pharmaceuticals: Other; Forma: Other; Imara: Other; National Heart, Lung, and Blood Institute: Other; Health Resources and Services Administration: Other; Centers for Disease Control and Prevention: Other; Seattle Children's Research: Other. Desai:Pfizer, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; GBT, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ironwood Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Rockpointe Continuing Medical Education Company: Consultancy. Lanzkron:GBT: Research Funding; HRSA: Research Funding; Ironwood: Research Funding; NHLBI: Research Funding; PCORI: Research Funding; Pfizer: Research Funding; Pharmacy Times Continuing Education: Honoraria; Prolong: Research Funding. Little:Hemex Health, Inc.: Patents & Royalties: Microfluidic electropheresis (patent, no royalties); BioChip Labs: Patents & Royalties: SCD Biochip (patent, no royalties); GBT: Research Funding; GBT: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Research Funding; NHLBI: Research Funding.

scholarly journals Gabarap Loss Mediates Immune Escape in High Risk Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 891-891
Author(s):  
Annamaria Gulla ◽  
Eugenio Morelli ◽  
Mehmet K. Samur ◽  
Cirino Botta ◽  
Megan Johnstone ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Clinical Outcome ◽  
Board Of Directors ◽  
Research Funding ◽  
Immune Escape ◽  
Publicly Traded ◽  
Advisory Committees

Abstract Immune therapies including CAR T cells and bispecific T cell engagers are demonstrating remarkable efficacy in relapsed refractory myeloma (MM). In this context, we have recently shown that proteasome inhibitor bortezomib (BTZ) results in immunogenic cell death (ICD) and in a viral mimicry state in MM cells, allowing for immune recognition of tumor cells. Induction of a robust anti-MM immune response after BTZ was confirmed both in vitro and in vivo: treatment of 5TGM1 MM cells with BTZ induced tumor regression associated with memory immune response, confirmed by ELISPOT of mouse splenocytes. We have confirmed the obligate role of calreticulin (CALR) exposure in phagocytosis and the ICD process, since BTZ-induced ICD is impaired in CALR KO MM cells both in vitro and in vivo. We further showed that the therapeutic efficacy of BTZ in patients was correlated with ICD induction: BTZ-induced ICD signature was positively correlated with OS (p=0.01) in patients enrolled in the IFM/DFCI 2009 study. Together, these studies indicate that ICD is associated with long-term response after BTZ treatment. In this work, we reasoned that genomic or transcriptomic alterations associated with shorter survival of MM patients after BTZ treatment may impair activation of the ICD pathway. To this aim, we performed a transcriptomic analysis of purified CD138+ cells from 360 newly diagnosed, clinically-annotated MM patients enrolled in the IFM/DFCI 2009 study. By focusing on genes involved in the ICD process, we found that low levels of GABA Type A Receptor-Associated Protein (GABARAP) were associated with inferior clinical outcome (EFS, p=0.0055). GABARAP gene locus is located on chr17p13.1, a region deleted in high risk (HR) MM with unfavorable prognosis. Remarkably, we found that correlation of low GABARAP levels with shorter EFS was significant (p=0.018) even after excluding MM patients with del17p; and GABARAP is therefore an independent predictor of clinical outcome. GABARAP is a regulator of autophagy and vesicular trafficking, and a putative CALR binding partner. Interestingly, among a panel of MM cell lines (n=6), BTZ treatment failed to induce exposure of CALR and MM cell phagocytosis by DCs in KMS11 cells, which carry a monoallelic deletion of GABARAP. This effect was rescued by stable overexpression of GABARAP. Moreover, CRISPR/Cas9-mediated KO of GABARAP in 3 ICD-sensitive cell lines (AMO1, H929, 5TGM1) abrogated CALR exposure and ICD induction by BTZ. GABARAP add-back by stable overexpression in KO clones restored both CALR exposure and induction of ICD, confirming GABARAP on-target activity. Similarly, pre-treatment of GABARAP KO cells with recombinant CALR restored MM phagocytosis, further confirming that GABARAP impairs ICD via inhibition of CALR exposure. Based on these findings, we hypothesized that GABARAP loss may alter the ICD pathway via CALR trapping, resulting in the ICD resistant phenotype observed in GABARAP null and del17p cells. To this end, we explored the impact of GABARAP KO on the CALR protein interactome, in the presence or absence of BTZ. Importantly, GABARAP KO produced a significant increase of CALR binding to stanniocalcin 1 (STC1), a phagocytosis checkpoint that mediates the mitochondrial trapping of CALR, thereby minimizing its exposure upon ICD. Consistently, GABARAP KO also affected CALR interactome in BTZ-treated cells, which was significantly enriched in mitochondrial proteins. Importantly, co-IP experiments confirmed GABARAP interaction with STC1. These data indicate a molecular scenario whereby GABARAP interacts with STC1 to avoid STC1-mediated trapping of CALR, allowing for the induction of ICD after treatment with ICD inducers; on the other hand, this mechanism is compromised in GABARAP null or del17p cells, and the STC1-CALR complex remains trapped in the mitochondria, resulting in ICD resistance. To functionally validate our findings in the context of the immune microenvironment, we performed mass Cytometry after T cell co-culture with DCs primed by both WT and GABARAP KO AMO1 clones. And we confirmed that treatment of GABARAP KO clones with BTZ failed to activate an efficient T cell response. In conclusion, our work identifies a unique mechanism of immune escape which may contribute to the poor clinical outcome observed in del17p HR MM patients. It further suggests that novel therapies to restore GABARAP may allow for the induction of ICD and improved patient outcome in MM. Disclosures Bianchi: Jacob D. Fuchsberg Law Firm: Consultancy; MJH: Honoraria; Karyopharm: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Richardson: AstraZeneca: Consultancy; Regeneron: Consultancy; Protocol Intelligence: Consultancy; Secura Bio: Consultancy; GlaxoSmithKline: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Takeda: Consultancy, Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Chauhan: C4 Therapeutics: Current equity holder in publicly-traded company; Stemline Therapeutics, Inc: Consultancy. Munshi: Legend: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Abbvie: Consultancy; Takeda: Consultancy; Adaptive Biotechnology: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy. Anderson: Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Scientific Founder of Oncopep and C4 Therapeutics: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Mana Therapeutics: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Humoral and cellular responses after a third dose of BNT162b2 vaccine in patients treated for lymphoid malignancies.

2021 ◽  
Author(s):  
Daniel Re ◽  
barbara Seitz-Polski ◽  
Michel Carles ◽  
Vesna Brglez ◽  
Daisy Graca ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Cellular Response ◽  
Vaccine Dose ◽  
Cellular Responses ◽  
Double Negative ◽  
Immunocompromised Patients ◽  
Ifn Gamma ◽  
Lymphoid Malignancies ◽  
Anti Cd20

Humoral and cellular responses after a third dose of BNT162b2 vaccine in patients treated for lymphoid malignancies. BACKGROUND: Immunocompromised patients such as patients with hematological malignancies have impaired immune response to two doses of BNT162b2 (Pfizer / BioNtech) vaccine against SARS-CoV-2. Evaluation of a repeated immune stimulation with a third vaccine dose is needed. METHODS: a vaccine monitoring observatory was conducted in outpatients who were treated for lymphoid malignancies (LM) to monitor both immune and cellular response measured the day of administration of the dose 3 of the mRNA vaccine BNT162b2 and again three to four weeks. Elecsys Anti-SARS-CoV-2 immunoassay was used to asses to the level of SARS-CoV-2 anti-Spike (S) antibodies (Abs) titer and SARS-CoV-2-specific T-cell responses were assessed by a whole blood Interferon-Gamma Release Immuno Assay (IGRA) (QuantiFERON Human IFN-gamma SARS-CoV-2, Qiagen). RESULTS: Among the 43 assessable patients (suffering from chronic lymphocytic leukemia (CLL) (n=15), indolent and aggressive B cell non-Hodgkin lymphoma (NHL) (n=14), and multiple myeloma (MM) (n=16)), 18 (41,8%) had no anti-S Abs before the dose 3 of BNT162b2 vaccine (n=9 CLL, n=8 NHL, n=1 MM), and they all 18 remained negative after the dose 3. Amongst the 25 patients with positive anti-S titers before dose 3, all patients remained positive and 23 patients increased their anti-S titer after dose 3. Patients with CLL and/or with previous anti-CD20 therapy treated within 12 months of administration of dose 3 had no significant increase of the humoral response. Among 22 available patients, dose 3 of BNT162b2 vaccine significantly increased the median IFN-gamma secretion. On eight (36.4%) patients who were double-negative for both immune and cellular response, five (22.7%) patients remained double-negative after dose 3. CONCLUSIONS Dose 3 of BNT162b2 vaccine stimulated humoral immune response among patients with LM, in particular patients with MM (who had higher anti-S baseline titer after dose 2) and those with no anti-CD20 treatment history within a year. T-cell response was increased among patients in particular with no active chemotherapy regimen. Our data support the use of an early third vaccine dose among immunocompromised patients followed for LM though some of them will still have vaccine failure.

scholarly journals Comparative kinetics of SARS-CoV-2 anti-spike protein RBD IgGs and neutralizing antibodies in convalescent and naïve recipients of the BNT162b2 mRNA vaccine versus COVID-19 patients

BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Ioannis P. Trougakos ◽  
Evangelos Terpos ◽  
Christina Zirou ◽  
Aimilia D. Sklirou ◽  
Filia Apostolakou ◽  
...  
Keyword(s):  
Immune Response ◽  
Neutralizing Antibodies ◽  
Mononuclear Cells ◽  
Natural Infection ◽  
Severe Disease ◽  
Vaccination Campaign ◽  
Hospitalized Patients ◽  
Peripheral Blood Mononuclear ◽  
Post Vaccination ◽  
Antibody Titers

Abstract Background Coronavirus SARS-CoV-2, the causative agent of COVID-19, has caused a still evolving global pandemic. Given the worldwide vaccination campaign, the understanding of the vaccine-induced versus COVID-19-induced immunity will contribute to adjusting vaccine dosing strategies and speeding-up vaccination efforts. Methods Anti-spike-RBD IgGs and neutralizing antibodies (NAbs) titers were measured in BNT162b2 mRNA vaccinated participants (n = 250); we also investigated humoral and cellular immune responses in vaccinated individuals (n = 21) of this cohort 5 months post-vaccination and assayed NAbs levels in COVID-19 hospitalized patients (n = 60) with moderate or severe disease, as well as in COVID-19 recovered patients (n = 34). Results We found that one (boosting) dose of the BNT162b2 vaccine triggers robust immune (i.e., anti-spike-RBD IgGs and NAbs) responses in COVID-19 convalescent healthy recipients, while naïve recipients require both priming and boosting shots to acquire high antibody titers. Severe COVID-19 triggers an earlier and more intense (versus moderate disease) immune response in hospitalized patients; in all cases, however, antibody titers remain at high levels in COVID-19 recovered patients. Although virus infection promotes an earlier and more intense, versus priming vaccination, immune response, boosting vaccination induces antibody titers significantly higher and likely more durable versus COVID-19. In support, high anti-spike-RBD IgGs/NAbs titers along with spike (vaccine encoded antigen) specific T cell clones were found in the serum and peripheral blood mononuclear cells, respectively, of vaccinated individuals 5 months post-vaccination. Conclusions These findings support vaccination efficacy, also suggesting that vaccination likely offers more protection than natural infection. Graphical abstract

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