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Artikel ; Online: Targeting CD19-positive lymphomas with the antibody-drug conjugate loncastuximab tesirine: preclinical evidence as single agent and in combination therapy.

2024

Abstract: Antibody-drug conjugates (ADCs) represent one of the most successful therapeutic approaches introduced in clinical practice in the last few years. Loncastuximab tesirine (ADCT-402) is a CD19 targeting ADC, in which the antibody is conjugated through a ... ...

Abstract	Antibody-drug conjugates (ADCs) represent one of the most successful therapeutic approaches introduced in clinical practice in the last few years. Loncastuximab tesirine (ADCT-402) is a CD19 targeting ADC, in which the antibody is conjugated through a protease cleavable dipeptide linker to a pyrrolobenzodiazepine (PBD) dimer warhead (SG3199). Based on the results of a phase 2 study, loncastuximab tesirine was recently approved for adult patients with relapsed/refractory large B-cell lymphoma. We assessed the activity of loncastuximab tesirine using in vitro and in vivo models of lymphomas, correlated its activity with CD19 expression levels, and identified combination partners providing synergy with loncastuximab tesirine. Loncastuximab tesirine was tested across 60 lymphoma cell lines. Loncastuximab tesirine had strong cytotoxic activity in B-cell lymphoma cell lines. The in vitro activity was correlated with CD19 expression level and intrinsic sensitivity of cell lines to the ADC's warhead. Loncastuximab tesirine was more potent than other anti-CD19 ADCs (coltuximab ravtansine, huB4-DGN462), albeit the pattern of activity across cell lines was correlated. Loncastuximab tesirine activity was also largely correlated with cell line sensitivity to R-CHOP. Combinatorial in vitro and in vivo experiments identified the benefit of adding loncastuximab tesirine to other agents, especially BCL2 and PI3K inhibitors. Our data support the further development of loncastuximab tesirine as a single agent and in combination for patients affected by mature B-cell neoplasms. The results also highlight the importance of CD19 expression and the existence of lymphoma populations characterized by resistance to multiple therapies.
Sprache	Englisch
Erscheinungsdatum	2024-05-09
Erscheinungsland	Italy
Dokumenttyp	Journal Article
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2023.284197
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Humoral and Cellular Immune Response to Covid-19 Vaccination in Patients with Chronic Graft-versus-Host Disease on Immunosuppression.

Manjappa, Shivaprasad / Phi, Huy Q / Lee, Lik Wee / Onstad, Lynn / Gill, Darcy B / Connelly-Smith, Laura / Krakow, Elizabeth F / Flowers, Mary E / Carpenter, Paul A / Hill, Joshua A / Lee, Stephanie J

Transplantation and cellular therapy

2022 Band 28, Heft 11, Seite(n) 784.e1–784.e9

Abstract: Chronic graft-versus-host disease (cGVHD) and its management with immunosuppressive therapies increase the susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as well as progression to severe Coronavirus 19 disease ( ... ...

Abstract	Chronic graft-versus-host disease (cGVHD) and its management with immunosuppressive therapies increase the susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as well as progression to severe Coronavirus 19 disease (COVID-19). Vaccination against COVID-19 is strongly recommended, but efficacy data are limited in this patient population. In this study, responses to COVID-19 vaccination were measured at 3 time points-after the initial vaccine series, before the third dose, and after the third dose-in adults with cGVHD receiving immunosuppressive therapy. Humoral response was measured by quantitative anti-spike antibody and neutralizing antibody levels. Anti-nucleocapsid antibody levels were measured to detect natural infection. T cell response was evaluated by a novel immunosequencing technique combined with immune repertoire profiling from cryopreserved peripheral blood mononuclear cell samples. Present or absent T cell responses were determined by the relative proportion of unique SARS-CoV-2-associated T cell receptor sequences ("breadth") plus clonal expansion of the response ("depth") compared with those in a reference population. Based on both neutralizing antibody and T cell responses, patients were categorized as vaccine responders (both detected), nonresponders (neither detected), or mixed (one but not both detected). Thirty-two patients were enrolled for the initial series, including 17 (53%) positive responders, 7 (22%) mixed responders, and 8 (25%) nonresponders. All but one patient categorized as mixed responders had humoral responses while lacking T cell responses. No statistical differences were observed in patient characteristics among the 3 groups of patients categorized by immune response, although sample sizes were limited. Significant positive correlations were observed between the robustness of cellular and humoral responses after the initial series. Among the 20 patients with paired samples (pre- and post-third dose), a third vaccination resulted in increased neutralizing antibody titers. cGVHD worsened in 10 patients (26%; 6 after the initial series and 4 after the third dose), necessitating escalation of immunosuppressive doses in 5 patients, although 4 had been tapering immunosuppression and 5 had already worsening cGVHD at the time of vaccination, and a clear association between COVID-19 vaccination and cGVHD could not be drawn. Among the patients with cGVHD on immunosuppressive therapy, 72% demonstrated a neutralizing antibody response after a 2-dose primary COVID-19 vaccination, two-thirds of whom also developed a T cell response; 25% had neither a humoral nor a T cell response. A third dose further amplified the antibody response.
Mesh-Begriff(e)	Adult ; Humans ; COVID-19 Vaccines ; SARS-CoV-2 ; COVID-19 ; Graft vs Host Disease ; Antibodies, Viral ; Leukocytes, Mononuclear ; Vaccination/methods ; Immunity, Cellular ; Antibodies, Neutralizing ; Immunosuppression Therapy ; Immunologic Deficiency Syndromes
Chemische Substanzen	COVID-19 Vaccines ; Antibodies, Viral ; Antibodies, Neutralizing
Sprache	Englisch
Erscheinungsdatum	2022-09-02
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3062231-1
ISSN	2666-6367
ISSN (online)	2666-6367
DOI	10.1016/j.jtct.2022.08.026
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: The efficacy of salvage autologous stem cell transplant among patients with multiple myeloma who received maintenance therapy post initial transplant.

Manjappa, Shivaprasad / Fiala, Mark A / King, Justin / Kohnen, Daniel A / Vij, Ravi

Bone marrow transplantation

2018 Band 53, Heft 11, Seite(n) 1483–1486

Mesh-Begriff(e)	Adult ; Aged ; Female ; Hematopoietic Stem Cell Transplantation/methods ; Humans ; Male ; Middle Aged ; Multiple Myeloma/pathology ; Multiple Myeloma/therapy ; Salvage Therapy/methods ; Transplantation Conditioning/methods ; Transplantation, Autologous/methods
Sprache	Englisch
Erscheinungsdatum	2018-05-24
Erscheinungsland	England
Dokumenttyp	Letter
ZDB-ID	632854-4
ISSN	1476-5365 ; 0268-3369 ; 0951-3078
ISSN (online)	1476-5365
ISSN	0268-3369 ; 0951-3078
DOI	10.1038/s41409-018-0216-3
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Dynamic left ventricular changes in patients with gestational diabetes: A speckle tracking echocardiography study.

Meera, Srinidhi J / Ando, Tomo / Pu, Daniel / Manjappa, Shivaprasad / Taub, Cynthia C

Journal of clinical ultrasound : JCU

2017 Band 45, Heft 1, Seite(n) 20–27

Abstract: Purpose: The left ventricle (LV) undergoes physiologic remodeling in adaptation to the hemodynamic changes that occur in pregnancy. Speckle tracking echocardiography (STE) is a novel and reliable tool to evaluate subtle myocardial alterations that have ... ...

Abstract	Purpose: The left ventricle (LV) undergoes physiologic remodeling in adaptation to the hemodynamic changes that occur in pregnancy. Speckle tracking echocardiography (STE) is a novel and reliable tool to evaluate subtle myocardial alterations that have been utilized to assess myocardial changes in patients with diabetes mellitus (DM) but not in patients with gestational DM (GDM). We seek to evaluate changes in LV function using STE in patients with GDM compared with women with normal pregnancy. Methods: This was a single-center retrospective cohort study. A total of 312 pregnant patients that underwent transthoracic echocardiogram (TTE) between 2009 and 2014 were screened. After excluding patients with comorbidities or insufficient data, 90 women were included. TTE from the second and third trimester for each patient were then reviewed, and STE analysis was performed. Results: Of the 90 subjects, 72 had normal pregnancies and 18 developed GDM. There was no difference in LV end-diastolic diameter (4.73 ± 0.40 versus 4.60 ± 0.56, p = 0.25), LV end-systolic diameter (3.12 ± 0.35 versus 2.91 ± 0.61, p = 0.152), or ejection fraction (62.26 ± 4.12 versus 63.50 ± 5.24, p = 0.314) between the two groups. Global longitudinal strain was lower (-19.8 ± 3.34 versus -17.2 ± 2.18, p < 0.001) in patients with GDM, while time-to-peak strain was greater (0.43 ± 0.05 versus 0.50 ± 0.06, p < 0.001). Circumferential and radial strains were preserved in both groups. Conclusions: Although conventional TTE variables show preserved LV size and function, LV longitudinal strain suggests subclinical myocardial dysfunction in patients with GDM. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 45:20-27, 2017.
Sprache	Englisch
Erscheinungsdatum	2017-01
Erscheinungsland	United States
Dokumenttyp	Journal Article
ZDB-ID	189393-2
ISSN	1097-0096 ; 0091-2751
ISSN (online)	1097-0096
ISSN	0091-2751
DOI	10.1002/jcu.22399
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Chemical screening identifies novel small molecule activators of natural killer cell cytotoxicity against cancer cells.

Lee, Grace / Karunanithi, Sheela / Posner, Bruce / Niederstrasser, Hanspeter / Cheng, Hong / Federov, Yuriy / Manjappa, Shivaprasad / Musaitif, Karam / Wang, Huaiyu / Jackson, Zachary / Wald, David

Cancer immunology, immunotherapy : CII

2021 Band 71, Heft 7, Seite(n) 1671–1680

Abstract: Natural killer (NK) cells are cytotoxic lymphocytes that play a major role in the innate immune system. NK cells exhibit potent cytotoxic activity against cancer cells and virally infected cells without antigen priming. These unique cytotoxic properties ... ...

Abstract	Natural killer (NK) cells are cytotoxic lymphocytes that play a major role in the innate immune system. NK cells exhibit potent cytotoxic activity against cancer cells and virally infected cells without antigen priming. These unique cytotoxic properties make NK cells a promising therapeutic against cancer. Limitations of NK cell therapy include deficiencies in high clinical efficacy often due to a need for a high NK cell to target cell ratio to achieve effective killing. In order to address the suboptimal efficacy of current adoptive NK cell therapy, a high throughput screen (HTS) was designed and performed to identify drug-like compounds that increase NK cytotoxic activity against tumor cells without affecting the normal cells. This screen was performed in a 384-well plate format utilizing an expanded primary NK cell product and ovarian cancer cells as a target cell (TC) line. Of the 8000 diverse small molecules screened, 16 hits were identified (0.2% hit rate) based on both a robust Z (RZ) score < -3 and a greater than 10% increase in NK cell killing. A validation screen had a confirmation rate of 70%. Select compounds were further validated and characterized by additional cytotoxicity assays including activity against multiple blood cancer and solid tumor cell lines, with no effect on primary human T cells. This work demonstrates that high-throughput screening can be reliably used to identify compounds that increase NK tumoricidal activity in vitro that can be further investigated and translated for potential clinical application. Précis: Our work led to the identification of promising compound that potently increases NK cell-mediated killing of a variety of different cancer cells, but no impact on the killing of normal cells. This compound demonstrates the utility of this assay.
Mesh-Begriff(e)	Cell Line, Tumor ; Cytotoxicity, Immunologic ; Early Detection of Cancer ; Humans ; Immunotherapy, Adoptive ; Killer Cells, Natural ; Neoplasms/drug therapy ; Neoplasms/metabolism ; T-Lymphocytes
Sprache	Englisch
Erscheinungsdatum	2021-11-23
Erscheinungsland	Germany
Dokumenttyp	Journal Article
ZDB-ID	195342-4
ISSN	1432-0851 ; 0340-7004
ISSN (online)	1432-0851
ISSN	0340-7004
DOI	10.1007/s00262-021-03117-w
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Automated Manufacture of Autologous CD19 CAR-T Cells for Treatment of Non-hodgkin Lymphoma.

Jackson, Zachary / Roe, Anne / Sharma, Ashish Arunkumar / Lopes, Filipa Blasco Tavares Pereira / Talla, Aarthi / Kleinsorge-Block, Sarah / Zamborsky, Kayla / Schiavone, Jennifer / Manjappa, Shivaprasad / Schauner, Robert / Lee, Grace / Liu, Ruifu / Caimi, Paolo F / Xiong, Ying / Krueger, Winfried / Worden, Andrew / Kadan, Mike / Schneider, Dina / Orentas, Rimas /

Dropulic, Boro / Sekaly, Rafick-Pierre / de Lima, Marcos / Wald, David N / Reese, Jane S

Frontiers in immunology

2020 Band 11, Seite(n) 1941

Abstract: Chimeric antigen receptor T cells (CAR-T cell) targeting CD19 are effective against several subtypes of CD19-expressing hematologic malignancies. Centralized manufacturing has allowed rapid expansion of this cellular therapy, but it may be associated ... ...

Abstract	Chimeric antigen receptor T cells (CAR-T cell) targeting CD19 are effective against several subtypes of CD19-expressing hematologic malignancies. Centralized manufacturing has allowed rapid expansion of this cellular therapy, but it may be associated with treatment delays due to the required logistics. We hypothesized that point of care manufacturing of CAR-T cells on the automated CliniMACS Prodigy
Mesh-Begriff(e)	Animals ; Antigens, CD19/genetics ; Antigens, CD19/immunology ; Antigens, CD19/metabolism ; Automation ; Cell Culture Techniques ; Cell Engineering ; Cells, Cultured ; Clinical Trials, Phase I as Topic ; Clinical Trials, Phase II as Topic ; Cytotoxicity, Immunologic ; Humans ; Immunotherapy, Adoptive ; Lymphoma, Non-Hodgkin/immunology ; Lymphoma, Non-Hodgkin/metabolism ; Lymphoma, Non-Hodgkin/therapy ; Mice, Inbred NOD ; Phenotype ; Point-of-Care Systems ; Receptors, Chimeric Antigen/genetics ; Receptors, Chimeric Antigen/immunology ; Receptors, Chimeric Antigen/metabolism ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; T-Lymphocytes/transplantation ; Transplantation, Autologous ; Treatment Outcome ; Workload ; Xenograft Model Antitumor Assays
Chemische Substanzen	Antigens, CD19 ; CD19 molecule, human ; Receptors, Chimeric Antigen
Sprache	Englisch
Erscheinungsdatum	2020-08-07
Erscheinungsland	Switzerland
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2020.01941
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Hematologic Recovery after Pretransplant Chemotherapy Does Not Influence Survival after Allogeneic Hematopoietic Cell Transplantation in Acute Myeloid Leukemia Patients.

Vu, Khoan / Manjappa, Shivaprasad / DiPersio, John F / Gao, Feng / Westervelt, Peter / Vij, Ravi / Stockerl-Goldstein, Keith E / Uy, Geoffrey L / Abboud, Camille N / Schroeder, Mark A / Fehniger, Todd A / Cashen, Amanda F / Romee, Rizwan

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation

2015 Band 21, Heft 8, Seite(n) 1425–1430

Abstract: Pretransplant remission status in patients with acute myeloid leukemia (AML) is 1 of the most important factors determining their outcomes after allogeneic hematopoietic cell transplantation (allo-HCT). Most patients are in complete remission with full ... ...

Abstract	Pretransplant remission status in patients with acute myeloid leukemia (AML) is 1 of the most important factors determining their outcomes after allogeneic hematopoietic cell transplantation (allo-HCT). Most patients are in complete remission with full hematologic recovery (CR) before undergoing allo-HCT. However, some patients achieve CR without recovery of platelet count (CRp) or a morphologic leukemia-free state (MLFS), defined as meeting all CR criteria without recovery of both neutrophil and platelet counts. Currently, there is a paucity of data regarding transplant outcomes in AML patients achieving MLFS after chemotherapy. To address this question, we evaluated transplant outcomes in 270 AML patients who received 6/6 HLA-matched sibling or 10/10 HLA-matched unrelated donor transplantation at a single institution between 2006 and 2013. Of our 270 patients, 206 were in CR, 45 were in CRp, and 19 were in MLFS before allo-HCT. Patients in CR, CRp, or MLFS had similar 3-year overall survival rates (49%, 46%, and 47%, respectively; P = .88) and 3-year event-free survival rates (45%, 36%, and 40%, respectively; P = .53). However, the cumulative incidence of nonrelapse mortality was significantly higher in patients in MLFS compared with those in CR (58% versus 22%, P = .0004), whereas the cumulative incidence of relapse in patients in MLFS was significantly lower compared with those in CR (11% versus 36%, P = .03). Our results suggest that survival outcomes in AML patients are not influenced by degree of hematologic recovery before allo-HCT.
Mesh-Begriff(e)	Adolescent ; Adult ; Aged ; Cohort Studies ; Female ; Hematologic Diseases/etiology ; Hematopoietic Stem Cell Transplantation/methods ; Hematopoietic Stem Cell Transplantation/mortality ; Humans ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/mortality ; Leukemia, Myeloid, Acute/therapy ; Male ; Middle Aged ; Transplantation Conditioning/methods ; Transplantation Conditioning/mortality ; Transplantation, Homologous/methods ; Transplantation, Homologous/mortality ; Treatment Outcome ; Young Adult
Sprache	Englisch
Erscheinungsdatum	2015-08
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1474865-4
ISSN	1523-6536 ; 1083-8791
ISSN (online)	1523-6536
ISSN	1083-8791
DOI	10.1016/j.bbmt.2015.03.022
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Protective effect of cytomegalovirus reactivation on relapse after allogeneic hematopoietic cell transplantation in acute myeloid leukemia patients is influenced by conditioning regimen.

Manjappa, Shivaprasad / Bhamidipati, Pavan Kumar / Stokerl-Goldstein, Keith E / DiPersio, John F / Uy, Geoffrey L / Westervelt, Peter / Liu, Jingxia / Schroeder, Mark A / Vij, Ravi / Abboud, Camille N / Fehniger, Todd A / Cashen, Amanda F / Pusic, Iskra / Jacoby, Meagan / Meera, Srinidhi J / Romee, Rizwan

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation

2013 Band 20, Heft 1, Seite(n) 46–52

Abstract: Cytomegalovirus (CMV) reactivation after allogeneic hematopoietic cell transplant (allo-HCT) has been associated with a reduced risk of relapse in patients with acute myeloid leukemia (AML). However, the influence of the conditioning regimen on this ... ...

Abstract	Cytomegalovirus (CMV) reactivation after allogeneic hematopoietic cell transplant (allo-HCT) has been associated with a reduced risk of relapse in patients with acute myeloid leukemia (AML). However, the influence of the conditioning regimen on this protective effect of CMV reactivation after allo-HCT is relatively unexplored. To address this, we evaluated the risk of relapse in 264 AML patients who received T cell-replete, 6/6 HLA matched sibling or 10/10 HLA matched unrelated donor transplantation at a single institution between 2006 and 2011. Of these 264 patients, 206 received myeloablative (MA) and 58 received reduced-intensity conditioning (RIC) regimens. CMV reactivation was observed in 88 patients with MA conditioning and 37 patients with RIC. At a median follow-up of 299 days, CMV reactivation was associated with significantly lower risk of relapse in patients who received MA conditioning both in univariate (P = .01) and multivariate analyses (hazard ratio, .5246; P = .006); however, CMV reactivation did not significantly affect the risk of relapse in our RIC cohort. These results confirm the protective effect of CMV reactivation on relapse in AML patients after allo-HCT reported by previous studies but suggest this protective effect of CMV reactivation on relapse is influenced by the conditioning regimen used with the transplant.
Mesh-Begriff(e)	Adolescent ; Adult ; Aged ; Cytomegalovirus/physiology ; Female ; Graft vs Leukemia Effect ; HLA Antigens/immunology ; Hematopoietic Stem Cell Transplantation ; Humans ; Leukemia, Myeloid, Acute/immunology ; Leukemia, Myeloid, Acute/pathology ; Leukemia, Myeloid, Acute/therapy ; Leukemia, Myeloid, Acute/virology ; Lymphocyte Depletion ; Male ; Middle Aged ; Multivariate Analysis ; Myeloablative Agonists/therapeutic use ; Risk ; Secondary Prevention ; Siblings ; T-Lymphocytes/drug effects ; T-Lymphocytes/immunology ; T-Lymphocytes/pathology ; Transplantation Conditioning/methods ; Transplantation, Homologous ; Unrelated Donors ; Virus Activation/drug effects
Chemische Substanzen	HLA Antigens ; Myeloablative Agonists
Sprache	Englisch
Erscheinungsdatum	2013-10-10
Erscheinungsland	United States
Dokumenttyp	Journal Article
ZDB-ID	1474865-4
ISSN	1523-6536 ; 1083-8791
ISSN (online)	1523-6536
ISSN	1083-8791
DOI	10.1016/j.bbmt.2013.10.003
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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