Kooperativer Bibliotheksverbund

In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1362-1362

Abstract: Chimeric Antigen Receptor (CAR) T cell therapy has resulted in remarkable clinical outcomes in the context of acute and chronic lymphoblastic leukemia, but remains unsuccessful in the treatment of solid tumors. One reason for this failure is thought to be T cell dysfunction or exhaustion promoted by suppressive soluble factors within the tumor microenvironment (TME). High extracellular levels of the immunosuppressive factor adenosine (Ado) are generated in the TME via breakdown of ATP by ecto-enzymes CD39 and CD73 expressed on tumor-infiltrating immune cells. Binding of extracellular Ado to its receptor A2a on T cells results in inhibition of proliferation and effector function. Interestingly, CD39 has recently been described as a surrogate marker of exhaustion on human CAR-T cells and non-engineered T cells. Therefore, we hypothesized that CD39 expression on exhausted CAR-T cells promotes dysfunction through generation of extracellular adenosine. Using an in vitro model of T cell exhaustion, whereby human T cells express a CAR that tonically signals in an antigen-independent manner (HA CAR), we demonstrate that exhausted HA CAR T cells actively hydrolyze extracellular ATP via their elevated expression of CD39 and CD73. Moreover, exhausted CD39+ CAR T cells upregulate several genes associated with a Treg phenotype at the mRNA and protein levels, suggesting that this cell population might be suppressive. To assess whether CD39+/CD73+ CAR T cells exhibit suppressive functions, we co-cultured them with non-exhausted CD19-CAR T cells. Indeed, proliferation and secretion of IL-2 by CD19 CAR T cells were diminished when they were co-cultured with exhausted CD39+ CAR T cells, and that this suppression is dependent on the A2a receptor. Using this knowledge, we used gene-editing and overexpression approaches to engineer CAR-T cells with resistance to suppressive adenosine signaling. In contrast to genetic deletion of CD39 or CD73, which did not alleviate CAR T cell dysfunction, genetic deletion of adenosine receptor A2aR in exhausted CAR T cells resulted in phenotypic changes and a modest improvement in tumor-specific killing. Further, ectopic overexpression of adenosine deaminase (ADA) in CAR T cells led to decreased exhaustion marker expression and significantly enhanced effector function. These data indicate that ADA overexpression is an innovative approach to increase the functionality of CAR T cells through avoidance of suppressive adenosine signaling, and provides proof-of-concept that metabolic engineering of CAR-T cells can pave the way for responses in patients with solid tumors. Citation Format: Dorota Klysz, Meena Malipatlolla, Katherine Freitas, Malek Bashti, Louai Labanieh, Peng Xu, Cecilia Ramello, Amaury Lerust, Hyatt Balke Want, Kaithlen Zen Pacheco, Evan W. Weber, Shabnum Patel, Steven Feldman, Elena Sotillo, Crystal L. Mackall. Metabolic engineering of CAR-T cells overcomes suppressive adenosine signaling and enhances functionality [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1362.

Type of Medium: Online Resource

ISSN: 1538-7445

URL: Article

DOI: 10.1158/1538-7445.AM2022-1362

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2022

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detail.hit.zdb_id: 410466-3

In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 18, No. 17 ( 2012-09-01), p. 4682-4690

Abstract: Purpose: ALK rearrangement–positive lung cancers can be effectively treated with ALK inhibitors. However, the magnitude and duration of response is heterogeneous. In addition, acquired resistance limits the efficacy of ALK inhibitors, with most upfront resistance mechanisms being unknown. Experimental Design: By making use of the Ba/F3 cell line model, we analyzed the cytotoxic efficacy of ALK kinase inhibitors as a function of different EML4-ALK fusion variants v1, v2, v3a, and v3b as well as of three artificially designed EML4-ALK deletion constructs and the ALK fusion genes KIF5b-ALK and NPM1-ALK. In addition, the intracellular localization, the sensitivity to HSP90 inhibition and the protein stability of ALK fusion proteins were studied. Results: Different ALK fusion genes and EML4-ALK variants exhibited differential sensitivity to the structurally diverse ALK kinase inhibitors crizotinib and TAE684. In addition, differential sensitivity correlated with differences in protein stability in EML4-ALK–expressing cells. Furthermore, the sensitivity to HSP90 inhibition also varied depending on the ALK fusion partner but differed from ALK inhibitor sensitivity patterns. Finally, combining inhibitors of ALK and HSP90 resulted in synergistic cytotoxicity. Conclusions: Our results might explain some of the heterogeneous responses of ALK-positive tumors to ALK kinase inhibition observed in the clinic. Thus, targeted therapy of ALK-positive lung cancer should take into account the precise ALK genotype. Furthermore, combining ALK and HSP90 inhibitors might enhance tumor shrinkage in EML4-ALK–driven tumors. Clin Cancer Res; 18(17); 4682–90. ©2012 AACR.

Type of Medium: Online Resource

ISSN: 1078-0432 , 1557-3265

URL: Article

DOI: 10.1158/1078-0432.CCR-11-3260

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2012

detail.hit.zdb_id: 1225457-5

detail.hit.zdb_id: 2036787-9

In: European Journal of Haematology, Wiley, Vol. 107, No. 2 ( 2021-08), p. 202-210

Abstract: Primary central nervous system lymphoma (PCNSL) is a rare type of aggressive lymphoma of the central nervous system. Treatment strategies improved significantly over the past decades differ regionally but mainly consist of rituximab and high‐dosed methotrexate (MTX)‐based therapies. Methods We assessed clinical outcomes of 100 patients with newly diagnosed PCNSL between 2010‐2020 at the University Hospital of Cologne, Germany. Results Patients were 23‐88 years of age and either treated with MTX‐based regimens (PRIMAIN, MARTA, MATRix), individual regimens, or best supportive care, respectively. Overall response rates were generally high (66,7‐83,8%), but different organ toxicities required dose adjustments in most groups. Two‐year overall survival rates were 57,9% (PRIMAIN), 63,6% (MARTA), 65,4% (MATRix), and 37,5% (Other), respectively. Out of 9 patients suffering from relapse 〉 12 months from primary diagnosis, 7 patients (77,8%) received methotrexate‐based salvage therapy with 2‐year overall survival of 4/6 patients (66,7%). Conclusion Although a relevant proportion of patients are not eligible for clinical trials due to age, performance status, or comorbidities, these results prove feasibility of different MTX‐based treatment strategies in clinical routine. Even elderly patients displayed surprisingly favorable outcomes. However, with compromising organ toxicities, reduction of intensity should be part of strategies in future clinical trials.

Type of Medium: Online Resource

ISSN: 0902-4441 , 1600-0609

URL: Issue

URL: Article

DOI: 10.1111/ejh.v107.2

DOI: 10.1111/ejh.13639

Language: English

Publisher: Wiley

Publication Date: 2021

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In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 42 ( 2012-10-16), p. 17034-17039

Abstract: Small cell lung cancer (SCLC) accounts for about 15% of all lung cancers. The prognosis of SCLC patients is devastating and no biologically targeted therapeutics are active in this tumor type. To develop a framework for development of specific SCLC-targeted drugs we conducted a combined genomic and pharmacological vulnerability screen in SCLC cell lines. We show that SCLC cell lines capture the genomic landscape of primary SCLC tumors and provide genetic predictors for activity of clinically relevant inhibitors by screening 267 compounds across 44 of these cell lines. We show Aurora kinase inhibitors are effective in SCLC cell lines bearing MYC amplification, which occur in 3–7% of SCLC patients. In MYC -amplified SCLC cells Aurora kinase inhibition associates with G2/M-arrest, inactivation of PI3-kinase (PI3K) signaling, and induction of apoptosis. Aurora dependency in SCLC primarily involved Aurora B, required its kinase activity, and was independent of depletion of cytoplasmic levels of MYC. Our study suggests that a fraction of SCLC patients may benefit from therapeutic inhibition of Aurora B. Thus, thorough chemical and genomic exploration of SCLC cell lines may provide starting points for further development of rational targeted therapeutic intervention in this deadly tumor type.

Type of Medium: Online Resource

ISSN: 0027-8424 , 1091-6490

URL: Article

DOI: 10.1073/pnas.1207310109

Language: English

Publisher: Proceedings of the National Academy of Sciences

Publication Date: 2012

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detail.hit.zdb_id: 1461794-8

SSG: 11

SSG: 12

In: Molecular Cancer, Springer Science and Business Media LLC, Vol. 22, No. 1 ( 2023-06-26)

Abstract: Chimeric Antigen Receptor (CAR) T cells are now standard of care (SOC) for some patients with B cell and plasma cell malignancies and could disrupt the therapeutic landscape of solid tumors. However, access to CAR-T cells is not adequate to meet clinical needs, in part due to high cost and long lead times for manufacturing clinical grade virus. Non-viral site directed CAR integration can be accomplished using CRISPR/Cas9 and double-stranded DNA (dsDNA) or single-stranded DNA (ssDNA) via homology-directed repair (HDR), however yields with this approach have been limiting for clinical application (dsDNA) or access to large yields sufficient to meet the manufacturing demands outside early phase clinical trials is limited (ssDNA). Methods We applied homology-independent targeted insertion (HITI) or HDR using CRISPR/Cas9 and nanoplasmid DNA to insert an anti-GD2 CAR into the T cell receptor alpha constant (TRAC) locus and compared both targeted insertion strategies in our system. Next, we optimized post-HITI CRISPR EnrichMENT (CEMENT) to seamlessly integrate it into a 14-day process and compared our knock-in with viral transduced anti-GD2 CAR-T cells. Finally, we explored the off-target genomic toxicity of our genomic engineering approach. Results Here, we show that site directed CAR integration utilizing nanoplasmid DNA delivered via HITI provides high cell yields and highly functional cells. CEMENT enriched CAR T cells to approximately 80% purity, resulting in therapeutically relevant dose ranges of 5.5 × 10 8 –3.6 × 10 9 CAR + T cells. CRISPR knock-in CAR-T cells were functionally comparable with viral transduced anti-GD2 CAR-T cells and did not show any evidence of off-target genomic toxicity. Conclusions Our work provides a novel platform to perform guided CAR insertion into primary human T-cells using nanoplasmid DNA and holds the potential to increase access to CAR-T cell therapies.

Type of Medium: Online Resource

ISSN: 1476-4598

URL: Article

DOI: 10.1186/s12943-023-01799-7

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2023

detail.hit.zdb_id: 2091373-4

In: Blood, American Society of Hematology, Vol. 141, No. 19 ( 2023-05-11), p. 2285-2286

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.2023020188

Language: English

Publisher: American Society of Hematology

Publication Date: 2023

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 899-899

Abstract: Background Quantitative polymerase chain reaction (qPCR) is an analytical method that has been used to investigate the in vivo kinetics of chimeric receptor antigen (CAR) transgene following the infusion of tisagenlecleucel. B cell aplasia, likely an "on-target toxicity" of tisagenlecleucel, has been considered a measure of functional persistence. (Maude SL et al. Blood 2015;125(26):4017-4023) Although the CAR transgene can be detected in peripheral blood of tisagenlecleucel treated patients, it is unclear whether CAR transgene detection by qPCR could be reliably used to inform treatment decision in an individual patient. Methods Transgene levels in blood measured by qPCR from pivotal phase II studies in relapsed/refractory (r/r) pediatric and young adult acute lymphoblastic leukemia (B-ALL) patients (pts) (ELIANA [NCT02435849, N=75]; ENSIGN [NCT02228096, N=29] ) and adult diffuse large B cell lymphoma (DLBCL) pts (JULIET [NCT02445248, N=93]) were used to investigate the relationship between transgene persistence and clinical response. Results To determine whether CAR qPCR measurements are associated with or predictive of response, CAR transgene levels and timing of peak levels were examined. In both ALL and DLBCL pts, there were detectable CAR transgene levels by qPCR in both responders and non-responders. The geometric mean maximal expansion (geo mean Cmax) was similar between responding and non-responding adult DLBCL pts, while 1.7 fold differences were observed in pediatric ALL pts (geo mean Cmax in copies/µg: responders, 32700, n=79; non-responders, 19500, n=10; Table 1). For both DLBCL and ALL pts, high inter-individual variability in transgene levels was noted. Similarly, higher CAR-T cell expansion from flow cytometry data pooled from responding pediatric ALL and chronic lymphocytic leukemia (CLL) pts were observed relative to non-responding pts (Mueller KT et al. Blood 2017;130(21):2317-2325), while the levels in DLBCL pts were comparatively lower in blood, likely due to partitioning of functional CAR-T cells to the target sites including lymph nodes. The median time to maximal transgene level ranged from 9-10 days in DLBCL responders and non-responders and pediatric ALL responders, while non-responding pediatric ALL pts showed delayed expansion with median Tmax of 20 days. The median time corresponding to last quantifiable transgene level (Tlast), an indicator of persistence, was higher in responding pts compared to non-responding pts, indicating a trend for longer persistence in both DLBCL and ALL pts with continued response (Table 1). Similarly, the half-life estimated from the terminal slope of the cellular kinetic profile, an additional indicator of persistence, was higher in responding pts relative to non-responding pts for both DLBCL and ALL (Table 1). Despite this general trend, in some cases, transgene levels were not detectable at later time points in pts with continued response. The swimmer plot for representative responder ALL (Figure 1a) and DLBCL pts (Figure 1b) with responses and transgene levels demonstrate that although the majority of responding pts show persistent transgene levels, some pts maintained a favorable clinical response despite a decline in transgene levels to below the level of quantification of 50 copies/µg. Conclusion In both ALL and DLBCL, CAR transgene is initially detected at high levels with high variability in both responders and non-responders. While the majority of responding pts tend to have persistent transgene levels, some pts maintain favorable clinical responses despite a lack of quantifiable transgene. These results indicate that qPCR testing for CAR transgene in blood of tisagenlecleucel treated pts should not be used for making treatment decisions for individual pts. In addition, the qPCR measurements in peripheral blood do not reflect on the trafficking of CAR positive cells to sites outside peripheral blood. The assessment by flow cytometry remains an important assay to distinguish high expression in responding vs non-responding pts in ALL and CLL, and further evaluation of target tissue is needed in DLBCL to understand the utility of CAR expression as a means to distinguish responder and non-responders. Also, further data are needed to improve our understanding of how CAR transgene levels relate to disease burden and duration of response and whether this information is clinically useful. Disclosures Awasthi: Exelixis: Equity Ownership; Celgene: Equity Ownership; Novartis Institutes for Biomedical Research: Employment. Mueller:Novartis Institutes for Biomedical Research: Employment; Novartis Pharmaceuticals Corporation: Equity Ownership, Other: Patent pending. Tam:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding. Rives:Amgen: Consultancy, Other: advisory board ; Novartis Pharmaceuticals Corporation: Consultancy, Other: Symposia, advisory boards ; Jazz Pharma: Consultancy, Other: Symposia, advisory boards ; Shire: Consultancy, Other: Symposia, advisory boards . McGuirk:Bellicum Pharmaceuticals: Research Funding; Fresenius Biotech: Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Other: speaker, Research Funding; Astellas Pharma: Research Funding; Gamida Cell: Research Funding; Kite Pharma: Honoraria, Other: travel accommodations, expenses, speaker ; Pluristem Ltd: Research Funding. Pulsipher:Adaptive Biotech: Consultancy, Research Funding; Amgen: Honoraria; CSL Behring: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau. Jaeger:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria; Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; MSD: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Baruchel:Novartis: Membership on an entity's Board of Directors or advisory committees; Shire: Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Travel, accommodations or expenses; Amgen: Consultancy; Roche: Consultancy; Servier: Consultancy; Celgene: Consultancy. Myers:Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau. Balke-Want:Novartis Pharmaceuticals Corporation: Honoraria. Schuster:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Dava Oncology: Consultancy, Honoraria; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Research Funding. Stefanski:Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Speakers Bureau. Bishop:Novartis Pharmaceuticals Corporation: Speakers Bureau; Juneau Therapeutics: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; United Healthcare: Employment. Waldron:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Anak:Novartis Pharma AG: Employment. Chakraborty:Novartis Institutes for Biomedical Research: Employment. Bleickardt:Novartis Pharmaceuticals Corporation: Employment. Wong:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Bubuteishvili Pacaud:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Waller:Kalytera: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celldex: Research Funding; Pharmacyclics: Other: Travel Expenses, EHA, Research Funding; Cambium Medical Technologies: Consultancy, Equity Ownership. Maude:Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-116385

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 48-48

Abstract: Background CD19 redirected chimeric antigen receptor (CAR) T-cell therapy has proven efficacy in relapsed or chemotherapy-refractory (r/r) aggressive B-cell non-Hodgkin lymphoma (B-NHL). However, targeting a single B-cell antigen leads to selective pressure with potential antigen-escape and subsequent relapse. A tandem CAR targeting CD20 and CD19 (pLTG1497) has been developed to overcome this limitation. Preclinical evaluation showed improved anti-lymphoma activity. Thus, we initiated a first-in-human, phase I clinical study of autologous pLTG1497-transduced CAR T-cells (MB-CART2019.1) in r/r B-NHL patients. Aims In this phase I prospective multi-center trial (NCT03870945) we aimed to evaluate the maximum tolerated dose (MTD) of MB-CART2019.1 in adult patients with CD20 and CD19 positive r/r B-NHL as determined by dose limiting toxicities (DLTs). Methods This was a 6+3 trial design with two predefined dose levels (DL1 1x106 and DL2 2.5x106 CAR T-cells/kg body weight, respectively). Secondary endpoints included adverse events (AEs) and best overall response rate (ORR). Pharmacodynamic assessments included maximum concentration (Cmax) of CAR T-cells, time to peak expansion (tmax), AUC (d0 to d28), and persistence. MB-CART2019.1 was produced by lentiviral transduction of autologous fresh leukapheresis in the closed automated CliniMACS Prodigy® System (Miltenyi Biotec, Bergisch Gladbach, Germany). Re-infusion (Day 0) of fresh MB-CART2019.1 was scheduled 14 days after leukapheresis. Fludarabine/cyclophosphamide lymphodepleting chemotherapy was administered from day -5 to -3. Results A total of 12 patients, 6 per dose level have been enrolled and treated between February and December 2019, 5 female and 7 male patients. Median age was 72 y (range 20, 78 y), with 10 patients & gt;65 y and 8 & gt;70 y. Histologies included aggressive B-NHL (11) and mantle cell lymphoma (1). Five (5) patients had refractory disease at study entry and IPI was ≥3 in 7 patients. Median time from leukapheresis to re-infusion was 14 d (range 13, 14 d). No DLT and no cytokine release syndrome (CRS) or neurotoxicity grade ≥3 were observed. One patient in dose level 1 experienced a grade 5 AE, which was due to disease progression. CRS grade 1 occurred in 3/6 patients on DL1 and DL2 each, and CRS grade 2 in 2 patients on DL2. Tocilizumab was given in 1 patient. Neurotoxicity grade 1 occurred in 1 patient on DL2. The above described CRS and neurotoxicity resolved completely. Mean Cmax of MB-CART2019.1 was 348.3 cells/µl (range 3.9, 830.4 cells/µl) on DL1 and 692 cells/µl (range 5.3, 3147.8 cells/µl) on DL2. Mean tmax was 15.8 d (range 9, 21 d) on DL1 and 11.5 d (range 9, 14 d) on DL2. Mean AUC was 3155 d*cells/µl (DL1) and 4339 d*cells/µl (DL2). Persistence of MB-CART2019.1 was observed in 12/12 patients until data cut-off. Altogether 9/12 patients (ORR 75%) responded to MB-CART2019.1 with 5/12 CRs. In DL1 3/6 patients responded (ORR 50%) and in DL2 6/6 patients (ORR 100%). The 3 patients without response to MB-CART2019.1 had a mean AUC0-28 of 870 d*cells/µl, whereas mean AUC0-28 in 9 responders was 4843 d*cells/µl reflecting the correlation between the pharmacodynamic parameters and the clinical response. Responses are ongoing in 5/9 patients, with a maximum duration of response of 330 days at data cut-off. Summary/Conclusions In this first-in-human dose finding study of MB-CART2019.1 no DLT and no severe (grade ≥3) CRS or neurotoxicity were observed. Feasibility and safety were very good in this cohort of elderly r/r B-NHL patients. The sustained expansion of tandem CAR T-cells was accompanied by efficacy: all patients (6/6) treated on DL2 responded and all 5 patients with CR (5/5) are in ongoing remission by the time of this report. Based on the promising risk-to-benefit ratio observed in our study, evaluation of MB-CART2019.1 at a dose of 2.5x106/kg body weight in clinical phase II and phase III trials for patients with relapsed aggressive B-NHL is underway. Disclosures Borchmann: Miltenyi Biotec B.V. & Co. KG: Honoraria. Balke-Want:Miltenyi Biotec B.V. & Co. KG: Honoraria. Ayuk:Celgene: Consultancy, Honoraria; Kite/Gilead: Honoraria; Therakos/Mallinckrodt: Honoraria, Research Funding; Neovii: Research Funding; Novartis: Honoraria. Holtkamp:Miltenyi Biomedicine GmbH: Current Employment. Preussner:Miltenyi Biomedicine GmbH: Ended employment in the past 24 months. Zadoyan:Miltenyi Biomedicine GmbH: Current Employment. Hanssens:Miltenyi Biomedicine GmbH: Current Employment. Kaiser:Miltenyi Biotec B.V. & Co. KG: Current Employment. Jurk:Miltenyi Biotec B.V. & Co. KG: Current Employment. Bürger:Miltenyi Biotec B.V. & Co. KG: Current Employment. Schneider:Lentigen Technology Inc., A Miltenyi Company: Current Employment, Patents & Royalties. Dropulic:Lentigen Technology Inc., A Miltenyi Company: Current Employment. Overstijns:Miltenyi Biomedicine GmbH: Current Employment, Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotec B.V. & Co. KG: Current Employment, Membership on an entity's Board of Directors or advisory committees. Scheid:Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria; Takeda: Honoraria, Research Funding. Holtick:Miltenyi Biotec B.V. & Co. KG: Honoraria. Miltenyi:Miltenyi Biomedicine GmbH: Current Employment, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Lentigen Technology Inc., A Miltenyi Company: Current Employment, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Miltenyi Biotec B.V. & Co. KG: Current Employment, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-136067

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

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detail.hit.zdb_id: 80069-7

In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 17, No. 23 ( 2011-12-01), p. 7394-7401

Abstract: Purpose: EML4–ALK fusions define a subset of lung cancers that can be effectively treated with anaplastic lymphoma kinase (ALK) inhibitors. Unfortunately, the duration of response is heterogeneous and acquired resistance limits their ultimate efficacy. Thus, a better understanding of resistance mechanisms will help to enhance tumor control in EML4–ALK-positive tumors. Experimental Design: By applying orthogonal functional mutagenesis screening approaches, we screened for mutations inducing resistance to the aminopyridine PF02341066 (crizotinib) and/or the diaminopyrimidine TAE684. Results: Here, we show that the resistance mutation, L1196M, as well as other crizotinib resistance mutations (F1174L and G1269S), are highly sensitive to the structurally unrelated ALK inhibitor TAE684. In addition, we identified two novel EML4–ALK resistance mutations (L1198P and D1203N), which unlike previously reported mutations, induced resistance to both ALK inhibitors. An independent resistance screen in ALK-mutant neuroblastoma cells yielded the same L1198P resistance mutation but defined two additional mutations conferring resistance to TAE684 but not to PF02341066. Conclusions: Our results show that different ALK resistance mutations as well as different ALK inhibitors impact the therapeutic efficacy in the setting of EML4–ALK fusions and ALK mutations. Clin Cancer Res; 17(23); 7394–401. ©2011 AACR.

Type of Medium: Online Resource

ISSN: 1078-0432 , 1557-3265

URL: Article

DOI: 10.1158/1078-0432.CCR-11-1648

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2011

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detail.hit.zdb_id: 2036787-9

In: European Journal of Haematology, Wiley, Vol. 108, No. 5 ( 2022-05), p. 403-412

Abstract: Burkitt lymphoma (BL) and diffuse large B‐cell lymphoma (DLBCL) are aggressive B‐cell non‐Hodgkin lymphomas (B‐NHL) with a generally favorable prognosis after immunochemotherapy. The outcome of BL is superior to DLBCL. In 2016, a distinct group of lymphomas displaying characteristics of both BL and DLBCL (high grade B‐cell lymphoma, HGBL) was introduced into the WHO classification. Histopathological discrimination of BL, DLBCL, and HGBL may be challenging. Data on the frequency of histopathological difficulties resulting in revision of the final diagnosis of BL/DLBCL/HGBL and its impact on the prognosis are limited. Methods We assessed histopathological features and clinical outcomes of 66 patients with suspected diagnosis of BL at the reporting institution between 2010 and 2020. Results The median age was 51 years (range 19‐82) and final histopathological diagnosis revealed BL (n = 40), DLBCL (n = 12), or HGBL (n = 14). Patients with DLBCL and HGBL were either treated with DLBCL‐directed (83.3% and 35.7%) or BL‐directed (16.7% and 64.3%) protocols. Patients in whom diagnosis was revised from DLBCL to BL after initiation of DLBCL‐directed treatment had a significantly inferior progression‐free survival (PFS) than patients initially diagnosed with BL (p = 0.045), thus resembling rather the prognosis of DLBCL/HGBL. There was no difference between patients with DLBCL and HGBL, respectively, regarding PFS and OS (p = 0.38 and p = 0.27). Conclusion These results suggest that timely and precise histopathological diagnosis as well as reference histopathological review of the underlying lymphoma is critical to determine up‐front treatment strategies. Consequently, selection of more aggressive treatment protocols in case of difficulties with discrimination between DLBCL/HGBL/BL may be a reasonable approach.

Type of Medium: Online Resource

ISSN: 0902-4441 , 1600-0609

URL: Issue

URL: Article

DOI: 10.1111/ejh.v108.5

DOI: 10.1111/ejh.13747

Language: English

Publisher: Wiley

Publication Date: 2022

detail.hit.zdb_id: 2027114-1