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  1. Article: Restricting CAR T Cell Trafficking Expands Targetable Antigen Space.

    Morales, Erin A / Dietze, Kenneth A / Baker, Jillian M / Wang, Alexander / Avila, Stephanie V / Iglesias, Fiorella / Radhakrishnan, Sabarinath V / Mause, Erica Vander / Olson, Michael L / Sun, Wenxiang / Rosati, Ethan / Chidester, Sadie L / Iraguha, Thierry / Fan, Xiaoxuan / Atanackovic, Djordje / Luetkens, Tim

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Chimeric antigen receptor (CAR) T cells are an effective treatment for some blood cancers. However, the lack of tumor-specific surface antigens limits their wider use. We identified a set of surface antigens that are limited in their expression to cancer ...

    Abstract Chimeric antigen receptor (CAR) T cells are an effective treatment for some blood cancers. However, the lack of tumor-specific surface antigens limits their wider use. We identified a set of surface antigens that are limited in their expression to cancer and the central nervous system (CNS). We developed CAR T cells against one of these antigens, LINGO1, which is widely expressed in Ewing sarcoma (ES). To prevent CNS targeting, we engineered LINGO1 CAR T cells lacking integrin α
    Language English
    Publishing date 2024-02-11
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.02.08.579002
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: A novel multicolor fluorescent spot assay for the functional assessment of chimeric antigen receptor (CAR) T-cell products.

    Atanackovic, Djordje / Iraguha, Thierry / Omili, Destiny / Avila, Stephanie V / Fan, Xiaoxuan / Kocoglu, Mehmet / Gebru, Etse / Baker, Jillian M / Dishanthan, Nishanthini / Dietze, Kenneth A / Oluwafemi, Ayooluwakiitan / Hardy, Nancy M / Yared, Jean A / Hankey, Kim / Dahiya, Saurabh / Rapoport, Aaron P / Luetkens, Tim

    Cytotherapy

    2024  Volume 26, Issue 4, Page(s) 318–324

    Abstract: Background aims: Chimeric antigen receptor (CAR) T-cell (CAR-T) therapies have revolutionized the treatment of B-cell lymphomas. Unfortunately, relapses after CD19-targeted CAR-T are relatively common and, therefore, there is a critical need for assays ... ...

    Abstract Background aims: Chimeric antigen receptor (CAR) T-cell (CAR-T) therapies have revolutionized the treatment of B-cell lymphomas. Unfortunately, relapses after CD19-targeted CAR-T are relatively common and, therefore, there is a critical need for assays able to assess the function and potency of CAR-T products pre-infusion, which will hopefully help to optimize CAR-T therapies. We developed a novel multicolor fluorescent spot assay (MFSA) for the functional assessment of CAR-T products on a single-cell level, combining the numerical assessment of CAR-T products with their functional characterization.
    Methods: We first used a standard single-cell interferon (IFN)-γ enzyme-linked immune absorbent spot assay to measure CD19-targeted CAR-T responses to CD19-coated beads. We then developed, optimized and validated an MFSA that simultaneously measures the secretion of combinations of different cytokines on a single CAR-T level.
    Results: We identified IFN-γ/tumor necrosis factor-α/granzyme B as the most relevant cytokine combination, and we used our novel MFSA to functionally and numerically characterize two clinical-grade CAR-T products.
    Conclusions: In conclusion, we have developed a novel assay for the quantitative and functional potency assessment of CAR-T products. Our optimized MFSA is cost-effective, easy to perform, reliable, can be performed overnight, allowing for a fast delivery of the product to the patient, and requires relatively minimal maintenance and training. The clinical value of our novel assay will be assessed in studies correlating the pre-infusion assessment of CAR-T products with the patients' outcome in a prospective fashion.
    MeSH term(s) Humans ; Receptors, Chimeric Antigen/genetics ; Neoplasm Recurrence, Local ; Immunotherapy, Adoptive ; Cytokines ; Antigens, CD19 ; T-Lymphocytes ; Receptors, Antigen, T-Cell/genetics
    Chemical Substances Receptors, Chimeric Antigen ; Cytokines ; Antigens, CD19 ; Receptors, Antigen, T-Cell
    Language English
    Publishing date 2024-02-10
    Publishing country England
    Document type Journal Article
    ZDB-ID 2039821-9
    ISSN 1477-2566 ; 1465-3249
    ISSN (online) 1477-2566
    ISSN 1465-3249
    DOI 10.1016/j.jcyt.2024.01.006
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5601: Show issues Location:
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  3. Article ; Online: Immune-mediated facial nerve paralysis in a myeloma patient post B-cell maturation antigen-targeted chimeric antigen receptor T cells.

    Kathari, Yamini K / Ahmad, Haroon / Kallen, Michael E / Koka, Rima / Omili, Destiny / Iraguha, Thierry / Clement, Jean / Pham, Lily / Khalid, Mazhar / Fan, Xiaoxuan / Gebru, Etse / Lesho, Patricia / Park, Esther / Dishanthan, Nishanthini / Baker, Jillian M / Dietze, Kenneth A / Hankey, Kim G / Badros, Ashraf / Yared, Jean A /
    Dahiya, Saurabh / Hardy, Nancy M / Kocoglu, Hakan / Luetkens, Tim / Rapoport, Aaron P / Atanackovic, Djordje

    Haematologica

    2024  Volume 109, Issue 2, Page(s) 682–688

    MeSH term(s) Humans ; Multiple Myeloma/complications ; Multiple Myeloma/therapy ; Receptors, Chimeric Antigen ; B-Cell Maturation Antigen ; Facial Nerve ; Immunotherapy, Adoptive/adverse effects ; T-Lymphocytes ; Paralysis
    Chemical Substances Receptors, Chimeric Antigen ; B-Cell Maturation Antigen
    Language English
    Publishing date 2024-02-01
    Publishing country Italy
    Document type 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.2023.283296
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Treatment of secondary CNS lymphoma using CD19-targeted chimeric antigen receptor (CAR) T cells.

    Kline, Kathryn / Luetkens, Tim / Koka, Rima / Kallen, Michael E / Chen, Wengen / Ahmad, Haroon / Omili, Destiny / Iraguha, Thierry / Gebru, Etse / Fan, Xiaoxuan / Miller, Alexis / Dishanthan, Nishanthini / Baker, Jillian M / Dietze, Kenneth A / Hankey, Kim G / Yared, Jean A / Hardy, Nancy M / Rapoport, Aaron P / Dahiya, Saurabh /
    Atanackovic, Djordje

    Cancer immunology, immunotherapy : CII

    2024  Volume 73, Issue 3, Page(s) 45

    Abstract: Background: Aggressive B cell lymphoma with secondary central nervous system (CNS) involvement (SCNSL) carries a dismal prognosis. Chimeric antigen receptor (CAR) T cells (CAR-T) targeting CD19 have revolutionized the treatment for B cell lymphomas; ... ...

    Abstract Background: Aggressive B cell lymphoma with secondary central nervous system (CNS) involvement (SCNSL) carries a dismal prognosis. Chimeric antigen receptor (CAR) T cells (CAR-T) targeting CD19 have revolutionized the treatment for B cell lymphomas; however, only single cases with CNS manifestations successfully treated with CD19 CAR-T have been reported.
    Methods: We prospectively enrolled 4 patients with SCNSL into our study to assess clinical responses and monitor T cell immunity.
    Results: Two of four SNCSL patients responded to the CD19-targeted CAR-T. Only one patient showed a substantial expansion of peripheral (PB) CAR-T cells with an almost 100-fold increase within the first week after CAR-T. The same patient also showed marked neurotoxicity and progression of the SNCSL despite continuous surface expression of CD19 on the lymphoma cells and an accumulation of CD4
    Conclusions: Our results demonstrate expansion and homing of CAR-T cells into the CNS in SNCSL patients. Local production of chemokines such as IP-10 may support CNS infiltration by CAR-T cells but also carry the potential of amplifying local toxicity. Future studies investigating numbers, phenotype, and function of CAR-T in the different body compartments of SNSCL patients receiving CAR-T will help to improve local delivery of "fit" and highly tumor-reactive CAR-T with low off-target reactivity into the CNS.
    MeSH term(s) Humans ; Receptors, Chimeric Antigen ; Chemokine CXCL10 ; Lymphoma ; Central Nervous System Neoplasms/therapy ; Antigens, CD19
    Chemical Substances Receptors, Chimeric Antigen ; Chemokine CXCL10 ; Antigens, CD19
    Language English
    Publishing date 2024-02-13
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 195342-4
    ISSN 1432-0851 ; 0340-7004
    ISSN (online) 1432-0851
    ISSN 0340-7004
    DOI 10.1007/s00262-023-03619-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1237: Show issues Location:
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  5. Article ; Online: Systematic single amino acid affinity tuning of CD229 CAR T cells retains efficacy against multiple myeloma and eliminates on-target off-tumor toxicity.

    Vander Mause, Erica R / Baker, Jillian M / Dietze, Kenneth A / Radhakrishnan, Sabarinath V / Iraguha, Thierry / Omili, Destiny / Davis, Patricia / Chidester, Sadie L / Modzelewska, Katarzyna / Panse, Jens / Marvin, James E / Olson, Michael L / Steinbach, Mary / Ng, David P / Lim, Carol S / Atanackovic, Djordje / Luetkens, Tim

    Science translational medicine

    2023  Volume 15, Issue 705, Page(s) eadd7900

    Abstract: T cells expressing chimeric antigen receptors (CARs) have shown remarkable therapeutic activity against different types of cancer. However, the wider use of CAR T cells has been hindered by the potential for life-threatening toxicities due to on-target ... ...

    Abstract T cells expressing chimeric antigen receptors (CARs) have shown remarkable therapeutic activity against different types of cancer. However, the wider use of CAR T cells has been hindered by the potential for life-threatening toxicities due to on-target off-tumor killing of cells expressing low amounts of the target antigen. CD229, a signaling lymphocyte-activation molecule (SLAM) family member, has previously been identified as a target for CAR T cell-mediated treatment of multiple myeloma (MM) due to its high expression on the surfaces of MM cells. CD229 CAR T cells have shown effective clearance of MM cells in vitro and in vivo. However, healthy lymphocytes also express CD229, albeit at lower amounts than MM cells, causing their unintended targeting by CD229 CAR T cells. To increase the selectivity of CD229 CAR T cells for MM cells, we used a single amino acid substitution approach of the CAR binding domain to reduce CAR affinity. To identify CARs with increased selectivity, we screened variant binding domains using solid-phase binding assays and biolayer interferometry and determined the cytotoxic activity of variant CAR T cells against MM cells and healthy lymphocytes. We identified a CD229 CAR binding domain with micromolar affinity that, when combined with overexpression of c-Jun, confers antitumor activity comparable to parental CD229 CAR T cells but lacks the parental cells' cytotoxic activity toward healthy lymphocytes in vitro and in vivo. The results represent a promising strategy to improve the efficacy and safety of CAR T cell therapy that requires clinical validation.
    MeSH term(s) Humans ; Multiple Myeloma/pathology ; Amino Acids/metabolism ; T-Lymphocytes ; Receptors, Chimeric Antigen/metabolism ; Immunotherapy, Adoptive/methods ; Antineoplastic Agents/metabolism ; Xenograft Model Antitumor Assays ; Cell Line, Tumor
    Chemical Substances Amino Acids ; Receptors, Chimeric Antigen ; Antineoplastic Agents
    Language English
    Publishing date 2023-07-19
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2518854-9
    ISSN 1946-6242 ; 1946-6234
    ISSN (online) 1946-6242
    ISSN 1946-6234
    DOI 10.1126/scitranslmed.add7900
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    Zs.A 6941: Show issues Location:
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  6. Article ; Online: Chimeric antigen receptor (CAR) T cells for the treatment of a kidney transplant patient with post-transplant lymphoproliferative disorder (PTLD).

    Kline, Kathryn / Chen, Wengen / Kallen, Michael E / Koka, Rima / Omili, Destiny / Fan, Xiaoxuan / Iraguha, Thierry / Gebru, Etse / Dishanthan, Nishanthini / Baker, Jillian M / Dietze, Kenneth A / Yared, Jean A / Hankey, Kim / Dahiya, Saurabh / Niederhaus, Silke V / Dunleavy, Kieron / Hardy, Nancy M / Luetkens, Tim / Rapoport, Aaron P /
    Atanackovic, Djordje

    Human vaccines & immunotherapeutics

    2023  Volume 19, Issue 2, Page(s) 2216116

    Abstract: Post-transplant lymphoproliferative disorder (PTLD) is a potentially fatal complication following kidney transplantation, and there is a critical and unmet need for PTLD treatments associated with more pronounced and durable responses. To date, reports ... ...

    Abstract Post-transplant lymphoproliferative disorder (PTLD) is a potentially fatal complication following kidney transplantation, and there is a critical and unmet need for PTLD treatments associated with more pronounced and durable responses. To date, reports on the use of CD19-targeted chimeric antigen receptor (CAR) T (CAR-T) cells in patients after solid organ transplant (SOT) have been anecdotal, clinical presentations and outcomes have been heterogenous, and a longitudinal analysis of CAR-T cell expansion and persistence in PTLD patients has not been reported. Our report describes a patient with a history of renal transplant who received CD19-directed CAR-T cell therapy for the treatment of refractory PTLD, diffuse large B cell lymphoma (DLBCL)-type. We show that even with the background of prolonged immunosuppression for SOT, it is possible to generate autologous CAR-T products capable of expansion and persistence in vivo, without evidence of excess T-cell exhaustion. Our data indicate that CAR-T cells generated from a SOT recipient with PTLD can yield deep remissions without increased toxicity or renal allograft dysfunction. Future clinical studies should build on these findings to investigate CAR-T therapy, including longitudinal monitoring of CAR-T phenotype and function, for PTLD in SOT recipients.
    MeSH term(s) Humans ; Kidney Transplantation/adverse effects ; Receptors, Chimeric Antigen/therapeutic use ; Organ Transplantation/adverse effects ; Lymphoproliferative Disorders/etiology ; Lymphoproliferative Disorders/therapy ; T-Lymphocytes/pathology
    Chemical Substances Receptors, Chimeric Antigen
    Language English
    Publishing date 2023-06-06
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2664176-8
    ISSN 2164-554X ; 2164-5515
    ISSN (online) 2164-554X
    ISSN 2164-5515
    DOI 10.1080/21645515.2023.2216116
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 6967: Show issues Location:
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