Dual targeting of CD19 and CD22 with Bicistronic CAR-T cells in Patients with Relapsed/Refractory Large B Cell Lymphoma

Roddie, Claire; Lekakis, Lazaros J.; Marzolini, Maria A V; Ramakrishnan, Aravind; Zhang, Yiyun; Hu, Yanqing; Peddareddigari, Vijay; Khokhar, Nushmia Z.; Chen, Robert W.; Basilico, Silvia; Raymond, Meera; Vargas, Frederick Arce; Duffy, Kevin; Brugger, Wolfram; O’Reilly, Maeve; Wood, L. Michael; Linch, David C.; Peggs, Karl S.; Bachier, Carlos; Budde, Lihua E.; Batlevi, Connie Lee; Bartlett, Nancy L.; Irvine, David; Tholouli, Eleni; Osborne, Wendy; Ardeshna, Kirit M.; Pulé, Martin

doi:10.1182/blood.2022018598

Cited by 27 publications

(28 citation statements)

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“…Consequently, a goal is to find strategies in which CAR T cells have the capacity to detect the antigen loss and switch their specificity or can detect multiple targets a priori. In multiple myeloma, dual CAR T‐cell targeting was tested by co‐infusion of two different CAR T‐cell constructs (dual CAR) or one CAR T‐cell construct targeting multiple molecules (tandem CAR) including BCMA and CD19, CD22, or GPRC5D 79–81 . Currently, a variety of combinations are being tested.…”

Section: Antigen Loss or Downregulationmentioning

confidence: 99%

Chimeric antigen receptor T cells for acute myeloid leukemia

Fetsch

Zeiser

2023

European J of Haematology

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The use of T cells expressing chimeric antigen receptors (CARs) that can target and eliminate cancer cells has revolutionized the treatment of B‐cell malignancies. In contrast, CAR T cells have not yet become a routine treatment for myeloid malignancies such as acute myeloid leukemia (AML) or myeloproliferative neoplasms (MPNs). For these disease entities, allogeneic hematopoietic cell transplantation (allo‐HCT) relying on polyclonal allo‐reactive T cells is still the major cellular immunotherapy used in clinical routine. Here, we discuss major hurdles of CAR T‐cell therapy for myeloid malignancies and novel approaches to enhance their efficacy and reduce toxicity. Heterogeneity of the malignant myeloid clone, CAR T‐cell induced toxicity against normal hematopoietic cells, lack of long‐term CAR T‐cell persistence, and loss or downregulation of targetable antigens on myeloid cells are obstacles for successful CAR T cells therapy against AML and MPNs. Strategies to overcome these hurdles include pharmacological interventions, for example, demethylating therapy to increase target antigen expression, multi‐targeted CAR T cells, and gene‐therapy based approaches that delete the CAR target antigen in the hematopoietic cells of the recipient to protect them from CAR‐induced myelotoxicity. Most of these approaches are still in preclinical testing but may reach the clinic in the coming years. In summary, we report on barriers to CAR T‐cell use against AML and novel therapeutic strategies to overcome these challenges, with the goal of clinical treatment of myeloid malignancies with CAR T cells.

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Section: Antigen Loss or Downregulationmentioning

confidence: 99%

Chimeric antigen receptor T cells for acute myeloid leukemia

Fetsch

Zeiser

2023

European J of Haematology

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“…Analysis of the clinical outcome led to the development of a novel bicistronic CD19.28ζ/CD22.BBζ construct with enhanced cytokine production against CD22 in preclinical models 37 . Another strategy targeting CD19 and CD22 with bicistronic CAR T‐cells (AUTO3) was tested in patients with ALL 38 (AMELIA trial: NCT03289455) as well as in relapsed/refractory DLBCL 39 (ALEXANDER trial: NCT03287817) and convincing primary results have been reported. As the position of the two scFv domains has an influence on their functionality, these CAR T‐cells still require optimization 117 .…”

Section: Strategies For Controlling Car T‐cell Activitymentioning

confidence: 99%

“…CD22 with bicistronic CAR T-cells (AUTO3) was tested in patients with ALL38 (AMELIA trial: NCT03289455) as well as in relapsed/ refractory DLBCL39 (ALEXANDER trial: NCT03287817) and convincing primary results have been reported. As the position of the two scFv domains has an influence on their functionality, these CAR Tcells still require optimization 117.…”

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confidence: 99%

Mechanisms and strategies for safe chimeric antigen receptor T‐cell activity control

Stock,

Klüver,

Fertig

et al. 2023

Intl Journal of Cancer

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The clinical application of chimeric antigen receptor (CAR) T‐cell therapy has rapidly changed the treatment options for terminally ill patients with defined blood‐borne cancer types. However, CAR T‐cell therapy can lead to severe therapy‐associated toxicities including CAR‐related hematotoxicity, ON‐target OFF‐tumor toxicity, cytokine release syndrome (CRS) or immune effector cell‐associated neurotoxicity syndrome (ICANS). Just as CAR T‐cell therapy has evolved regarding receptor design, gene transfer systems and production protocols, the management of side effects has also improved. However, because of measures taken to abrogate adverse events, CAR T‐cell viability and persistence might be impaired before complete remission can be achieved. This has fueled efforts for the development of extrinsic and intrinsic strategies for better control of CAR T‐cell activity. These approaches can mediate a reversible resting state or irreversible T‐cell elimination, depending on the route chosen. Control can be passive or active. By combination of CAR T‐cells with T‐cell inhibiting compounds, pharmacologic control, mostly independent of the CAR construct design used, can be achieved. Other strategies involve the genetic modification of T‐cells or further development of the CAR construct by integration of molecular ON/OFF switches such as suicide genes. Alternatively, CAR T‐cell activity can be regulated intracellularly through a self‐regulation function or extracellularly through titration of a CAR adaptor or of a priming small molecule. In this work, we review the current strategies and mechanisms to control activity of CAR T‐cells reversibly or irreversibly for preventing and for managing therapy‐associated toxicities.

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“…103 Current efforts to "diversify" CAR T-cell populations that are already in clinical testing include the development of bicistronic (expression of two separate receptors in the same cell) and tandem (two binders in the same receptor) CAR T cells with dual specificity. 104,105 Whether one strategy is superior to the other awaits more results from the trials.…”

Section: Synthetic Circuits That Diversify T-cell Populationsmentioning

confidence: 99%

A synthetic biology approach to engineering circuits in immune cells

Hoces

Miguens‐Blanco

Hernández-López

2023

Immunological Reviews

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SummaryA synthetic circuit in a biological system involves the designed assembly of genetic elements, biomolecules, or cells to create a defined function. These circuits are central in synthetic biology, enabling the reprogramming of cellular behavior and the engineering of cells with customized responses. In cancer therapeutics, engineering T cells with circuits have the potential to overcome the challenges of current approaches, for example, by allowing specific recognition and killing of cancer cells. Recent advances also facilitate engineering integrated circuits for the controlled release of therapeutic molecules at specified locations, for example, in a solid tumor. In this review, we discuss recent strategies and applications of synthetic receptor circuits aimed at enhancing immune cell functions for cancer immunotherapy. We begin by introducing the concept of circuits in networks at the molecular and cellular scales and provide an analysis of the development and implementation of several synthetic circuits in T cells that have the goal to overcome current challenges in cancer immunotherapy. These include specific targeting of cancer cells, increased T‐cell proliferation, and persistence in the tumor microenvironment. By harnessing the power of synthetic biology, and the characteristics of certain circuit architectures, it is now possible to engineer a new generation of immune cells that recognize cancer cells, while minimizing off‐target toxicities. We specifically discuss T‐cell circuits for antigen density sensing. These circuits allow targeting of solid tumors that share antigens with normal tissues. Additionally, we explore designs for synthetic circuits that could control T‐cell differentiation or T‐cell fate as well as the concept of synthetic multicellular circuits that leverage cellular communication and division of labor to achieve improved therapeutic efficacy. As our understanding of cell biology expands and novel tools for genome, protein, and cell engineering are developed, we anticipate further innovative approaches to emerge in the design and engineering of circuits in immune cells.

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Dual targeting of CD19 and CD22 with Bicistronic CAR-T cells in Patients with Relapsed/Refractory Large B Cell Lymphoma

Cited by 27 publications

References 0 publications

Chimeric antigen receptor T cells for acute myeloid leukemia

Chimeric antigen receptor T cells for acute myeloid leukemia

Mechanisms and strategies for safe chimeric antigen receptor T‐cell activity control

A synthetic biology approach to engineering circuits in immune cells

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