Proof of concept for a rapidly switchable universal CAR-T platform with UniCAR-T-CD123 in relapsed/refractory AML

Wermke, Martin; Kraus, Sabrina; Ehninger, Armin; Bargou, Ralf C.; Goebeler, Maria-Elisabeth; Middeke, Jan Moritz; Kreissig, Carla; Bonin, Malte von; Koedam, Jan; Pehl, Michael; Bornhäuser, Martin; Einsele, Hermann; Ehninger, Gerhard; Cartellieri, Marc

doi:10.1182/blood.2020009759

Cited by 85 publications

(83 citation statements)

References 20 publications

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“…Moreover, the first clinical data revealed that CRS-related side effects can be rapidly abrogated by withdrawal of TM123 (NCT04230265). 47 Costimulation via 4-1BB was reported to enhance survival, cytokine release, effector functions, and clonal expansion of preferably CD8 + T cells, thus leading to enhanced antitumor effects. 64 Similarly, TM123-4-1BBL mediated costimulatory properties including increased effector functions and persistence of UniCAR-T in a long-term in vitro cytotoxic rechallenge assay resulting in enhanced killing capability of UniCAR-T.…”

Section: Discussionmentioning

confidence: 99%

“… 54 We are currently exploring our switch-controllable UniCAR platform targeting CD123 40 , 46 in an ongoing clinical phase I study (NCT04230265), which already provided clinical proof-of-concept. 47 , 55 Rapid functional interruption of UniCAR-T-CD123 therapy could abrogate on-target/on-tumor toxicities (e.g. CRS) and should prevent severe long-term toxicity due to CD123 expression in hematopoietic progenitors and mature myelocytes.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the first clinical data revealed that CRS-related side effects can be rapidly abrogated by withdrawal of TM123 (NCT04230265). 47 …”

Section: Discussionmentioning

confidence: 99%

“… 46 Subsequently, proof-of-concept for safety and efficacy of UniCAR-T in combination with a CD123-specific targeting module (TM), TM123, was demonstrated in a phase I clinical trial including relapsed/refractory AML patients (NCT04230265). 47 Rapid clearance of TM123 due to its small size and short terminal plasma half-life offers a fast safety switch during the onset of therapy, where high tumor burden and elevated toxicity risks require a particularly tight controllability of UniCAR-T. However, during consolidation cycles, patients might benefit from TMs with extended terminal plasma half-life and enhanced potential of UniCAR-T stimulation.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of switch-mediated costimulation in trans on universal CAR-T cells (UniCAR) targeting CD123-positive AML

et al. 2021

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Chimeric antigen receptor T cells (CAR-T) targeting CD19 have achieved significant success in patients with B cell malignancies. To date, implementation of CAR-T in other indications remains challenging due to the lack of truly tumor-specific antigens as well as control of CAR-T activity in patients. CD123 is highly expressed in acute myeloid leukemia (AML) blasts including leukemia-initiating cells making it an attractive immunotherapeutic target. However, CD123 expression in normal hematopoietic progenitor cells and endothelia bears the risk of severe toxicities and may limit CAR-T applications lacking fine-tuned control mechanisms. Therefore, we recently developed a rapidly switchable universal CAR-T platform (UniCAR), in which CAR-T activity depends on the presence of a soluble adapter called targeting module (TM), and confirmed clinical proof-of-concept for targeting CD123 in AML with improved safety. As costimulation via 4-1BB ligand (4-1BBL) can enhance CAR-T expansion, persistence, and effector functions, a novel CD123-specific TM variant (TM123-4-1BBL) comprising trimeric single-chain 4-1BBL was developed for transient costimulation of UniCAR-T cells (UniCAR-T) at the leukemic site in trans. TM123-4-1BBL-directed UniCAR-T efficiently eradicated CD123-positive AML cells in vitro and in a CDX in vivo model. Moreover, additional costimulation via TM123-4-1BBL enabled enhanced expansion and persistence with a modulated UniCAR-T phenotype. In addition, the increased hydrodynamic volume of TM123-4-1BBL prolonged terminal plasma half-life and ensured a high total drug exposure in vivo. In conclusion, expanding the soluble adapter optionality for CD123-directed UniCAR-T maintains the platforms high anti-leukemic efficacy and immediate control mechanism for a flexible, safe, and individualized CAR-T therapy of AML patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…Moreover, the first clinical data revealed that CRS-related side effects can be rapidly abrogated by withdrawal of TM123 (NCT04230265). 47 …”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Evaluation of switch-mediated costimulation in trans on universal CAR-T cells (UniCAR) targeting CD123-positive AML

et al. 2021

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“…AML, as previously mentioned, is a heterogeneous disease, and therefore finding an optimal target has been challenging. To date, different CAR-T's have been used in the setting of in-vivo AML with promising findings [94][95][96][97][98][99] and currently several AML CAR-T trials targeting different antigens like CD33 (NCT03971799), CD38 (NCT04351022), CD123 (NCT03190278), and NKG2D (NCT02203825), are underway mainly in the relapse-refractory setting, though not specifically for the elderly population.…”

Section: Chimeric Antigen Receptor T-cell Therapy (Car-t)mentioning

confidence: 99%

Updates on Acute Myeloid Leukemia Management in older patients

Otoukesh¹,

Thiebaud²,

Marcucci³

et al. 2021

Trends in Transplant

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Acute myeloid Leukemia (AML)'s incidence increases with age and more than 50% of patients are older than 60 years old. The treatment of AML in this age group population has been drastically changed since 2017 with all new innovative drugs approved by FDA highlighting the fact that "one size fit all" approach is not suitable to treat older patients with AML. However, the treatment of AML in elderly population yet to be defined as choosing the right treatment would depend on several other factors including performance status, comorbidities, along with diversities in leukemia subtype and characteristics (next gene sequencing, cytogenetics). Herein we have tried to focus on this specific age group and describe different treatment options (chemotherapy, immune checkpoint inhibitors, Bispecific T-cell engagers (BiTES), Chimeric Antigen Receptor T-cell Therapies (CAR-T), and Allogeneic Hematopoietic Stem Cell Transplantation) based on the available studies and ongoing clinical trials preliminary results.

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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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Proof of concept for a rapidly switchable universal CAR-T platform with UniCAR-T-CD123 in relapsed/refractory AML

Cited by 85 publications

References 20 publications

Evaluation of switch-mediated costimulation in trans on universal CAR-T cells (UniCAR) targeting CD123-positive AML

Evaluation of switch-mediated costimulation in trans on universal CAR-T cells (UniCAR) targeting CD123-positive AML

Updates on Acute Myeloid Leukemia Management in older patients

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

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