Switching CAR T cells on and off: a novel modular platform for retargeting of T cells to AML blasts

Cartellieri, Marc; Feldmann, Anja; Koristka, Stefanie; Arndt, Claudia; Loff, Simon; Ehninger, Armin; Bonin, Malte von; Bejestani, Elham Pishali; Ehninger, Gerhard; Bachmann, Michael

doi:10.1038/bcj.2016.61

Cited by 200 publications

(247 citation statements)

References 45 publications

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“…The specificity of the TM tells such armed UniCAR T cells which cells to attack. Theoretically, the modular UniCAR format has the advantage of an internal self-limiting switch as UniCAR T cells should automatically turn off in the absence of a TM 40 . Therefore, the steerage of such a modular CAR activity should be by far much easier than of a conventional CAR.…”

Section: Discussionmentioning

confidence: 99%

“…1, we recently described a modular CAR platform termed UniCAR. 40 To redirect UniCAR T cells to target cells TMs are required. On the one hand, TMs bind to the surface of the tumor cell, on the other hand, they form an immune complex with the antibody domain of the UniCAR via a peptide epitope (E5B9) recognized by the UniCAR (Fig.…”

Section: Development Of a Novel Nanobody-based Tm For Retargeting Ofmentioning

confidence: 99%

“…40 T cells genetically modified with UniCARs are directed against a peptide epitope (E5B9), which is physiologically not accessible on the surface of intact living cells.…”

Section: Introductionmentioning

confidence: 99%

“…40 The inert UniCAR-expressing lymphocytes can be redirected via target modules (TM). For this purpose, the peptide epitope recognized by the UniCAR has to be fused to the respective TM.…”

Section: Introductionmentioning

confidence: 99%

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A novel nanobody-based target module for retargeting of T lymphocytes to EGFR-expressing cancer cells via the modular UniCAR platform

et al. 2017

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Recent treatments of leukemias with chimeric antigen receptor (CAR) expressing T cells underline their impressive therapeutic potential. However, once adoptively transferred into patients, there is little scope left to shut them down after elimination of tumor cells or in case adverse side effects occur. This becomes of special relevance if they are directed against commonly expressed tumor associated antigens (TAAs) such as receptors of the ErbB family. To overcome this limitation, we recently established a modular CAR platform technology termed UniCAR. UniCARs are not directed against TAAs but instead against a unique peptide epitope on engineered recombinant targeting modules (TMs), which guide them to the target. In the absence of a TM UniCAR T cells are inactive. Thus an interruption of any UniCAR activity requires an elimination of unbound TM and the TM complexed with UniCAR T cells. Elimination of the latter one requires a disassembly of the UniCAR-TM complexes. Here, we describe a first nanobody (nb)-based TM directed against EGFR. The novel TM efficiently retargets UniCAR T cells to EGFR positive tumors and mediates highly efficient target-specific and target-dependent tumor cell lysis both in vitro and in vivo. After radiolabeling of the novel TM with 64 Cu and 68 Ga, we analyzed its biodistribution and clearance as well as the stability of the UniCAR-TM complexes. As expected unbound TM is rapidly eliminated while the elimination of the TM complexed with UniCAR T cells is delayed. Nonetheless, we show that UniCAR-TM complexes dissociate in vitro and in vivo in a concentration-dependent manner in line with the concept of a repeated stop and go retargeting of tumor cells via the UniCAR technology.

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Section: Discussionmentioning

confidence: 99%

Section: Development Of a Novel Nanobody-based Tm For Retargeting Ofmentioning

confidence: 99%

“…40 T cells genetically modified with UniCARs are directed against a peptide epitope (E5B9), which is physiologically not accessible on the surface of intact living cells.…”

Section: Introductionmentioning

confidence: 99%

“…40 The inert UniCAR-expressing lymphocytes can be redirected via target modules (TM). For this purpose, the peptide epitope recognized by the UniCAR has to be fused to the respective TM.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A novel nanobody-based target module for retargeting of T lymphocytes to EGFR-expressing cancer cells via the modular UniCAR platform

et al. 2017

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“…Several approaches are being investigated, including CAR T cells with additional functionality, novel CAR T dosing strategies, and mechanistic studies of observed clinical correlates of safety and efficacy ( Figure 5). For example, results of preclinical studies have demonstrated the viability of various switch mechanisms for CAR T cells [51,[63][64][65]. Switch technology may give clinicians real-time, tunable control of CAR T cell activity and the ability to widen the CAR T therapeutic window.…”

Section: Discussionmentioning

confidence: 99%

Axicabtagene ciloleucel, a first-in-class CAR T cell therapy for aggressive NHL

Roberts

Better

Bot

et al. 2017

Leukemia & Lymphoma

103

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Development and Use of the Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy Axicabtagene Ciloleucel in Large B-Cell Lymphoma

Locke

Neelapu

2020

JAMA Oncol

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xicabtagene ciloleucel is an autologous, anti-CD19 chimeric antigen receptor (CAR) T-cell therapy with significantly improved efficacy in patients with refractory large B-cell lymphoma (LBCL) compared with other currently available treatment options. 1 Although standard-of-care therapies can cure approximately 60% of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL), 2,3 outcomes for patients with relapsed or refractory LBCL are poor. 4-8 A large, international, retrospective patient-level analysis of outcomes in refractory LBCL prior to the availability of CAR T-cell therapy, SCHOLAR-1, reported an objective response rate (ORR) of 26%, a complete response (CR) rate of 7%, and a short median overall survival of 6.3 months, 1 highlighting the need for innovative therapeutic approaches.The antigen CD19 is an optimal target for CAR T-cell therapy given its expression across a wide range of B-cell cancers and its restricted expression in healthy tissues. 9,10 However, targeting CD19 can lead to B-cell aplasia and hypogammaglobulinemia, similar to routinely used CD20-targeting monoclonal antibody therapies, and immunoglobulin supplementation can mitigate the increased risk of infections attributable to B-cell aplasia. 11 B-cell recovery has been observed 2 years after receiving anti-CD19 CAR T-cell therapy in patients with ongoing CR. 12 The cell product that became axicabtagene ciloleucel was collaboratively developed with Kite, a Gilead Company, and the National Cancer Institute (Figure 1A). [13][14][15][16][17] Early work revealed that, although first-generation CAR T cells (ie, CARs with only a single T-cell signaling domain) demonstrated cytotoxic activity, they lacked functional persistence. [18][19][20] For optimal T-cell activity, antigen recognition must occur in conjunction with appropriate costimulation, such as through CD28. 21 In 2009, Kochenderfer and colleagues 22 described the development of the CAR construct used in axicabtagene ciloleucel, which consists of an extracellular CD19-targeting, single-chain variable fragment, an intracellular CD28 costimulatory domain, and a CD3ζ signaling domain (Figure 1B). This development was quickly followed in 2010 by, to our knowledge, the first reported successful use of this CAR in a patient with B-cell lymphoma. 13 Additional studies from the National Cancer Institute using the CD19-CD28-CD3ζ CAR demonstrated the importance of conditioning IMPORTANCE Axicabtagene ciloleucel, an anti-CD19-CD28-CD3ζ chimeric antigen receptor T-cell therapy, was the first US Food and Drug Administration-approved, genetically engineered T-cell therapy for adults with relapsed or refractory large B-cell lymphoma (LBCL) after 2 or more lines of systemic therapy. There has not been a US Food and Drug Administration-approved product for these cancers in more than 4 decades.OBSERVATIONS Unlike traditional anticancer therapies, axicabtagene ciloleucel is a patient-specific, live-cell product that has unique requirements for manufacturing, shipping, and storage, as we...

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Switching CAR T cells on and off: a novel modular platform for retargeting of T cells to AML blasts

Cited by 200 publications

References 45 publications

A novel nanobody-based target module for retargeting of T lymphocytes to EGFR-expressing cancer cells via the modular UniCAR platform

A novel nanobody-based target module for retargeting of T lymphocytes to EGFR-expressing cancer cells via the modular UniCAR platform

Axicabtagene ciloleucel, a first-in-class CAR T cell therapy for aggressive NHL

Development and Use of the Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy Axicabtagene Ciloleucel in Large B-Cell Lymphoma

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