Theranostic CAR T cell targeting: A brief review

Arndt, Claudia; Bachmann, Michael; Bergmann, Ralf; Berndt, Nicole; Feldmann, Anja; Koristka, Stefanie

doi:10.1002/jlcr.3727

Cited by 20 publications

(27 citation statements)

References 56 publications

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“…Especially in this context, it is also important that the interaction/binding properties of the adaptor molecules toward the tumor target and CAR T cells have to be well balanced in a way, that they allow an association as well as dissociation of the complex. 3,27,51,52 In summary, here we emphasize the novel RevCAR platform combining all the mentioned features and advantages in one single system. The RevCAR system is completely humanized and based on carefully selected human peptide epitopes minimizing its risk for immunogenicity and cross-reactivity.…”

Section: Discussionmentioning

confidence: 88%

Versatile chimeric antigen receptor platform for controllable and combinatorial T cell therapy

et al. 2020

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Chimeric antigen receptor (CAR) T cells show remarkable therapeutic effects in some hematological malignancies. However, CAR T cells can also cause life-threatening side effects. In order to minimize offtarget and on-target/off-tumor reactions, improve safety, enable controllability, provide high flexibility, and increase tumor specificity, we established a novel humanized artificial receptor platform termed RevCARs. RevCAR genes encode for small surface receptors lacking any antigen-binding moiety. Steering of RevCAR T cells occurs via bispecific targeting molecules (TMs). The small size of RevCAR-encoding genes allows the construction of polycistronic vectors. Here, we demonstrate that RevCAR T cells efficiently kill tumor cells, can be steered by TMs, flexibly redirected against multiple targets, and used for combinatorial targeting following the "OR" and "AND" gate logic.

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Section: Discussionmentioning

confidence: 88%

Versatile chimeric antigen receptor platform for controllable and combinatorial T cell therapy

et al. 2020

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“…12 Hence, adapter CAR platforms were developed to improve the safety profile of CAR T cells [e.g. [13][14][15][16][17][18][19] ]. In 2014, we introduced the switchable UniCAR system in which UniCAR T cell activity can be directly controlled by separated short-lived target modules (TMs) (Figure 1a).…”

Section: Introductionmentioning

confidence: 99%

“…In 2014, we introduced the switchable UniCAR system in which UniCAR T cell activity can be directly controlled by separated short-lived target modules (TMs) (Figure 1a). [16][17][18][19][20] TMs are tumor-specific binding molecules, e.g., small peptides, 21 nanobodies 22,23 or single-chain fragment variables (scFv) [e.g. [24][25][26][27] ] equipped with the E5B9 peptide epitope from the nuclear protein La/SS-B.…”

Section: Introductionmentioning

confidence: 99%

UniCAR T cell immunotherapy enables efficient elimination of radioresistant cancer cells

et al. 2020

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Induction or selection of radioresistant cancer (stem) cells following standard radiotherapy is presumably one of the major causes for recurrence of metastatic disease. One possibility to prevent tumor relapse is the application of targeted immunotherapies including, e.g., chimeric antigen receptor (CAR) T cells. In light of long-term remissions, it is highly relevant to clarify whether radioresistant cancer cells are susceptible to CAR T cell-mediated killing. To answer this question, we evaluated the anti-tumor activity of the switchable universal chimeric antigen receptor (UniCAR) system against highly radioresistant head and neck squamous cell carcinoma cells both in vitro and in vivo. Following specific UniCAR T cell engagement via EGFR or CD98 target modules, T cell effector mechanisms were induced including secretion of pro-inflammatory cytokines, up-regulation of granzyme B and perforin, as well as T cell proliferation. CD98-or EGFR-redirected UniCAR T cells further possess the capability to efficiently lyse radioresistant tumor cells. Observed anti-tumor effects were comparable to those against the radiosensitive parental cell lines. Finally, redirected UniCAR T cells significantly inhibited the growth of radioresistant cancer cells in immunodeficient mice. Taken together, our obtained data underline that the UniCAR system is able to overcome radioresistance. Thus, it represents an attractive technology for the development of combined radioimmunotherapeutic approaches that might improve the outcome of patients with metastatic radioresistant tumor diseases.

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“…Since the first presentation of the UniCAR idea in 2014, 43 several, so far only Ab-based TMs were described including TMs directed against the TAAs CD33, CD123, prostate stem cell antigen, PSMA, epidermal growth factor receptor, GD2, CD19, or STn. [43][44][45][46][47][48][49][50][51][52][53][54] The aim of the presented study was to develop a novel theranostic PSMA ligand for management of PCa patients that combines the fields of nuclear medicine and CAR T cell technology. Thus, we converted PSMA-11, one of the most commonly used PCa imaging agent, by fusion of the 10-amino acid peptide epitope E5B9 into a TM for the UniCAR system ( Figure 1b).…”

Section: Introductionmentioning

confidence: 99%

A theranostic PSMA ligand for PET imaging and retargeting of T cells expressing the universal chimeric antigen receptor UniCAR

et al. 2019

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Chimeric antigen receptor (CAR) T cells have shown impressive therapeutic potential. Due to the lack of direct control mechanisms, therapy-related adverse reactions including cytokine release-and tumor lysis syndrome can even become life-threatening. In case of target antigen expression on non-malignant cells, CAR T cells can also attack healthy tissues. To overcome such side effects, we have established a modular CAR platform termed UniCAR: UniCAR T cells per se are inert as they recognize a peptide epitope (UniCAR epitope) that is not accessible on the surface of living cells. Bifunctional adapter molecules termed target modules (TM) can cross-link UniCAR T cells with target cells. In the absence of TMs, UniCAR T cells automatically turn off. Until now, all UniCAR TMs were constructed by fusion of the UniCAR epitope to an antibody domain. To open up the wide field of low-molecular-weight compounds for retargeting of UniCAR T cells to tumor cells, and to follow in parallel the progress of UniCAR T cell therapy by PET imaging we challenged the idea to convert a PET tracer into a UniCAR-TM. For proof of concept, we selected the clinically used PET tracer PSMA-11, which binds to the prostatespecific membrane antigen overexpressed in prostate carcinoma. Here we show that fusion of the UniCAR epitope to PSMA-11 results in a low-molecular-weight theranostic compound that can be used for both retargeting of UniCAR T cells to tumor cells, and for non-invasive PET imaging and thus represents a member of a novel class of theranostics.

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Theranostic CAR T cell targeting: A brief review

Cited by 20 publications

References 56 publications

Versatile chimeric antigen receptor platform for controllable and combinatorial T cell therapy

Versatile chimeric antigen receptor platform for controllable and combinatorial T cell therapy

UniCAR T cell immunotherapy enables efficient elimination of radioresistant cancer cells

A theranostic PSMA ligand for PET imaging and retargeting of T cells expressing the universal chimeric antigen receptor UniCAR

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