Uncovering the mode of action of engineered T cells in patient cancer organoids

Dekkers, Johanna F.; Alieva, María; Cleven, Astrid; Keramati, Farid; Wezenaar, Amber K. L.; Vliet, Esmée J. van; Puschhof, Jens; Brázda, Péter; Johanna, Inez; Meringa, Angelo D.; Rebel, Heggert; Buchholz, Maj‐Britt; Román, Mario Barrera; Zeeman, Amber L.; Blank, Sam de; Fasci, Domenico; Geurts, Maarten H.; Cornel, Annelisa M.; Driehuis, Else; Millen, Rosemary; Straetemans, Trudy; Nicolasen, Mara J.T.; Aarts-Riemens, Tineke; Ariese, Hendrikus C R; Johnson, Hannah R.; Ineveld, Ravian L. van; Karaiskaki, Froso; Kopper, Oded; Bar-Ephraïm, Yotam E.; Kretzschmar, Kai; Eggermont, Alexander; Nierkens, Stefan; Wehrens, Ellen J.; Stunnenberg, Hendrik G.; Clevers, Hans; Kuball, Jürgen; Sebestyén, Zsolt; Rios, Anne C.

doi:10.1038/s41587-022-01397-w

Cited by 82 publications

(72 citation statements)

References 61 publications

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“…The capacity of TAMs to penetrate into and persist in solid malignancies might not only be crucial for targeted CAR-M treatment in LC, but it could also be utilized for organoid immunotherapy testing. A recent study by Dekkers et al, 2023 , details how single-cell imaging of engineered T cells with solid tumor PDOs could prove useful in establishing the extent of their immunotherapeutic potential. Their newly developed cell tracking system enabled them to track and pinpoint engineered T cells with a particularly potent tumor-killing capacity ( Dekkers et al, 2023 ).…”

Section: Discussion and Future Directionsmentioning

confidence: 99%

The role of macrophages in non-small cell lung cancer and advancements in 3D co-cultures

Balážová

Dost

2023

eLife

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Lung cancer (LC) is the leading cause of cancer-related deaths worldwide. Traditional therapeutic approaches such as chemotherapy or radiotherapy have provided only a marginal improvement in the treatment of lung carcinomas. Inhibitors targeting specific genetic aberrations present in non-small cell lung cancer (NSCLC), the most common subtype (85%), have improved the prognostic outlook, but due to the complexity of the LC mutational spectrum, only a fraction of patients benefit from these targeted molecular therapies. More recently, the realization that the immune infiltrate surrounding solid tumors can foster tumor-promoting inflammation has led to the development and implementation of anticancer immunotherapies in the clinic. In NSCLC, one of the most abundant leukocyte infiltrates is macrophages. These highly plastic phagocytes, which are part of the cellular repertoire of the innate immunity, can have a pivotal role in early NSCLC establishment, malignant progression, and tumor invasion. Emerging macrophage-targeting therapies have been focused on the re-differentiation of the macrophages toward an antitumorigenic phenotype, depletion of tumor-promoting macrophage subtypes, or combination therapies combining traditional cytotoxic treatments with immunotherapeutic agents. The most extensively used models employed for the exploration of NSCLC biology and therapy have been 2D cell lines and murine models. However, studying cancer immunology requires appropriately complex models. 3D platforms, including organoid models, are quickly advancing powerful tools to study immune cell-epithelial cell interactions within the tumor microenvironment. Co-cultures of immune cells along with NSCLC organoids allow for an in vitro observation of the tumor microenvironment dynamics closely resembling in vivo settings. Ultimately, the implementation of 3D organoid technology into tumor microenvironment-modeling platforms might facilitate the exploration of macrophage-targeted therapies in NSCLC immunotherapeutic research, thus establishing a new frontier in NSCLC treatment.

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Section: Discussion and Future Directionsmentioning

confidence: 99%

The role of macrophages in non-small cell lung cancer and advancements in 3D co-cultures

Balážová

Dost

2023

eLife

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“…Single‐cell‐based sequencing provides unprecedented opportunities to reveal the dynamics of transcriptome and epigenome; however, these data are a snapshot of the cell state at a given time. 199 Furthermore, the regulators identified from different studies do not act in isolation but instead orchestrate a cross‐regulated and highly coordinated signalling network to control the interactions between cancer and immune cells; however, this interaction is not clear. The integration of live cell imaging and single‐cell omics analysis of CAR‐T cells should provide this missing link in these studies.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, elucidating the bidirectional interactions of CAR‐T cells with tumour cells in its microenvironment is critical for designing next‐generation CAR‐T cell therapy for solid tumours. Single‐cell‐based sequencing provides unprecedented opportunities to reveal the dynamics of transcriptome and epigenome; however, these data are a snapshot of the cell state at a given time 199 . Furthermore, the regulators identified from different studies do not act in isolation but instead orchestrate a cross‐regulated and highly coordinated signalling network to control the interactions between cancer and immune cells; however, this interaction is not clear.…”

Section: Discussionmentioning

confidence: 99%

Engineering chimeric antigen receptor T cells for solid tumour therapy

Liu

Cheng

et al. 2022

Clinical & Translational Med

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Cell‐based immunotherapy, for example, chimeric antigen receptor T (CAR‐T) cell immunotherapy, has revolutionized cancer treatment, particularly for blood cancers. However, factors such as insufficient T cell tracking, tumour heterogeneity, inhibitory tumour microenvironment (TME) and T cell exhaustion limit the broad application of CAR‐based immunotherapy for solid tumours. In particular, the TME is a complex and evolving entity, which is composed of cells of different types (e.g., cancer cells, immune cells and stromal cells), vasculature, soluble factors and extracellular matrix (ECM), with each component playing a critical role in CAR‐T immunotherapy. Thus, developing approaches to mitigate the inhibitory TME factors is critical for future success in applying CAR‐T cells for solid tumour treatment. Accordingly, understanding the bilateral interaction of CAR‐T cells with the TME is in pressing need to pave the way for more efficient therapeutics. In the following review, we will discuss TME‐associated aspects with an emphasis on T cell trafficking, ECM barriers, abnormal vasculature, solid tumour heterogenicity and immune suppressive microenvironment. We will then summarize current engineering strategies to overcome the challenges posed by the TME‐associated factors. Lastly, the future directions for engineering efficient CAR‐T cells for solid tumour therapy will be discussed.

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“…Live cell imaging was performed as described previously with minor modifications 49 . In brief, to visualize 70- and 20-4_1BBζ CAR T cells in the co-culture assay, cells were washed with PBS and stained with eBioscience Cell Proliferation Dye eFluor 450 (Thermo Fisher Scientific) in PBS in a 1:1000 dilution for 10 minutes at 37°C.…”

Section: Methodsmentioning

confidence: 99%

Knocking out CD70 rescues CD70-specific nanoCAR T cells from antigen induced exhaustion

Munter

Buhl

Cock

et al. 2023

Preprint

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CD70 is an attractive target for chimeric antigen receptor (CAR) T cell therapy as treatment for both solid and liquid malignancies. However, functionality of CD70-specific CARs is only modest. Here, we optimized a CD70-specific VHH based CAR (nanoCAR). We evaluated the nanoCARs in clinically relevant models in vitro, using co-cultures of CD70-specific nanoCAR T cells with malignant rhabdoid tumor organoids, and in vivo by using a diffuse large B cell lymphoma (DLBCL) patient-derived xenograft (PDX) model. Whereas the nanoCAR T cells were highly efficient in organoid co-cultures, they showed only modest efficacy in the PDX model. Knocking out CD70 expression by the nanoCAR T cells resulted in dramatically enhanced functionality in the PDX model, suggesting that endogenous CD70 interaction with the nanoCAR induces exhaustion. Through single-cell transcriptomics, we obtained evidence that CD70KO CD70-specific nanoCAR T cells are protected from antigen induced exhaustion. Our data shows that CARs targeted to endogenous T cell antigens, negatively affect CAR T cell functionality by inducing an exhausted state which can be overcome by knocking out the specific target, in this case CD70.

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Uncovering the mode of action of engineered T cells in patient cancer organoids

Cited by 82 publications

References 61 publications

The role of macrophages in non-small cell lung cancer and advancements in 3D co-cultures

The role of macrophages in non-small cell lung cancer and advancements in 3D co-cultures

Engineering chimeric antigen receptor T cells for solid tumour therapy

Knocking out CD70 rescues CD70-specific nanoCAR T cells from antigen induced exhaustion

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