Targeted Cellular Micropharmacies: Cells Engineered for Localized Drug Delivery

Gardner, Thomas J.; Bourne, Christopher M.; Dacek, Megan M.; Kurtz, Keifer G.; Malviya, Manish; Peraro, Leila; Silberman, Pedro C.; Vogt, Kristen; Unti, Mildred J; Brentjens, Renier J.; Scheinberg, David A.

doi:10.3390/cancers12082175

Cited by 23 publications

(12 citation statements)

References 229 publications

(308 reference statements)

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“…Moreover, if a safe target can be identified, TAAs are often heterogeneously expressed and selection pressures from targeted therapies ultimately lead to antigen-loss and tumor escape 7,8 . Emerging strategies to address the antigen bottleneck have focused on improving CAR-T cells with additional genetic circuitry [9][10][11] , modulatory proteins [12][13][14][15] , and combinations with nanoparticles and oncolytic viruses [16][17][18] .…”

Section: Main Textmentioning

confidence: 99%

Probiotic-guided CAR-T cells for universal solid tumor targeting

Vincent

Gurbatri

Redenti

et al. 2021

Preprint

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Synthetic biology enables the engineering of interactions between living medicines to overcome the specific limitations of any singular therapy. One major challenge of tumor-antigen targeting therapies like chimeric antigen receptor (CAR)-T cells is the identification of targetable antigens that are specifically and uniformly expressed on heterogenous solid tumors. In contrast, certain species of bacteria selectively colonize immune-privileged tumor cores and can be readily engineered as antigen-independent platforms for therapeutic delivery. Bridging these approaches, we develop a platform of probiotic-guided CAR-T cells (ProCARs), in which T cells are engineered to sense synthetic antigens (SA) that are produced and released by tumor-colonizing probiotic bacteria. We demonstrate increased CAR-T cell activation and tumor-cell lysis when SAs anchor to components of the extracellular matrix. Moreover, we show that ProCARs are intratumorally activated by probiotically-delivered SAs, receive further stimulation from bacterial TLR agonists, and are safe and effective in multiple xenograft models. This approach repurposes tumor-colonizing bacteria as beacons that guide the activity of engineered T cells, and in turn builds the foundation for communities of living medicines.

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Section: Main Textmentioning

confidence: 99%

Probiotic-guided CAR-T cells for universal solid tumor targeting

Vincent

Gurbatri

Redenti

et al. 2021

Preprint

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“…Solid tumors, however, have remained refractory to such therapies and even most B-cell neoplasms ultimately relapse due to tumor heterogeneity and multiple immune escape mechanisms (6). We and many others are further exploring the therapeutic potential of adoptive T cells that can serve as delivery vehicles for drugs or biologic agents, also known as "targeted micropharmacies", in addition to their intrinsic cytotoxic activity (7)(8)(9)(10)(11)(12)(13)(14). More complex, and potentially more effective, engineered cells are in development, but the interactions of these highly modified cells with the host are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Host-cell Interactions of Engineered T cell Micropharmacies

Bourne

Wallisch

Dacek

et al. 2023

Preprint

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Genetically engineered, cytotoxic, adoptive T cells localize to antigen positive cancer cells inside patients, but tumor heterogeneity and multiple immune escape mechanisms have prevented the eradication of most solid tumor types. More effective, multifunctional engineered T cells are in development to overcome the barriers to the treatment of solid tumors, but the interactions of these highly modified cells with the host are poorly understood. We previously engineered prodrug-activating enzymatic functions into chimeric antigen receptor (CAR) T cells, endowing them with an orthogonal killing mechanism to conventional T-cell cytotoxicity. These drug-delivering cells, termed Synthetic Enzyme-Armed KillER (SEAKER) cells, demonstrated efficacy in mouse lymphoma xenograft models. However, the interactions of an immunocompromised xenograft with such complex engineered T cells are distinct from those in an immunocompetent host, precluding an understanding of how these physiologic processes may affect the therapy. Here, we also expand the repertoire of SEAKER cells to target solid-tumor melanomas in syngeneic mouse models using specific targeting with TCR-engineered T cells. We demonstrate that SEAKER cells localize specifically to tumors, and activate bioactive prodrugs, despite host immune responses. We additionally show that TCR-engineered SEAKER cells are efficacious in immunocompetent hosts, demonstrating that the SEAKER platform is applicable to many adoptive cell therapies.

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“…The fourth-generation CAR-T cell therapy refers to the second-generation CAR-T cells armed with immune stimulatory cytokines (e.g., IL-12, IL-15, and IL-18) that are released while they engage targeted tumor cells, leading to the improvement of CAR-T cell expansion/persistence as well as the promotion of the antigen spreading by recruiting endogenous T cells or NK cells (11)(12)(13)(14)(15)(16). Moreover, the encouraging preclinical results of fourth-generation CAR has renewed interest in the concept of "targeted cellular micropharmacies" (17,18), which utilize immune cells as a tumor-targeted living carrier to deliver therapeutic agents, including antibodies, enzymes, immunostimulatory molecules, as well as nanoparticles loaded with anti-cancer drugs (17,18). The structure of the fifthgeneration CAR is also based on the second-generation CAR, but with the addition of truncated cytoplasmic domains of cytokine receptors and a STAT3-binding motif (19) that permits cytokine engagement signaling (signal 3), resulting in the optimization of T-cell activation and thus superior in vivo persistence and antitumor effects in preclinical models as compared with the second-generation CAR (19).…”

Section: Introductionmentioning

confidence: 99%

Challenges in the Treatment of Glioblastoma by Chimeric Antigen Receptor T-Cell Immunotherapy and Possible Solutions

Zhang

2022

Front. Immunol.

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Glioblastoma (GBM), one of the most lethal brain cancers in adults, accounts for 48.6% of all malignant primary CNS tumors diagnosed each year. The 5-year survival rate of GBM patients remains less than 10% even after they receive the standard-of-care treatment, including maximal safe resection, adjuvant radiation, and chemotherapy with temozolomide. Therefore, new therapeutic modalities are urgently needed for this deadly cancer. The last decade has witnessed great advances in chimeric antigen receptor T (CAR-T) cell immunotherapy for the treatment of hematological malignancies. Up to now, the US FDA has approved six CAR-T cell products in treating hematopoietic cancers including B-cell acute lymphoblastic leukemia, lymphoma, and multiple myeloma. Meanwhile, the number of clinical trials on CAR-T cell has increased significantly, with more than 80% from China and the United States. With its achievements in liquid cancers, the clinical efficacy of CAR-T cell therapy has also been explored in a variety of solid malignancies that include GBMs. However, attempts to expand CAR-T cell immunotherapy in GBMs have not yet presented promising results in hematopoietic malignancies. Like other solid tumors, CAR-T cell therapies against GBM still face several challenges, such as tumor heterogeneity, tumor immunosuppressive microenvironment, and CAR-T cell persistence. Hence, developing strategies to overcome these challenges will be necessary to accelerate the transition of CAR-T cell immunotherapy against GBMs from bench to bedside.

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Targeted Cellular Micropharmacies: Cells Engineered for Localized Drug Delivery

Cited by 23 publications

References 229 publications

Probiotic-guided CAR-T cells for universal solid tumor targeting

Probiotic-guided CAR-T cells for universal solid tumor targeting

Host-cell Interactions of Engineered T cell Micropharmacies

Challenges in the Treatment of Glioblastoma by Chimeric Antigen Receptor T-Cell Immunotherapy and Possible Solutions

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