Tumor-Targeting Domains for Chimeric Antigen Receptor T Cells

Bezverbnaya, Ksenia; Mathews, Ashish; Sidhu, Jesse; Helsen, Christopher W.; Bramson, Jonathan L.

doi:10.2217/imt-2016-0103

Cited by 8 publications

(8 citation statements)

References 113 publications

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“…Recent advances in immune checkpoint inhibitor and chimeric antigen receptor T-cell therapy have revolutionized the field of cancer therapy (27,28). Although conceptually more conducive to patient-specific tumor immunity, DC-based advances have encountered greater difficulties in the clinical reduction to practice (29).…”

Section: Discussionmentioning

confidence: 99%

Extracorporeal Photochemotherapy Drives Monocyte-to-Dendritic Cell Maturation to Induce Anticancer Immunity

et al. 2018

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Extracorporeal photochemotherapy (ECP) is a cancer immunotherapy for cutaneous T-cell lymphoma (CTCL) operative in more than 350 centers worldwide. Although its efficacy and favorable safety profile have driven its widespread use, elucidation of its underlying mechanism has been difficult. In this study, we identify the principal contributors to the anticancer immunotherapeutic effects of ECP, with the goal of enhancing potency and broadening applicability to additional malignancies. First, we scaled down the clinical ECP leukocyte-processing device to mouse size. Second, we used that miniaturized device to produce a cellular vaccine that regularly initiated therapeutic antimelanoma immunity. Third, we individually subtracted key factors from either the immunizing inoculum or the treated animal to ascertain their contribution to the antimelanoma response. Platelet-signaled monocyte-to-dendritic cell (DC) differentiation followed by sorting/processing/presentation of tumor antigens derived from internalized apoptotic tumor cells were absolute requirements. As in clinical ECP, immunogenic cell death of tumor cells was finely titrated by DNA cross-linkage mediated by photoactivated 8-methoxypsoralen (8-MOPA). ECP-induced tumor-loaded DC were effective immunotherapeutic agents only if they were spared exposure to 8-MOPA, indicating that healthy DC are required for ECP. Infusion of responder T cells into naïve tumor-challenged mice established the protective role of stimulated T-cell antitumor immunity. Collectively, these results reveal that selective antitumor effects of ECP are initiated by tumor antigen-loaded, ECP-induced DC, which promote potent collaboration between CD4 and CD8 tumor-specific T cells. These mechanistic insights suggest potential therapeutic applicability of ECP to solid tumors in addition to CTCL. These findings identify principal cellular contributors to the anticancer immunotherapeutic impact of ECP and suggest this treatment may be applicable to a broad spectrum of immunogenic malignancies. .

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Section: Discussionmentioning

confidence: 99%

Extracorporeal Photochemotherapy Drives Monocyte-to-Dendritic Cell Maturation to Induce Anticancer Immunity

et al. 2018

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“…The issue of scFv clustering may also be circumvented by utilising endogenous receptors or ligands as CAR extracellular targeting moieties. A wide variety of such constructs have been designed with several already undergoing clinical evaluation [9, 124]. Those that have progressed furthest along clinical development include interleukin 13 (IL-13)-zetakine CARs incorporating membrane-tethered IL-13 to target the interleukin 13 receptor subunit alpha-2 (IL13Rα2) decoy receptor, a glioma-restricted cell-surface epitope [125, 126]; CARs armed with an epidermal growth factor (EGF) / transforming growth factor alpha (TGFα) fusion molecule capable of targeting pan-ErbB homo- and heterodimers expressed on a plethora of solid tumours [127, 128]; CARs armed with the natural killer group 2D (NKG2D) protein fused to CD3ζ alone [129]or in combination with an intracellular costimulatory domain [130] to target a wide variety of haematological malignancies and solid tumours overexpressing NKG2D stress inducible ligands (such as MHC class I chain-related protein A (MICA), MHC class I chain-related protein B (MICB) and UL16 binding proteins 1 to 6 (ULBP1-6) in humans) [131]; and CARs utilising CD27 to target CD70 [132], an antigen aberrantly expressed by a broad range of haematological malignancies and some solid tumours including renal cell carcinoma and glioma.…”

Section: Potential Strategies To Address Car Tonic Signallingmentioning

confidence: 99%

Strategies to Address Chimeric Antigen Receptor Tonic Signaling

Ajina

Maher

2018

Molecular Cancer Therapeutics

164

151

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Adoptive cell transfer using chimeric antigen receptors (CAR) has emerged as one of the most promising new therapeutic modalities for patients with relapsed or refractory B-cell malignancies. Thus far, results in patients with advanced solid tumors have proven disappointing. Constitutive tonic signaling in the absence of ligand is an increasingly recognized complication when deploying these synthetic fusion receptors and can be a cause of poor antitumor efficacy, impaired survival, and reduced persistence In parallel, ligand-dependent tonic signaling can mediate toxicity and promote T-cell anergy, exhaustion, and activation-induced cell death. Here, we review the mechanisms underpinning CAR tonic signaling and highlight the wide variety of effects that can emerge after making subtle structural changes or altering the methodology of CAR transduction. We highlight strategies to prevent unconstrained tonic signaling and address its deleterious consequences. We also frame this phenomenon in the context of endogenous TCR tonic signaling, which has been shown to regulate peripheral tolerance, facilitate the targeting of foreign antigens, and suggest opportunities to coopt ligand-dependent CAR tonic signaling to facilitate persistence and efficacy. .

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“…Very little discussion can be found on the binding domains of the CAR constructs, yet they comprise an important part of these molecules. Most CD19 CARs utilize the same murine single chain variable fragment (scFv, FMC63), yet for other B-cell targets and for solid tumors humanized or fully human antibody sequences and other binding elements like repeat proteins are utilized [ 45 ]. In addition, a human counterpart for FMC63 has been developed and tested in non-clinical models [ 46 ].…”

Section: Balance Between Efficacy and Safetymentioning

confidence: 99%

“…This, together with possibility of viral recombination, is the reason why free virus particles in the final product are expected to be analyzed and controlled. Concerns are expressed also about very high affinity of the antibody fragments, as it may lead to responses against cells that have low levels of target expression [ 45 ] and it may also reduce the actual anti-tumor activity [ 48 ]. On the other hand, the affinity of the scFvs may be reduced over time in vivo and careful selection of the binding domain is critical.…”

Section: Balance Between Efficacy and Safetymentioning

confidence: 99%

Chimeric Antigen Receptor T-Cells (CAR T-Cells) for Cancer Immunotherapy – Moving Target for Industry?

Salmikangas¹,

Kinsella²,

Chamberlain³

2018

Pharm Res

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The first CD19 CAR T-cell products, Kymriah and Yescarta, are entering the US market and also being evaluated for marketing authorization in the EU. This breakthrough has expanded the interest and also investments towards novel chimeric antigen receptor (CAR) designs, both for hematological malignancies and solid tumors. At the same time, there is active development in moving from autologous products to allogeneic, off-the-shelf -products. New manufacturing technologies are also emerging for production of these complex genetically-modified cells and even decentralized manufacturing in hospitals is under consideration. However, the high potency of CAR T-cells is associated with toxicity and not all patients respond to the treatment. In addition, the number of patient and product variables impacting the clinical outcome is high. The race towards novel CAR T treatment options for cancer patients has begun, but without careful design of the constructs and overall understanding of the factors that impact the ultimate outcome in each case, the road towards commercial success may be long and winding. This review discusses the product- and patient-related variables that may pose challenges for the industry and developers both from the scientific and regulatory perspective.

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Tumor-Targeting Domains for Chimeric Antigen Receptor T Cells

Cited by 8 publications

References 113 publications

Extracorporeal Photochemotherapy Drives Monocyte-to-Dendritic Cell Maturation to Induce Anticancer Immunity

Extracorporeal Photochemotherapy Drives Monocyte-to-Dendritic Cell Maturation to Induce Anticancer Immunity

Strategies to Address Chimeric Antigen Receptor Tonic Signaling

Chimeric Antigen Receptor T-Cells (CAR T-Cells) for Cancer Immunotherapy – Moving Target for Industry?

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