Exploiting Cytokines in Adoptive T-Cell Therapy of Cancer

Petrozziello, Elisabetta; Sturmheit, Tabea; Mondino, Anna

doi:10.2217/imt.15.19

Cited by 10 publications

(14 citation statements)

References 85 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Clinical validation for the therapeutic potential of CAR T cell products manufactured using OKT3/CD28 bead stimulation has been extensively established for CD19-CARs (1, 3-5). Inclusion of γc cytokines during ex vivo manufacturing, including IL-2, IL-7, IL-15 and/or IL-21, promotes extended expansion of the engineered T cells [reviewed in (51)]. Historically, IL-2 has been utilized during the expansion process, however, it is well-established that IL-2 promotes T cell differentiation.…”

Section: Mechanics Of Car T-cell Engineeringmentioning

confidence: 99%

Smart CARs engineered for cancer immunotherapy

Priceman

Forman

Brown

2015

Current Opinion in Oncology

View full text Add to dashboard Cite

Purpose Chimeric antigen receptors (CARs) are synthetic immunoreceptors that can redirect T cells to selectively kill tumor cells, and as “living-drugs” have the potential to generate long-term anti-tumor immunity. Given their recent clinical successes for the treatment of refractory B-cell malignancies, there is a strong push toward advancing this immunotherapy to other hematological diseases and solid cancers. Here, we summarize the current state of the field, highlighting key variables for the optimal application of CAR T cells for cancer immunotherapy. Recent Findings Advances in CAR T cell therapy have highlighted intrinsic CAR design and T cell manufacturing methods as critical components for maximal therapeutic success. Similarly, addressing the unique extrinsic challenges of each tumor type, including overcoming the immunosuppressive tumor microenvironment and tumor heterogeneity, as well as mitigating potential toxicity, will dominate the next wave of CAR T cell development. Summary CAR T cell therapeutic optimization, including intrinsic and extrinsic factors, is critical to developing effective CAR T cell therapies for cancer. The excitement of CAR T cell immunotherapy has just begun, and will continue with new insights revealed in laboratory research and in ongoing clinical investigations.

show abstract

Section: Mechanics Of Car T-cell Engineeringmentioning

confidence: 99%

Smart CARs engineered for cancer immunotherapy

Priceman

Forman

Brown

2015

Current Opinion in Oncology

View full text Add to dashboard Cite

show abstract

“…Recently, peptides containing the asparagine-glycine-arginine (Asn-Gly-Arg, NGR) motif [16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75] and their deamidation products containing the iso DGR motif [38,41,46,48,56,59,74,76,77,78,79,80,81...…”

Section: Introductionmentioning

confidence: 99%

Succinimide Formation from an NGR-Containing Cyclic Peptide: Computational Evidence for Catalytic Roles of Phosphate Buffer and the Arginine Side Chain

Kirikoshi

Manabe

Takahashi

2017

IJMS

View full text Add to dashboard Cite

The Asn-Gly-Arg (NGR) motif and its deamidation product isoAsp-Gly-Arg (isoDGR) have recently attracted considerable attention as tumor-targeting ligands. Because an NGR-containing peptide and the corresponding isoDGR-containing peptide target different receptors, the spontaneous NGR deamidation can be used in dual targeting strategies. It is well known that the Asn deamidation proceeds via a succinimide derivative. In the present study, we computationally investigated the mechanism of succinimide formation from a cyclic peptide, c[CH2CO-NGRC]-NH2, which has recently been shown to undergo rapid deamidation in a phosphate buffer. An H2PO4− ion was explicitly included in the calculations. We employed the density functional theory using the B3LYP functional. While geometry optimizations were performed in the gas phase, hydration Gibbs energies were calculated by the SM8 (solvation model 8) continuum model. We have found a pathway leading to the five-membered ring tetrahedral intermediate in which both the H2PO4− ion and the Arg side chain act as catalyst. This intermediate, once protonated at the NH2 group on the five-membered ring, was shown to easily undergo NH3 elimination leading to the succinimide formation. This study is the first to propose a possible catalytic role for the Arg side chain in the NGR deamidation.

show abstract

“…The systemic administration of cytokines for ameliorating T-cell survival and clinical efficacy is often associated with severe toxicity owing to their pleiotropic effects and with unfavorable consumption, particularly of IL-2 and IL-15, by counteracting Tregs at the tumor microenvironment. 43 We reasoned that expressing FIGURE 3. Membrane cytokines support ex vivo proliferation of mRNA-transfected human and mouse T cells.…”

Section: Discussionmentioning

confidence: 99%

Membrane-attached Cytokines Expressed by mRNA Electroporation Act as Potent T-Cell Adjuvants

Weinstein-Marom

Pato

Levin

et al. 2016

Journal of Immunotherapy

View full text Add to dashboard Cite

Proinflammatory cytokines are widely explored in different adoptive cell therapy protocols for enhancing survival and function of the transferred T cells, but their systemic administration is often associated with severe toxicity which limits their clinical use. To confine cytokine availability to the therapeutic T cells, we expressed 3 key cytokines, IL-2, IL-12, and IL-15, as integral T-cell membrane proteins. To prevent permanent activation of growth signaling pathways, we delivered these genes to T cells through mRNA electroporation. The engineered cytokines could be detected on the surface of mRNA-transfected cells and binding to their cell-surface receptors mainly occurred in cis. The 3 human cytokines supported the ex vivo growth of activated human CD8 and CD4 T cells for at least 6 days posttransfection, comparably to high-dose soluble IL-2. Similarly, membrane IL-2, membrane IL-12, and, to a lesser extent, membrane IL-15, were comparable with their soluble counterparts in supporting proliferation of splenic mouse CD8 T cells. Following electroporation of human CD8 T cells and antimelanoma tumor-infiltrating lymphocytes, membrane cytokines synergized with constitutively active toll-like receptor 4 in inducing interferon-γ secretion. Efficient cooperation with TLR4 was also evident in the upregulation of the activation molecules CD25, CD69, CD137 (4-1BB), and CD134 (OX40). Taken together, membrane cytokines expressed through mRNA transfection emerge as effective tools for enhancing T-cell proliferation and function and may have potential use in adoptive T-cell therapy.

show abstract

Exploiting Cytokines in Adoptive T-Cell Therapy of Cancer

Cited by 10 publications

References 85 publications

Smart CARs engineered for cancer immunotherapy

Smart CARs engineered for cancer immunotherapy

Succinimide Formation from an NGR-Containing Cyclic Peptide: Computational Evidence for Catalytic Roles of Phosphate Buffer and the Arginine Side Chain

Membrane-attached Cytokines Expressed by mRNA Electroporation Act as Potent T-Cell Adjuvants

Contact Info

Product

Resources

About