A novel biologic platform elicits profound T cell costimulatory activity and antitumor immunity in mice

Ryan, Joseph M.; Mittal, Payal; Ménoret, Antoine; Svedova, Julia; Wasser, Jeffrey S.; Adler, Adam J.; Vella, Anthony T.

doi:10.1007/s00262-018-2116-1

Cited by 5 publications

(3 citation statements)

References 49 publications

(46 reference statements)

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“…Additionally, expression of OX40 and 4-1BB peaks at approximately 48 hours after antigen presentation to naive T cells 5 . Coexpression of the receptors is likely to continue for approximately 2–4 days post-activation 34,35 which represents a critical phase of effector T cell differentiation, and is thus clinically important for development of sufficient numbers of these antigen-specific cytotoxic T cells 36 . Thus, focusing the modeling effort on this time period represents an efficient effort to understand and simulate a critical phase of T cell differentiation during which OX40 and 4-1BB play an important role in the quality of T cell effector generation.…”

Section: Resultsmentioning

confidence: 99%

A mathematical model of combined CD8 T cell costimulation by 4-1BB (CD137) and OX40 (CD134) receptors

Konstorum

Vella

Adler

et al. 2019

Sci Rep

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Combined agonist stimulation of the TNFR costimulatory receptors 4-1BB (CD137) and OX40(CD134) has been shown to generate supereffector CD8 T cells that clonally expand to greater levels, survive longer, and produce a greater quantity of cytokines compared to T cells stimulated with an agonist of either costimulatory receptor individually. In order to understand the mechanisms for this effect, we have created a mathematical model for the activation of the CD8 T cell intracellular signaling network by mono- or dual-costimulation. We show that supereffector status is generated via downstream interacting pathways that are activated upon engagement of both receptors, and in silico simulations of the model are supported by published experimental results. The model can thus be used to identify critical molecular targets of T cell dual-costimulation in the context of cancer immunotherapy.

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Section: Resultsmentioning

confidence: 99%

A mathematical model of combined CD8 T cell costimulation by 4-1BB (CD137) and OX40 (CD134) receptors

Konstorum

Vella

Adler

et al. 2019

Sci Rep

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“…Costimulation of CD8 + T cells induces their differentiation into effector cells contributing to inflammatory physiological and pathological response 1 . Two costimulatory signals, TNF superfamily receptors CD134 (OX40) and CD137 (41BB), are expressed on activated CD8 + T cells and are triggered in both protective and pathological conditions to induce differentiation into surviving T effector cells 2 – 6 . Textbook immunology stipulates that T cell costimulation induces upregulation of many transcriptional pathways including JAK-STAT, mTOR, and NF-kB that contribute to inflammatory cytokine production (IFNγ, TNF, and IL-2) and clonal expansion 1 .…”

Section: Introductionmentioning

confidence: 99%

Optimal CD8+ T cell effector function requires costimulation-induced RNA-binding proteins that reprogram the transcript isoform landscape

2022

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Boosting T cell activation through costimulation directs defense against cancer and viral infections. Despite multiple studies targeting costimulation in clinical trials, the increased potency and reprogramming of T cells endowed by costimulation is poorly understood. Canonical dogma states that transcription mediates T cell activation. Here, we show that the spliceosome, controlling post-transcriptional alternative splicing and alternative polyadenylation, is the most enriched pathway in T cells after CD134/CD137 costimulation. Costimulation of CD8+ T cells significantly increases expression of 29 RNA-binding proteins while RNA-seq uncovers over 1000 differential alternative splicing and polyadenylation events. Using in vivo mouse and in vitro human models, we demonstrate that RNA-binding protein Tardbp is required for effector cytokine production, CD8+ T cell clonal expansion, and isoform regulation after costimulation. The prospect of immune response optimization through reprogramming of mRNA isoform production offered herein opens new avenues for experimentally and therapeutically tuning the activities of T cells.

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“…Co-stimulation through 4-1BB and OX40 has the potential to amplify the cytotoxic function and the number of activated T and NK cells in multiple solid tumor indications. [1][2] Methods scFv binding domains to 4-1BB and OX40 were optimized to increase affinity, function and stability, and then incorporated into the ADAPTIR™ bispecific antibody platform to produce the APVO603 lead candidate. NF-kB/luciferase reporter cell lines expressing OX40 or 4-1BB were initially used to assess the agonistic function of APVO603's binding domains.…”

mentioning

confidence: 99%

633 Dual-targeting of 4–1BB and OX40 with an ADAPTIR™ bispecific antibody enhances anti-tumor responses to solid tumor

Nelson

Miller

Blahnik-Fagan

et al. 2020

Regular and Young Investigator Award Abstracts

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Background4-1BB (CD137) and OX40 (CD134) are critical activation-induced co-stimulatory receptors that regulate immune responses of activated T and NK cells by enhancing proliferation, cytokine production, survival, and cytolytic activity. A superagonist 4-1BB antibody has shown clinical activity but severe toxicities. APVO603, is a 4-1BB x OX40 targeting bispecific antibody with conditional agonism, activating these receptors only when both are co-engaged. The Fc portion was mutated to eliminate FcγR-mediated interactions. Co-stimulation through 4-1BB and OX40 has the potential to amplify the cytotoxic function and the number of activated T and NK cells in multiple solid tumor indications.1–2Methods scFv binding domains to 4-1BB and OX40 were optimized to increase affinity, function and stability, and then incorporated into the ADAPTIR™ bispecific antibody platform to produce the APVO603 lead candidate. NF-κB/luciferase reporter cell lines expressing OX40 or 4-1BB were initially used to assess the agonistic function of APVO603’s binding domains. Primary PBMC were sub-optimally stimulated with an anti-CD3 antibody and T and NK cell proliferation was assessed using Cell TraceTM-labelled PBMC. Cytokine secretion was measured at 48 hrs using Luminex-based assays. For in vitro tumor lysis studies, PBMC were co-cultured with tumor cells expressing a tumor-associated antigen (TAA) and activated with TAA x CD3 bispecific protein. 7-AAD expression was assessed on tumor cells at 72 hrs. The in vivo therapeutic efficacy of APVO603 was evaluated using a murine MB49 bladder cancer model in human 4-1BB and OX40 double knock-in mice.ResultsAPVO603 stimulates 4-1BB and OX40 NF-κB/luciferase reporter activity in a dose-dependent manner, and is strictly dependent on engagement of the reciprocal receptor to elicit 4-1BB or OX40 activity. In primary PBMC assays, APVO603 induces synergistic proliferation of CD4+, CD8+ T and NK cells when compared to OX40 or 4-1BB monospecific molecules with a wt Fc, either individually or in combination. Additionally, APVO603 enhances proinflammatory cytokine production and granzyme B expression, and augments in vitro tumor cell lysis induced by a TAAx CD3 engager. In vivo, APVO603 reduces growth of established MB49 tumors in human 4-1BB and OX40 double knock-in mice.ConclusionsAPVO603 is a dual-agonistic bispecific antibody that augments the effector function of activated CD4+ and CD8+ T and NK cells in a dose-dependent manner, and reduces growth of established tumors in vivo. This preclinical data, demonstrates conditional dual stimulation of 4-1BB and OX40 and supports further development of APVO603, a promising immuno-oncology therapeutic with potential for benefit in solid tumors.Ethics ApprovalTreatment of study animals was in accordance with conditions specified in the Guide for the Care and Use of Laboratory Animals, and the study protocol (ACUP 20) was approved by the Institutional Animal Care and Use Committee (IACUC).ReferencesBandyopadhyay S, Long M, Qui H, Hagymasi A, Slaiby A, Mihalyo M, Aguila H, Mittler R, Vella A, Adler A. Self-antigen prevents CD8 T cell effector differentiation by CD134 and CD137 dual costimulation. J Immunol 2008;181(11):7728–37.Ryan J, Mittal P, Menoret A, Svedova J, Wasser J, Adler A, Vella A. A novel biologic platform elicits profound T cell costimuloaroty activity and antitumor immunity in mice. Cancer Immunol Immunother 2018;67(4):605–613.

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A novel biologic platform elicits profound T cell costimulatory activity and antitumor immunity in mice

Cited by 5 publications

References 49 publications

A mathematical model of combined CD8 T cell costimulation by 4-1BB (CD137) and OX40 (CD134) receptors

A mathematical model of combined CD8 T cell costimulation by 4-1BB (CD137) and OX40 (CD134) receptors

Optimal CD8+ T cell effector function requires costimulation-induced RNA-binding proteins that reprogram the transcript isoform landscape

633 Dual-targeting of 4–1BB and OX40 with an ADAPTIR™ bispecific antibody enhances anti-tumor responses to solid tumor

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