Agonists of Co-stimulation in Cancer Immunotherapy Directed Against CD137, OX40, GITR, CD27, CD28, and ICOS

doi:10.1053/j.seminoncol.2015.05.014

Seminars in Oncology

Volume 42, Issue 4, August 2015, Pages 640-655

https://doi.org/10.1053/j.seminoncol.2015.05.014 Get rights and content

T and natural killer (NK) lymphocytes are considered the main effector players in the immune response against tumors. Full activation of T and NK lymphocytes requires the coordinated participation of several surface receptors that meet their cognate ligands through structured transient cell-to-cell interactions known as immune synapses. In the case of T cells, the main route of stimulation is driven by antigens as recognized in the form of short polypeptides associated with major histocompatibility complex (MHC) antigen-presenting molecules. However, the functional outcome of T-cell stimulation towards clonal expansion and effector function acquisition is contingent on the contact of additional surface receptor-ligand pairs and on the actions of cytokines in the milieu. While some of those interactions are inhibitory, others are activating and are collectively termed co-stimulatory receptors. The best studied belong to either the immunoglobulin superfamily or the tumor necrosis factor-receptor (TNFR) family. Co-stimulatory receptors include surface moieties that are constitutively expressed on resting lymphocytes such as CD28 or CD27 and others whose expression is induced upon recent previous antigen priming, ie, CD137, GITR, OX40, and ICOS. Ligation of these glycoproteins with agonist antibodies actively conveys activating signals to the lymphocyte. Those signals, acting through a potentiation of the cellular immune response, give rise to anti-tumor effects in mouse models. Anti-CD137 antibodies are undergoing clinical trials with evidence of clinical activity and anti-OX40 monoclonal antibodies (mAbs) induce interesting immunomodulation effects in humans. Antibodies anti-CD27 and GITR have recently entered clinical trials. The inherent dangers of these immunomodulation strategies are the precipitation of excessive systemic inflammation or/and invigorating silent autoimmunity. Agonist antibodies, recombinant forms of the natural ligands, and polynucleotide-based aptamers constitute the pharmacologic tools to manipulate such receptors. Preclinical data suggest that the greatest potential of these agents is achieved in combined treatment strategies.

Section snippets

CD28 and ICOS

CD28 is the canonical and best studied co-stimulatory glycoprotein.¹⁸ Its function is critical for costimulation of naïve T lymphocytes.¹⁹ Activation through CD28 results in protection from cell death,²⁰ stronger cytokine secretion and much enhanced proliferation. Indeed agonist anti-CD28 antibodies are routinely used in the laboratory to culture T-cell lines and clones.²¹ CD28 ligation results in the activation of various transcription factors and in the persistence of various pro-immune mRNAs,

Rna Aptamers as Novel Therapeutic for Costimulation of 41bb, Ox40, Or Cd28

The most frequently used therapeutic platform for agonist molecules triggering co-stimulatory receptors has been conventional mAbs. This topic has been extensively reviewed elsewhere.153, 154 Therefore, in this last part of the review, we will discuss as an alternative platform in the form of polynucleotides able to bind to proteins. In this regard, three important co-stimulatory RNA aptamers have been recently described against 4-1BB, OX40, and CD28.155, 156, 157 We will also review the use of

The Road Ahead

The clinical success of ipilimumab,¹⁷⁴, anti–PD-1,175, 176 and anti–PD-L1177, 178, 179 mAbs has validated the principle that modulation of the immune response can overcome immune evasion mechanisms of tumors and produce objective anti-tumor responses. However, different mechanisms to evade immune attack can be developed by each patient׳s tumor and now the challenge is to determine which mechanism is dominant and which is the most suitable immunotherapy. Clinical experience has revealed that

References (181)

K.A. Frauwirth et al.
The CD28 signaling pathway regulates glucose metabolism
Immunity
(2002)
J.M. Curtsinger et al.
Inflammatory cytokines as a third signal for T cell activation
Curr Opin Immunol
(2010)
M.L. Dustin
What counts in the immunological synapse?
Mol Cell
(2014)
J.R. Muller et al.
Paracrine and transpresentation functions of IL-15 are mediated by diverse splice versions of IL-15Ralpha in human monocytes and dendritic cells
J Biol Chem
(2012)
P.S. Linsley et al.
Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors
Immunity
(1994)
E.A. Tivol et al.
Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4
Immunity
(1995)
L. Chen et al.
Costimulation of anti-tumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4
Cell
(1992)
T.R. Simpson et al.
Regulation of CD4 T cell activation and effector function by inducible costimulator (ICOS)
Curr Opin Immunol
(2010)
M.E. van Berkel et al.
CD28 and ICOS: similar or separate costimulators of T cells?
Immunol Lett
(2006)
Y.S. Choi et al.
ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6
Immunity
(2011)

R.A. Shilling et al.

CD28 and ICOS play complementary non-overlapping roles in the development of Th2 immunity in vivo

Cell Immunol

(2009)

R.I. Nurieva

Regulation of immune and autoimmune responses by ICOS-B7h interaction

Clin Immunol

(2005)

M. Croft et al.

TNF superfamily in inflammatory disease: translating basic insights

Trends Immunol

(2012)

I. Melero et al.

Multi-layered action mechanisms of CD137 (4-1BB)-targeted immunotherapies

Trends Pharmacol Sci

(2008)

I. Melero et al.

NK1.1 cells express 4-1BB (CDw137) co-stimulatory molecule and are required for tumor immunity elicited by anti-4-1BB monoclonal antibodies

Cell Immunol

(1998)

J.I. Quetglas et al.

Immunotherapeutic synergy between anti-CD137 mAb and intratumoral administration of a cytopathic Semliki Forest virus encoding IL-12

Mol Ther

(2012)

L.M. Myers et al.

Interfacing T-cell effector and regulatory function through CD137 (4-1BB) co-stimulation

Trends Immunol

(2005)

H.E. Kohrt et al.

CD137 stimulation enhances the antilymphoma activity of anti-CD20 antibodies

Blood

(2011)

P.A. Ascierto et al.

Clinical experiences with anti-CD137 and anti-PD1 therapeutic antibodies

Semin Oncol

(2010)

D.J. Paterson et al.

Antigens of activated rat T lymphocytes including a molecule of 50,000 Mr detected only on CD4 positive T blasts

Mol Immunol

(1987)

B. Valzasina et al.

Triggering of OX40 (CD134) on CD4(+)CD25+T cells blocks their inhibitory activity: a novel regulatory role for OX40 and its comparison with GITR

Blood

(2005)

P.R. Rogers et al.

OX40 promotes Bcl-xL and Bcl-2 expression and is essential for long-term survival of CD4 T cells

Immunity

(2001)

J. Song et al.

Sustained survivin expression from OX40 co-stimulatory signals drives T cell clonal expansion

Immunity

(2005)

M.K. Jenkins et al.

On the composition of the preimmune repertoire of T cells specific for peptide-major histocompatibility complex ligands

Ann Rev Immunol

(2010)

P. Matzinger

The danger model: a renewed sense of self

Science

(2002)

R. Medzhitov et al.

Decoding the patterns of self and nonself by the innate immune system

Science

(2002)

L. Chen et al.

Molecular mechanisms of T cell co-stimulation and co-inhibition

Nat Rev Immunol

(2013)

M.L. Dustin

The immunological synapse

Cancer Immunol Res

(2014)

D.R. Fooksman et al.

Functional anatomy of T cell activation and synapse formation

Ann Rev Immunol

(2010)

K. Choudhuri et al.

Polarized release of T-cell-receptor-enriched microvesicles at the immunological synapse

Nature

(2014)

P. Penaloza-MacMaster et al.

Interplay between regulatory T cells and PD-1 in modulating T cell exhaustion and viral control during chronic LCMV infection

J Ex p Med

(2014)

T. Yokosuka et al.

Programmed cell death 1 forms negative co-stimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2

J Exp Med

(2012)

O. Acuto et al.

CD28-mediated co-stimulation: a quantitative support for TCR signalling

Nat Rev Immunol

(2003)

L.F. Dodson et al.

Targeted knock-in mice expressing mutations of CD28 reveal an essential pathway for costimulation

Mol Cell Biol

(2009)

I. Martinez-Forero et al.

Lysine 63 polyubiquitination in immunotherapy and in cancer-promoting inflammation

Clin Cancer Res

(2009)

V.G. Bhoj et al.

Ubiquitylation in innate and adaptive immunity

Nature

(2009)

P. Riha et al.

CD28 co-signaling in the adaptive immune response

Self Nonself

(2010)

H. Bour-Jordan et al.

Intrinsic and extrinsic control of peripheral T-cell tolerance by co-stimulatory molecules of the CD28/ B7 family

Immunol Rev

(2011)

T.H. Watts

Staying alive: T cell costimulation, CD28, and Bcl-xL

J Immunol

(2010)

M.V. Maus et al.

Ex vivo expansion of polyclonal and antigen-specific cytotoxic T lymphocytes by artificial APCs expressing ligands for the T-cell receptor, CD28 and 4-1BB

Nat Biotechnol

(2002)

J.A. Ragheb et al.

CD28-Mediated regulation of mRNA stability requires sequences within the coding region of the IL-2 mRNA

J Immunol

(1999)

P. Waterhouse et al.

Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4

Science

(1995)

X. Tai et al.

Induction of autoimmune disease in CTLA-4-/- mice depends on a specific CD28 motif that is required for in vivo costimulation

Proc Natl Acad Sci U S A

(2007)

R. Zhang et al.

An obligate cell-intrinsic function for CD28 in Tregs

J Clin Invest

(2013)

S.E. Townsend et al.

Tumor rejection after direct costimulation of CD8+T cells by B7-transfected melanoma cells

Science

(1993)

G. Winberg et al.

Surface expression of CD28 single chain Fv for costimulation by tumor cells

Immunol Rev

(1996)

R.J. Brentjens et al.

Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts

Clin Cancer Res

(2007)

S. Tammana et al.

4-1BB and CD28 signaling plays a synergistic role in redirecting umbilical cord blood T cells against B-cell malignancies

Hum Gene Ther

(2010)

T. Hunig

The storm has cleared: lessons from the CD28 superagonist TGN1412 trial

Nat Rev Immunol

(2012)

G. Suntharalingam et al.

Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412

N Engl J Med

(2006)

Cited by (169)

Aptamers combined with immune checkpoints for cancer detection and targeted therapy: A review
2024, International Journal of Biological Macromolecules
In recent years, remarkable strides have been made in the field of immunotherapy, which has emerged as a standard treatment for many cancers. As a kind of immunotherapy drug, monoclonal antibodies employed in immune checkpoint therapy have proven beneficial for patients with diverse cancer types. However, owing to the extensive heterogeneity of clinical responses and the complexity and variability of the immune system and tumor microenvironment (TME), accurately predicting its efficacy remains a challenge. Recent advances in aptamers provide a promising approach for monitoring alterations within the immune system and TME, thereby facilitating targeted immunotherapy, particularly focused on immune checkpoint blockade, with enhanced antitumor efficiency. Aptamers have been widely used in tumor cell detection, biosensors, drug discovery, and biomarker screening due to their high specificity and high affinity with their targets. This review aims to comprehensively examine the research status and progress of aptamers in cancer diagnosis and immunotherapy, with a specific emphasis on those related to immune checkpoints. Additionally, we will discuss the future research directions and potential therapeutic targets for aptamer-based immune checkpoint therapy, aiming to provide a theoretical basis for targeting immunotherapy molecules and blocking tumor immune escape.
Development of bispecific T cell engagers: harnessing quantitative systems pharmacology
2023, Trends in Pharmacological Sciences
Bispecific T cell engagers (bsTCEs) have emerged as a promising class of cancer immunotherapy. Several bsTCEs have achieved marketing approval; dozens more are under clinical investigation. However, the clinical development of bsTCEs remains rife with challenges, including nuanced pharmacology, limited translatability of preclinical findings, frequent on-target toxicity, and convoluted dosing regimens. In this opinion article we present a distinct perspective on how quantitative systems pharmacology (QSP) can serve as a powerful tool for overcoming these obstacles. Recent advances in QSP modeling have empowered developers of bsTCEs to gain a deeper understanding of their context-dependent pharmacology, bridge gaps in experimental data, guide first-in-human (FIH) dose selection, design dosing regimens with expanded therapeutic windows, and improve long-term treatment outcomes. We use recent case studies to exemplify the potential of QSP techniques to support future bsTCE development.
CAR-T cells for cancer immunotherapy
2023, Chinese Chemical Letters
Adoptive immunotherapy expressing synthetic chimeric antigen receptors (CAR) on T cells through in vitro modifications represents a new and innovative strategy in cancer treatment. This new approach enables T cells to recognize and bind tumor antigens via a single-chain variable fragment recognition domain, circumventing the restriction of major histocompatibility complex. This review summarized the structure/design of CAR-T cells and the evolution process this technology went through, displaying the theoretical foundation for CAR-T therapy, the marketed products and the latest preclinical and clinical research progress. Finally, we provided perspectives on this technology's development and potential future applications, especially for treating hematological malignant and solid tumors.
CircRNAs in tumor immunity and immunotherapy: Perspectives from innate and adaptive immunity
2023, Cancer Letters
Tumor immunotherapy is a new therapeutic approach that has been evolving in the last decade and has dramatically changed the treatment options for cancer. Circular RNAs (circRNAs) are non-coding RNAs (ncRNAs) with high stability, tissue-specific and cell-specific expression. There is growing evidence that circRNAs are involved in the regulation of both adaptive and innate immunity. They play important roles in tumor immunotherapy by affecting macrophage, NK and T cell function. The high stability and tissue specificity make them ideal candidate biomarkers for therapeutic effects. CircRNAs also represent one of promising targets or adjuvant for immunotherapy. Investigations in this field progress rapidly and provide essential support for the diagnosis, prognosis and treatment guidance of cancers in the future. In this review, we summarize the role of circRNAs on tumor immunity from the viewpoint of innate and adaptive immunity, and explore the role of circRNAs in tumor immunotherapy.
Monoclonal antibodies in breast cancer: A critical appraisal
2023, Critical Reviews in Oncology/Hematology
In breast cancer, mAbs can play multifunctional roles like targeting cancer cells, sometimes directly attacking them, helping in locating and delivering therapeutic drugs to targets, inhibiting cell growth and blocking immune system inhibitors, etc. Monoclonal antibodies are also one of the important successful treatment strategies especially against HER2 but they have not been explored much for other types of breast cancers especially in triple negative breast cancers. Monoclonal antibodies impact the feasibility of antigen specificity, bispecific and trispecific mAbs have opened new doors for more targeted specific efficacy. Monoclonal antibodies can be used diversly and with efficacy as compared to other methods of treatment thus maining it a suitable candidate for breast cancer treatment. However, mAbs treatment also causes various side effects such as fever, trembling, fatigue, headache and muscle pain, nausea/vomiting, difficulty in breathing, rashes and bleeding. Understanding the pros and cons of this strategy, we have explored in this review, the current and future potential capabilities of monoclonal antibodies with respect to diagnosis and treatment of breast cancer.
Not applicable
Checkpoint: Inspecting the barriers in glioblastoma immunotherapies
2022, Seminars in Cancer Biology
Despite an aggressive standard of care involving radiation therapy, temozolomide-based chemotherapy, and surgical resection, glioblastoma multiforme (GBM) continues to exhibit very high recurrence and mortality rates partly due to the highly plastic and heterogenous nature of the tumor. In recent years, activation of the immune system has emerged as a promising strategy in cancer therapies. However, despite recent successes in other fields, immunotherapeutic approaches continue to encounter challenges in GBM. In this review, we first discuss immunotherapies targeting the most well-studied immune checkpoint proteins, CTLA-4 and PD-1, followed by discussions on therapies targeting immune-stimulatory molecules and secreted metabolic enzymes. Finally, we address the major challenges with immunotherapy in GBM and the potential for combination and neoadjuvant immunotherapies to tip the scales in the fight against glioblastoma.

View all citing articles on Scopus

: Conflicts of interest: M.J.K. is full time employee at Bristol Myers Squibb and owns stock. I.M. is a consultant for Bristol Myers Squibb, Miltenyi-biotec, Merck and Roche-Genentech.

View full text

Agonists of Co-stimulation in Cancer Immunotherapy Directed Against CD137, OX40, GITR, CD27, CD28, and ICOS

Section snippets

CD28 and ICOS

Rna Aptamers as Novel Therapeutic for Costimulation of 41bb, Ox40, Or Cd28

The Road Ahead

Immunity

Curr Opin Immunol

Mol Cell

J Biol Chem

Immunity

Immunity

Cell

Curr Opin Immunol

Immunol Lett

Immunity

Cell Immunol

Clin Immunol

Trends Immunol

Trends Pharmacol Sci

Cell Immunol

Mol Ther

Trends Immunol

Blood

Semin Oncol

Mol Immunol

Blood

Immunity

Immunity

On the composition of the preimmune repertoire of T cells specific for peptide-major histocompatibility complex ligands

Ann Rev Immunol

The danger model: a renewed sense of self

Science

Decoding the patterns of self and nonself by the innate immune system

Science

Molecular mechanisms of T cell co-stimulation and co-inhibition

Nat Rev Immunol

The immunological synapse

Cancer Immunol Res

Functional anatomy of T cell activation and synapse formation

Ann Rev Immunol

Polarized release of T-cell-receptor-enriched microvesicles at the immunological synapse

Nature

Interplay between regulatory T cells and PD-1 in modulating T cell exhaustion and viral control during chronic LCMV infection

J Ex p Med

Programmed cell death 1 forms negative co-stimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2

J Exp Med

CD28-mediated co-stimulation: a quantitative support for TCR signalling

Nat Rev Immunol

Targeted knock-in mice expressing mutations of CD28 reveal an essential pathway for costimulation

Mol Cell Biol

Lysine 63 polyubiquitination in immunotherapy and in cancer-promoting inflammation

Clin Cancer Res

Ubiquitylation in innate and adaptive immunity

Nature

CD28 co-signaling in the adaptive immune response

Self Nonself

Intrinsic and extrinsic control of peripheral T-cell tolerance by co-stimulatory molecules of the CD28/ B7 family

Immunol Rev

Staying alive: T cell costimulation, CD28, and Bcl-xL

J Immunol

Ex vivo expansion of polyclonal and antigen-specific cytotoxic T lymphocytes by artificial APCs expressing ligands for the T-cell receptor, CD28 and 4-1BB

Nat Biotechnol

CD28-Mediated regulation of mRNA stability requires sequences within the coding region of the IL-2 mRNA

J Immunol

Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4

Science

Induction of autoimmune disease in CTLA-4-/- mice depends on a specific CD28 motif that is required for in vivo costimulation

Proc Natl Acad Sci U S A

An obligate cell-intrinsic function for CD28 in Tregs

J Clin Invest

Tumor rejection after direct costimulation of CD8+T cells by B7-transfected melanoma cells

Science

Surface expression of CD28 single chain Fv for costimulation by tumor cells

Immunol Rev

Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts

Clin Cancer Res

4-1BB and CD28 signaling plays a synergistic role in redirecting umbilical cord blood T cells against B-cell malignancies

Hum Gene Ther

The storm has cleared: lessons from the CD28 superagonist TGN1412 trial

Nat Rev Immunol