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  • Review Article
  • Published:

Immunostimulatory monoclonal antibodies for cancer therapy

Nature Reviews Cancer volume 7, pages 95–106 (2007)Cite this article

Key Points

  • Monoclonal antibodies (mAbs) have had a significant effect on current practice in oncology. Mechanisms of action include direct tumour cell destruction and indirect targeting of growth and pro-angiogenic mediators.

  • Using mAbs to stimulate the immune response against cancer cells is a new indirect mode of action, achieved by either blocking inhibitory 'immune checkpoint' receptors such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4, also known as CD152) or triggering activating receptors such as 4-1BB or CD40.

  • The list of mAbs that have clearly shown these kinds of effects in mouse tumour models is expanding, and can be grouped as mAbs that interfere with lymphocyte inhibitory receptors; mAbs that function as agonist or super-agonist ligands for co-stimulatory receptors; mAbs that enhance the activation and/or maturation of antigen-presenting cells (APCs); and mAbs that delete or inhibit immunosuppressive mechanisms such as regulatory T cells.

  • An obstacle to the application of immunostimulatory mAbs is their associated adverse toxicity, most commonly reversible autoimmunity and/or systemic inflammatory reactions.

  • Anti-CTLA-4, anti-4-1BB and anti-CD40 are the first immunostimulatory mAbs to reach the clinic. Anti-CTLA-4 is in phase III clinical trials for patients with malignant melanoma following successful phase II testing. Importantly, organ-specific autoimmunity was reported in about one third of patients and correlated with clinical response.

  • Synergistic combinations of immunostimulatory mAbs have been identified at the preclinical level, and combinatorial strategies with cancer vaccines, adoptive T-cell therapy, radiotherapy and chemotherapy will probably have important roles in future clinical development.

Abstract

Increasing immune responses with immunostimulatory monoclonal antibodies (mAbs) directed to immune-receptor molecules is a new and exciting strategy in cancer therapy. This expanding class of agents functions on crucial receptors, either antagonizing those that suppress immune responses or activating others that amplify immune responses. Complications such as autoimmunity and systemic inflammation are problematic side effects associated with these agents. However, promising synergy has been observed in preclinical models using combinations of immunostimulatory antibodies and other immunotherapy strategies or conventional cancer therapies. Importantly, mAbs of this type have now entered clinical trials with encouraging initial results.

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Figure 1: Schematic representation of points of intervention with immunostimulatory mAbs.
Figure 2: Co-stimulatory and co-inhibitory molecules targeted by immunostimulatory mAbs.
Figure 3: Efficacious combination strategies involving immunostimulatory mAbs.
Figure 4: Route from preclinical to clinical development of immunostimulatory monoclonal antibodies.

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Acknowledgements

We thank A. Melcher, A. Ribas, J. L. Perez-Gracia, J. Gómez-Navarro, A. Arina, O. Murillo, J. Dubrot and J. Prieto for critical reading and helpful discussion. We acknowledge financial support from Comisión Interministerial de Ciencia y Tecnología (CICYT), Gobierno de Navarra (Departamentos de Salud y Educación) and Redes Temáticas de Investigación Cooperativa FIS, Asociación española contra el cáncer (AECC) and UTE-project-CIMA.

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Authors and Affiliations

  1. Centro de Investigación Médica Aplicada (CIMA) and Clínica Universitaria, Universidad de Navarra, Pamplona, Spain

    Ignacio Melero & Sandra Hervas-Stubbs

  2. Cancer Sciences Division, Tenovus Research Laboratories, Southampton University School of Medicine, General Hospital, Southampton, UK

    Martin Glennie

  3. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Drew M. Pardoll & Lieping Chen

  4. Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Lieping Chen

Authors
  1. Ignacio Melero
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  2. Sandra Hervas-Stubbs
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  3. Martin Glennie
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  4. Drew M. Pardoll
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  5. Lieping Chen
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Corresponding authors

Correspondence to Ignacio Melero or Lieping Chen.

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Clinical trial NCT00309023

Clinical trial NCT00351325

UK Department of Health report on phase I clinical trials

Glossary

Monoclonal antibody

A unique immunoglobulin of known specificity that is produced by a B-lymphocyte clone usually immortalized by cell fusion with a non-secreting myeloma cell line.

Cellular immune response

An immune response that is predominantly mediated by activated lymphocytes and macrophages, resulting in inflammatory infiltrates such as those seen in granulomas.

Dendritic cells

A network of leukocyte populations that present antigen captured at peripheral tissues to T cells in lymphoid organs through both MHC class II and I antigen-presentation pathways. The MHC class II presentation pathway mainly presents endocytosed antigens to CD4+ T cells, whereas MHC class I molecules generally present peptides from the endogenously synthesized proteome to CD8+ T cells.

Natural killer cells

A lymphocyte type involved in cytolytic functions that is also exploitable in immunotherapy. These cells share many features with CTLs, but lack a TCR. NK cells are also decorated with receptors that activate cytotoxicity on contact with stressed, virally infected, transformed or antibody-coated cells. In addition, they are equipped with receptors that inhibit cytotoxicity if detecting normal MHC class I molecules on the target cell.

T-cell receptor

Surface receptors expressed on T cells that recognize specific peptides complexed with MHC molecules that convey intracellular signals through associated CD3 molecules. As a result of rearrangement of its genes during T-cell ontogeny, a clonally distributed array (repertoire) of receptors is generated.

Memory T lymphocytes

Some of the activated T cells in the CD4+ and CD8+ compartments become long lived, whereas most effector T lymphocytes die off. Surviving cells are termed memory T lymphocytes. Lower stimulation thresholds help to re-activate these cells after antigen re-exposure.

Regulatory T cells

TReg cells are defined by their expression of the FOXP-3 transcription factor, and are important inhibitors of immunity. TReg cells express CD25, CTLA-4, GITR and LAG3 in a constitutive fashion. Contact with TReg lymphocytes can directly inhibit T and NK cell activation, or indirect inhibition can take place through APCs.

Plasmapheresis

The procedure of circulating the blood of a patient in an extracorporeal closed system that eliminates autologous plasma at the same time as returning the cellular components and transfusing donated plasma.

Fully human mAbs

Antibodies rearranged in immunized mice that are transgenic for the human heavy and light immunoglobulin regions and therefore produce human immunoglobulins.

Good manufacturing practice

A set of regulations, codes and guidelines for the fabrication of drugs. GMP involves normalized production in a contaminant-free ambient environment, quality control, and labelling and toxicology studies to ensure the purity, identity, traceability, stability and activity of the administered drug formulation. The philosophy is to avoid contaminations, mistakes or variations, thereby achieving more safety for patients.

Bivalency

As a result of having two antigen-binding sites in each immunoglobulin molecule, antibodies can engage two antigens simultaneously.

Tumour antigens

Mutated, altered, viral or hyperexpressed protein sequences in cancer cells that can be recognized by T lymphocytes.

Immunological synapses

A supramolecular structure formed by the contacting membranes of APCs and lymphocytes that encompasses the interaction of ligand–receptor pairs, paracrine actions of cytokines, redistribution of surface molecules, intracellular signalling, reorientation of both cell cytoskeletons and the redistribution of lipid rafts.

Super-agonist mAb

A stimulatory mAb for lymphocytes with effects superior to those elicited by the natural ligands (in the case of TGN1412 this meant the induction of T-lymphocyte proliferation in the absence of antigen recognition).

Activation-induced T-cell death

Lymphocyte apoptosis to maintain lymphocyte homeostasis following T-cell activation, involving TRAIL and FASL interaction, as well as IL2, IFNγ and the intracellular pro-apoptotic molecule BIM. It is important to contract lymphocyte numbers after the initial phase of exponential clonal expansions.

Cross presentation and cross priming

There are DCs that are able to redirect exogenous antigens to the MHC class I pathway, a phenomenon that can result either in priming (crosspriming) of a specific CTL or their tolerization depending on the maturation status of the DC. Non-migrating DCs that reside in lymphoid organs have a key role in the cross presentation of foreign antigens, suggesting an exchange of antigenic material between immigrating and resident DC subpopulations in lymph nodes.

T helper cells

A differentiated class of CD4+ T cells chiefly characterized by their ability to produce IFNγ and their cooperative and effector roles in the cellular immune response.

Chimeric mAbs

MAbs in which the constant domains of the heavy and light chain are replaced by human counterparts.

Humanized mAbs

MAbs in which variable domain sequences dispensable for antigen binding have also been replaced.

Hypopituitarism

The failure of the anterior lobe of the pituitary gland to sustain normal levels of the hormones that it produces.

Comensal flora

Non-pathogenic microrganisms that normally colonize the epithelial barriers of the organism such as the skin or the intestinal mucosa.

Effector phase of CTL-mediated cell killing

The killing of a target cell by an activated CD8+ T cell that, after antigen recognition (in close cell–cell interactions), degranulates to release perforin and granzymes, and expresses ligands and cytokines for death-inducing receptors on the target cell. These events have been described as the kiss of death.

Clonal exhaustion

Chronic exposure to high levels of antigen drives T lymphocytes into a functional state of non-responsiveness termed 'exhaustion'. This phenomenon might have a role in impaired CD8+ T-cell response to persistent antigens. There is evidence that PD-1 and B7-H1 have crucial roles in the induction and maintenance of this status.

Waldenström macroglobulinaemia

A haematological malignancy resulting from the transformation of plasma cells that produce a multimeric IgM.

DC maturation

The phenotypic changes experienced by DCs that increase the expression of T cell co-stimulatory molecules, levels of antigen presentation and the production of T-cell stimulatory cytokines (IL12, IL2, IL23, IL15 and IFNγ).

Plasmacytoid DCs

A subpopulation of leukocytes that produce high amounts of type I IFN when detecting viral substances. Recently its expression of CD40 ligand seems to be important for activating conventional myeloid DCs. Their in vivo role in antigen presentation is not known.

Antibody-dependent cellular cytotoxicity

The NK and macrophage-mediated destruction of cells coated with antibodies that is triggered by Fc receptors expressed on the effector cells.

Complement

The set of serum proteins that is activated by antibodies bound to biological surfaces or by certain microbial moieties. Activated complement factors opsonize target cells and microrganisms for phagocytosis or cause osmotic cell lysis to form transmembrane pores.

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Melero, I., Hervas-Stubbs, S., Glennie, M. et al. Immunostimulatory monoclonal antibodies for cancer therapy. Nat Rev Cancer 7, 95–106 (2007). https://doi.org/10.1038/nrc2051

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