Enhancement of Antitumor Immunity by CTLA-4 Blockade

  title={Enhancement of Antitumor Immunity by CTLA-4 Blockade},
  author={Dana R. Leach and Matthew F. Krummel and James P. Allison},
  pages={1734 - 1736}
One reason for the poor immunogenicity of many tumors may be that they cannot provide signals for CD28-mediated costimulation necessary to fully activate T cells. [] Key Result Here, in vivo administration of antibodies to CTLA-4 resulted in the rejection of tumors, including preestablished tumors. Furthermore, this rejection resulted in immunity to a secondary exposure to tumor cells. These results suggest that blockade of the inhibitory effects of CTLA-4 can allow for, and potentiate, effective immune…

[The role of co-inhibitory signals driven by CTLA-4 in immune system].

To better understand the promising future and the limits of this immunotherapy, this review dissects the molecular inhibitory mechanisms induced by CTLA-4 in T cells.

CTLA-4 and PD-1 Control of T-Cell Motility and Migration: Implications for Tumor Immunotherapy

Data implicating CTLA-4 and PD-1 in the motility of T-cells is reviewed with a specific reference to the potential exploitation of these pathways for more effective tumor infiltration and eradication.

Two Distinct Mechanisms of Augmented Antitumor Activity by Modulation of Immunostimulatory/Inhibitory Signals

This study shows that combined treatment with different immune modulators can augment antitumor immune responses and provides justification for exploring anti-CTLA-4/anti-GITR mAb combination treatment in the clinic.

The complexity of the B7-CD28/CTLA-4 costimulatory pathway.

In vivo studies indicate the therapeutic potential of manipulating this important, but complex, immunoregulatory pathway and reveal a previously unsuspected means by which costimulation is involved in the maintenance and breakdown of self-tolerance.

Immune response enhancement by in vivo administration of B7.2Ig, a soluble costimulatory protein.

Using a mouse model, this work suggests that soluble forms of human B7.2 protein may provide a straightforward and practical method of supplying optimal costimulation during clinical immunotherapy.

CTLA-4 Blockade Enhances the CTL Responses to the p53 Self-Tumor Antigen1

It was found that blockade of CTLA-4 engagement at the time of antigenic stimulation induced a vigorous amplification of the CTL responses to p53 as well as proportionate expansion of the memory T cell pool.

CTLA-4 blockade synergizes with tumor-derived granulocyte-macrophage colony-stimulating factor for treatment of an experimental mammary carcinoma.

The combination of both CTLA-4 blockade and a vaccine consisting of granulocyte-macrophage colony-stimulating factor-expressing SM1 cells resulted in regression of parental SM1 tumors, despite the ineffectiveness of either treatment alone.



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

Results suggest that B7 expression renders tumor cells capable of effective antigen presentation, leading to their eradication in vivo.

Specificity and longevity of antitumor immune responses induced by B7-transfected tumors.

It is found that the immunity induced by K1735 is not restricted to the parental tumor cells but is effective against an additional melanoma line and an unrelated fibrosarcoma as well and irradiation severely diminishes the effectiveness of B7-positive tumor cells as immunogens.

CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation

It is shown here that the presence of low levels of B7-2 on freshly explanted T cells can partially inhibit T cell proliferation, and this inhibition is mediated by interactions with CTLA-4, which strongly suggests that the outcome of T cell antigen receptor stimulation is regulated by CD28 costimulatory signals, as well as inhibitory signals derived from CTla-4.

CTLA4 mediates antigen-specific apoptosis of human T cells.

  • J. GribbenG. Freeman G. Gray
  • Biology, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 1995
It is demonstrated that cross-linking of the inducible T-cell surface molecule CTLA4 can mediate apoptosis of previously activated human T lymphocytes, and Regulation of this pathway may provide a novel therapeutic strategy to delete antigen-specific activated T cells.

Lymphoproliferative Disorders with Early Lethality in Mice Deficient in Ctla-4

Although CTLA-4-deficient T cells proliferated spontaneously and strongly when stimulated through the T cell receptor, they were sensitive to cell death induced by cross-linking of the Fas receptor and by gamma irradiation, and is vital for the control of lymphocyte homeostasis.

Constitutive expression of B7 restores immunogenicity of tumor cells expressing truncated major histocompatibility complex class II molecules.

The role of B7 activation molecule is illustrated in stimulating potent tumor-specific CD4+ T cells that mediate rejection of wild-type tumors and provides a theoretical basis for immunotherapy of established tumors.