GITR: A Target to Enhance Antitumor Immune Response in Cancer

GITR receptor

TCR

The immune system plays a significant role in the recognition and destruction of cancer cells

The immune system plays a central role in host protection, guarding against both exogenous and endogenous threats,

including the recognition of cancer cells and providing anti-tumor defenses.1 However, the immune system will inevitably lose the ability to identify and destroy nascent tumors, as tumors continually adapt in order to evade surveillance, recognition and destruction by the immune system. To that end, tumors that grow sufficiently to be detected have by some mechanisms escaped eradication by the immune system.

One critical component of the immunological response to cancer cells is dependent on a robust T effector cell response that is specifi c for tumor associated-antigens.2 Effective T cell activation, a consequence of both receptor-antigen-major histocompatibility complex (MHC) binding and engagement of co-stimulatory molecules, is required to drive a strong immune response. The glucocorticoid-induced tumor necrosis factor-related protein, or GITR, is a key modulator of T cell response, an important part of the anti-tumor activities of the immune system. Research to validate the role of GITR as an important co-stimulatory molecule that enhances anti-tumor actions of effector T cells is ongoing.

Mature T cell

Dendritic cell

Tumor cell

T reg cell

Tumors use multiple mechanisms to evade immune destruction

While the exact mechanisms by which tumors evade immune detection are not yet fully understood, there is abundant

evidence that confers the importance of immune surveillance, and the need for therapeutic strategies to enhance host immune defenses for eradication of tumors. Despite ongoing surveillance by T cells and other components of the immune system, tumors develop and grow even in the presence of an intact immune system and eventually become clinically detectable.1

Dendritic cell

Tumor cell

Naïve T cell

Inhibition of T cell priming by interleukins

Dendritic cells may not recognize antigens as targets for destruction

The immune response to cancer cells can be inhibited or abrogated for a variety of reasons.3 For example, tumor antigens may not be properly detected, or may be inappropriately recognized as “self” by dendritic cells (DCs) and T cells, inhibiting production of a robust immune response. Certain interleukins and other molecules can inhibit T cell priming and activation, further diminishing the likelihood of effective response by the immune system. Furthermore, T cells may not localize to or properly infi ltrate tumors effectively, and may be unavailable to provide cytotoxic antitumor effects. Suppressive factors within the tumor microenvironment can also inhibit effector cells that manage to access the tumor, additionally abrogating the immune response. The terminal consequence of these varied immune events is that host immune functions ultimately fail to detect and control tumor growth.

Mature T cell

T reg cells

Suppressive factors within the tumor microenvironment may inhibit effector cells that manage to access the tumor

Approaches that modulate the immune system may improve the immune response to cancer

The cancer-immunity cycle illustrates the complex interactions that occur between the immune system and cancer that result

in effective killing of cancer cells.3 To exploit the potential benefits of the immune response, an appreciation of the immune system is essential. Tumor antigens or neoantigens on tumor cells are released and subsequently taken up by DCs. These antigens are processed and presented to T cells on MHC I and II molecules, consequently leading to the priming and activation of the T cells. T cell immune responses are a result of a balance between stimulatory and inhibitory signals. The ratio of T effector cells to T regulatory cells is one of many factors that determines the outcome of the anti-tumor immune response.

Naïve T cell

Tumor apoptosis

Dendritic cell

Tumor cell

Priming of T cells

Antigens

Tumor antigens are taken up by dendritic cells

Mature T cell

Infi ltration of T cells into tumors

In response to signaling through various molecules, activated effector T cells migrate to and subsequently infi ltrate a tumor, where they bind specifi cally to tumor cells as T cell receptors recognize tumor antigens.3 These activated cytotoxic T effector cells kill the tumor cells to which they are bound, triggering the release of additional tumor cell antigens, thus further driving the cancer-immunity cycle.

Understanding the mechanisms by which tumor surveillance occurs, and how these mechanisms ultimately fail, may guide approaches to tumor immune therapy. Effective cancer immunotherapies act to help the immune system overcome the mechanisms of tumor evasion that impair the immune response. Thus, agents that act to promote ongoing immunity may hold promise in the management of cancer.

Co-stimulatory molecules infl uence the T cell response

GITR receptor

GITR ligand

GITR enhances T cell stimulation while suppressing T reg cell activity and increasing anti-tumor immune response

T he success of immune checkpoint inhibitors has driven investigations for other agents that enhance the

anti-tumor immune response. One avenue of exploration that may have value is the activation of co-stimulatory pathways.4 The tumor necrosis factor receptor superfamily, or TNFRsf, is involved in a host of critical functions that infl uence B and T cell development, survival, immune activation, as well as modulating the immune antitumor response, and act by stimulating activation and pro-infl ammatory pathways. TNFRsf includes several molecules that are co-stimulatory proteins known to play key roles in immunomodulation. One TNFRsf member, GITR, is an important stimulatory protein that affects T cell activation.5

Reduced T cell response due to absence of GITR-GITRL interaction

Dendritic cell

NaïveT cell

TCR

MHC 1

GITR (CD357) is expressed at very low levels on resting CD4+ and CD8+ T cells, but it is up-regulated upon stimulation. However, in T regulatory cells (T regs) GITR is constitutively expressed. GITR is also present on DCs, monocytes, and natural killer cells.4 GITR ligand (GITRL) is a type 2 transmembrane protein, as is typical for most TNF ligand family members. GITRL is expressed at high levels on activated antigen presenting cells (APCs) and endothelial cells, and on activated T cells.6 Interactions between GITR on T cells and its ligand GITRL on APCs are bi-directional—both cell types are infl uenced by the interaction—ultimately resulting in T cell proliferation.5,6 Binding of GITR to GITRL triggers signaling which co-stimulates both CD8+ and CD4+ effector T cells, leading to enhanced T cell expansion and effector function, while suppressing the activity of T reg cells. GITR co-stimulation promotes the transition of anergic, hypoproliferative T cells to a hyperproliferative state. This may translate into markedly enhanced T cell activation, leading to a more effective anti-tumor immune response.7

Preclinical data has shown that ligation of GITR modulates T regs, which causes a signifi cant diminution in the accumulation of suppressive cells within the tumor microenvironment.4,8 This ultimately promotes higher local effector T cell—T reg ratios, which leads to improved antitumor cytotoxic T cell function.

The interaction of GITR with GITRL promotes T cell proliferation and enhances T effector cell activation

MatureT cells

GITR: A target to enhance antitumor immune response in cancer

The immune system serves to protect the host by recognizing and eliminating foreign and abnormal cells, yet it ultimately fails to

effectively detect and destroy cancer cells. Tumors continually evolve and adapt in order to evade immune surveillance and destruction. The goal of immunotherapy in cancer is to assist the immune system to overcome the multiple mechanisms of evasion employed by cancer cells, permitting an effective host anti-tumor immune response leading to prolonged responses.3 The cancer-immunity cycle describes the mechanisms by which tumors and immune cells interact, and it highlights different points at which immuno-therapeutic approaches may be considered. GITR is a key stimulatory protein involved in the priming and activation of effector T cell responses.4

GITR receptor

Priming ofT cells

TCR

Tumor cell

Tumor apoptosis

GITR-GITRL interactions support effective anti-tumor immune responses, both by promoting expansion and activation of effector T cell populations and by suppressing T reg functions, which suppress immune activity. This critical step is vulnerable to pharmacologic interventions that may enhance the anti-tumor response. Modulation of co-stimulatory members of TNFRsf such as GITR represents a promising approach to immunotherapy and may allow for elucidation of mechanisms by which tumor-specifi c immune responses may be enhanced.4

References1. Hanahan D, Weinberg RA. Cell. 2011;114:646–674. 2. Moran AE, Kovacsovics-Bankowski M, Weinberg AD. Curr Opin Immunol. 2013;25:230–237. 3. Chen DS, Mellman I. Immunity. 2013;39: http://dx.doi.org/10.1016/jimmuni.2013.07.012. 4. Schaer DA, Hirschhorn-Cymerman D, Wolchok JD. J Immunother Cancer. 2014;2:7.5. Schaer DA, Murphy JT, Wolchok JD. Curr Opin Immunol. 2012;24:217–224. 6. Chen L, Flies DB. Nat Rev Immunol. 2013;13:227–242. 7. Azuma M. Crit Rev Immunol. 2010;30:547–557. 8. Cohen AD, Schaer DA, Liu C et al. PLoS One. 2010;5;e10436.

Provided as an educational resource. Do not copy or distribute. ©2015 Amgen Inc. All rights reserved. USA-CRP-115065

This booklet contains forward-looking statements that are based on Amgen’s current expectations and beliefs and are subject to a number of risks, uncertainties, and assumptions that could cause actual results to differ materially from those described. All statements, other than statements of historical fact, are statements that could be deemed forward-looking statements. Forward-looking statements involve significant risks and uncertainties, including those more fully described in the Risk Factors found in the most recent Annual Report on Form 10-K and periodic reports on Form 10-Q and Form 8-K filed by Amgen with the U.S. Securities and Exchange Commission, and actual results may vary materially. Except where otherwise indicated, Amgen is providing this information as of November 15, 2015 and does not undertake any obligation to update any forward-looking statements contained in this booklet as a result of new information, future events, or otherwise.