Explore the PD-L1 Pathway

Tumor cells can escape the antitumor immune response in several ways

Tumor cells can evade the immune system by disrupting any of the key T-cell activities necessary to initiate and perpetuate an antitumor immune response: T-cell generation, T-cell infiltration, or tumor cell killing.^1-3

Disruption of any steps of the cancer immunity cycle can ultimately result in tumor growth.²

*Tumor cell killing by CD8+ T cells.

PD-L1 may need to be targeted simultaneously with other pathways to restore the cancer immunity cycle

As a key immunosuppressive driver, the PD-L1 pathway is an important target that can help invigorate antitumor T-cell activity in the tumor microenvironment.^1,4

• PD-L1 inhibition can help restore tumor cell killing⁴*

1. In cancer, the PD-L1 ligand is expressed on tumor cells and immune cells. When bound to its receptors, PD-1 and B7.1 on T cells, PD-L1 deactivates cytotoxic T cells
2. PD-L1 inhibition prevents T-cell deactivation
3. Reinvigorated T cells can then attack and kill tumor cells

*Tumor cell killing by CD8+ T cells.

However, cancers may use multiple immune escape mechanisms. Targeting PD-L1 simultaneously with other pathways may be necessary to restore a fully functional cancer immunity cycle.¹

We are actively researching pathway combinations with PD-L1.⁵

PD-L1=programmed death-ligand 1; VEGF=vascular endothelial growth factor.

Understanding the MAPK pathway as it relates to oncology

The mitogen-activated protein kinase (MAPK) pathway plays a role in the regulation of gene expression, cellular growth, and survival.⁷ Abnormal MAPK signaling may lead to increased or uncontrolled cell proliferation and resistance to apoptosis.⁸

Research into the MAPK pathway has shown it to be important in some cancers.⁸

What happens when MAPK signaling goes awry?

Dysregulated MAPK signaling is implicated in a wide range of cancers and occurs via multiple mechanisms, including abnormal expression of pathway receptors and/or genetic mutations that lead to activation of receptors and downstream signaling molecules in the absence of appropriate stimuli.^8,9

Abnormal MAPK signaling may lead to^9-12

• Increased or uncontrolled cell proliferation
  
• Resistance to apoptosis (programmed cell death)
• Resistance to chemotherapy, radiotherapy, and targeted therapies

Dysregulated MAPK signaling is implicated in a number of tumor types⁸

Overactivation of MAPK signaling by oncogenic BRAF occurs in multiple malignancies, making it a potential target in oncology.⁸ These malignancies include some melanoma tumors, papillary thyroid tumors, serous ovarian tumors, and colorectal tumors:

The MAPK pathway is an emerging target in cancer immunotherapy research

The mitogen-activated protein kinase (MAPK) pathway regulates cell growth, proliferation, and differentiation.^16,17

Emerging research has found MAPK pathway signaling can also disrupt a key step in the cancer immunity cycle: cancer cell recognition.^3,18

MAPK inhibition can increase tumor cell recognition

Targeting the MAPK pathway may help restore part of the cancer immunity cycle by exposing tumors through increased antigen presentation.^18,19

1. MAPK pathway inhibition upregulates major histocompatibility complex (MHC) class 1 expression, which can increase antigen presentation on the surface of tumor cells for recognition by CD8+ T cells
2. T cells are then able to recognize and kill tumor cells*

*Tumor cell killing by CD8+ T cells.
TCR=T-cell receptor. MHC=major histocompatibility complex.

Targeting MAPK pathway and PD-L1 may have a synergistic effect on restoring the body's antitumor immune response

Inhibition of the MAPK and PD-L1 pathways is a rational approach that may help invigorate T-cell activity against tumor cells.^19,20

Genentech is actively researching the combination of MAPK pathway inhibition and PD-L1 inhibition in various tumor types.⁵

PD-L1=programmed death-ligand 1.
*Tumor cell killing by CD8+ T cells.

VEGF can suppress the antitumor immune response

Vascular endothelial growth factor (VEGF) promotes vascularization, which is often exploited by tumors to stimulate angiogenesis needed for tumor growth and metastasis.²¹

VEGF also has the ability to disrupt a key step in the cancer immunity cycle: T-cell infiltration into the tumor.^1,2,22

VEGF inhibition may help T cells infiltrate the tumor microenvironment

Targeting VEGF may help restore part of the cancer immunity cycle by increasing T-cell infiltration into the tumor microenvironment.^2,22-24

1. VEGF pathway inhibition may lead to increased expression of cell adhesion molecules on endothelial cells, facilitating T-cell infiltration
2. Increased intratumoral T cells help create an inflamed tumor microenvironment

Targeting VEGF and PD-L1 may have a synergistic effect on restoring antitumor activity

Inhibition of the VEGF and PD-L1 pathways is a rational combination with the potential for enhancing immune responses. The effects of VEGF inhibition can create an inflamed tumor microenvironment that is optimized for PD-L1 inhibition.^1,3,23

We are actively researching the combination of VEGF inhibition and PD-L1 inhibition in various tumor types.⁵

PD-L1=programmed death-ligand 1.
*Tumor cell killing by CD8+ T cells.

Tumor antigen release is a critical step in initiating the cancer immunity cycle

The cancer immunity cycle can be initiated when tumor antigens from dying tumor cells are released and are captured by dendritic cells (DCs) to activate CD8+ T cells.²

Tumors may escape the immune response by disrupting the generation of active T cells in various ways^1,2:

• Tumors with low mutation burden release fewer diverse antigens that may result in poor tumor immunogenicity
• Tumors can inhibit the maturation of DCs, which are needed to activate cytotoxic T cells

Chemotherapy-induced cell death can help initiate the antitumor immune response

Certain classes of chemotherapy may help initiate the cancer immunity cycle by^6,25

1. Increasing tumor antigen release, which
2. Stimulates DC recruitment and maturation, leading to
3. T-cell priming

Combining this effect with PD-L1 inhibition may help perpetuate the antitumor immune response

The release of tumor antigens can ultimately result in activated T cells reaching the tumor microenvironment. PD-L1 inhibition may help maintain this effect by preventing T-cell deactivation, leading to T cells attacking the tumor and the release of additional tumor antigens.^2,3,6,26

We are researching the synergistic potential of increasing antigen release and targeting PD-L1 in various tumor types.⁵

PD-L1=programmed death-ligand 1.