Genentech Oncology
We are continuing to advance the understanding of cancer immunotherapy by researching pathways that can be targeted simultaneously with the PD-L1/PD-1 pathway to address various immune escape mechanisms in cancer.
As a scientifically validated approach to reinvigorating the antitumor immune response, PD-L1 pathway inhibition has taken an important role in restoring a key part of the cancer immunity cycle.1
PD-L1=programmed death-ligand 1.
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.
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
*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.
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
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 to9-12
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 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
Targeting the MAPK pathway may help restore part of the cancer immunity cycle by exposing tumors through increased antigen presentation.18,19
*Tumor cell killing by CD8+ T cells.
TCR=T-cell receptor. MHC=major histocompatibility complex.
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.
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
Targeting VEGF may help restore part of the cancer immunity cycle by increasing T-cell infiltration into the tumor microenvironment.2,22-24
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.
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 ways1,2:
Certain classes of chemotherapy may help initiate the cancer immunity cycle by6,25
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.
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