Efficacy and safety of agents targeting these pathways are currently under investigation. Regulatory approval of any of these agents is dependent upon completion of the study programs and regulatory review by authorities. The clinical trial information is available at www.clinicaltrials.gov. This information is current as of April 2017.
PD-1 (programmed death-1) is a checkpoint protein found on T-cells that helps keep the immune response in check. When PD-1 binds to another protein called PD-L1 (programmed death ligand-1), it helps keep T-cells from killing other cells, including cancer cells. Blockade of PD-1 with a checkpoint inhibitor may increase the ability of T-cells to kill cancer cells.1
PD-L1 (programmed death ligand-1) is a checkpoint protein that binds to a protein called PD-1 (programmed death-1) to help keep the immune response in check. The PD-L1/PD-1 pathway involves both innate and adaptive immune systems.1,2 Tumors may engage both of these systems to evade detection.3 Blockade of the PD-1/PD-L1 interaction may restore the ability of the adaptive immune system to recognize and eliminate tumor cells via T-cell-mediated respones.4-6
The CTLA-4 (cytotoxic T-lymphocyte–associated antigen-4) checkpoint pathway is involved in suppressing T-cell immune function. Inhibition of this pathway may result in increased activation of the immune system. CTLA-4 is believed to stop potentially reactive T-cells at their initial stage of activation, typically in the lymph nodes.1
The 4-1BB receptors are found on certain T-cells (primarily on CD8+, but also on CD4+ memory T- cells) and natural killer (NK) cells.1,2 Molecules that bind to 4-1BB receptors have been shown to stimulate and increase the number of immune cells. This may help augment anti-tumor immune function.1
The OX40 protein is found mostly on T-cells (primarily CD4+ and CD8+ memory T-cells) that have recently been exposed to antigens. When an OX40 agonist, or activator, binds to the OX40 protein receptor, it triggers a co-stimulatory signal that is associated with an increased production of T-cells and inflammatory cytokines. This mechanism may activate dormant immune settings, which may then help fight cancer cells.1
High levels of the enzyme IDO1 (indoleamine-2,3 dioxygenase 1) can be found in the tumor microenvironment and draining lymph nodes. IDO1 may induce immunosuppression through degradation of the amino acid tryptophan (an important regulator of innate and adaptive immunity) in the tumor microenvironment and downstream inhibition of T-cell responses.1 Targeting IDO1 may have the potential to reverse cancer-induced immunosuppression.
The MCSF (macrophage colony-stimulating factor) pathway appears to be involved in regulating processes such as tumor angiogenesis, or new blood vessel formation, and metastases. The MCSF pathway may also induce expression of VEGF (vascular endothelial growth factor), a protein that signals the induction of angiogenesis.1 Inhibition of the MCSF pathway may have the potential to counter tumor growth and progression.
BCMA (B cell maturation antigen) is a member of the tumor necrosis factor receptor super family,1 which can cause cell death in some tumor types.2 BCMA binds to B-cell-activating factor and a ligand (molecule on the cell surface) that stimulate cell growth. By bioengineering T-cells to express chimeric antigen receptors that recognize the tumor-associated antigens BCMA, it may be possible to disrupt growth and multiplication of cancer cells.1
Monoclonal antibodies, or mAbs, are proteins made in the laboratory that can bind to substances in the body such as cancer cells. There are many different types of monoclonal antibodies, and each is made to bind to only one substance, or antigen. Monoclonal antibodies may help treat cancer or carry drugs, toxins, or radioactive substances directly to cancer cells.1
Targeting P-cadherin with a bispecific antibody is a novel anti-tumor approach. Bispecific antibodies contain specialized fragments of two antibodies, to address two different cancer targets with the same molecule. A bispecific can target a tumor cell with one of its fragments (directed against P-cadherin in this case) and cause co-localization of another cell/particle/protein via its other antibody fragment (directed against CD3 in this case, thus bringing a cytotoxic T-cell into proximity).1 Targeting P-cadherin–bearing cells may inhibit tumor cell invasion and proliferation.2,3
CAR-T (chimeric antigen receptor T-cell therapy) cells are bioengineered T-cells collected from a patient’s own blood (autologous) or a donor’s blood (allogeneic). Collected T-cells are modified so that engineered chimeric antigen receptors are expressed, which can then interact with specific tumor antigens to activate an immune response. CAR-T cells are then multiplied and infused into the bloodstream1,2 CAR-T cells are designed to kill cancer cells with the targeted antigen, while continuing to multiply in the body.2
An oncolytic virus is bioengineered to selectively infect and kill cancer cells but not healthy cells. Although an oncolytic virus can enter normal cells and cancer cells alike, normal cells have mechanisms to kill the virus, while cancer cells do not. As the virus replicates, it causes cancer cells to burst and die. The dying cells release new viruses, GM-CSF, and tumor-specific antigens to stimulate an immune response.1 Oncolytic viruses may help make it easier to kill tumor cells with radiation or chemotherapy.2
GM-CSF=granulocyte macrophage colony-stimulating factor.
In VBIRs (vaccine-based immunotherapy regimens), a cancer vaccine may work synergistically with an immunotherapy to induce an immune response.1 Cancer vaccines activate cell-killing T-cells and direct them to recognize and act against specific types of cancer. To accomplish this, vaccines introduce one or more cancer-specific antigens into the body, where they induce an immune response that results in T-cell activation or antibody production.2 Immunotherapy with a checkpoint inhibitor may boost the immune response induced by a cancer vaccine.1
The CXCR4 (C-X-C chemokine receptor 4) pathway is thought to play an important role in signaling the movement of cells during inflammation. When a molecule, or ligand, known as CXCL12 binds to CXCR4 receptors in tumor cells, the result can be cell growth, migration, and invasion, resulting in metastases. Therefore, blocking the interaction between CXCL12 and CXCR4 may hinder cancer progression.1
Our strategy is built on the depth and breadth of our portfolio:
- We have robust capabilities in developing traditional compounds, including small molecules and monoclonal antibodies
- We focus on the novel use of cutting-edge technologies in the development of CAR-T cells, IO vaccines, oncolytic viruses, and bispecific antibodies
- We have a broad array of compounds at various stages of clinical development Explore the IO assets in our product pipeline
OUR R&D PROGRAM
We are making significant contributions to the science of IO with research and development efforts that span diverse modalities and mechanisms of action.
We see our R&D program as being in a strong position to help advance IO science, because we are the company with the most advanced IO pipeline that includes a PDL-1, 4-1BB, and OX40 agent. As of April 2017, we have 11 compounds in ongoing IO clinical trials. We are committed to going wherever the science leads.
In addition to our IO assets, we are also exploring a broad range of antibody-drug conjugates (ADCs) and small molecules in various combinations.
OVERVIEW OF OUR IO CLINICAL TRIALS PROGRAM*
Click below to see all of the IO combinations we’re investigating.
PD-L1 Monoclonal Antibodies BackBone
Combinations with Pfizer IO agents
|⚪||4-1BB agonist||∇||CCR2 inhibitor||∇||VBIR|
|⚪||OX40 agonist||⚪||MCSF inhibitor||∇||IDO1 inhibitor|
Combinations with Pfizer targeted agents
|⚪||ALK inhibitor||⚪||PARP inhibitor||∇||
Combinations developed through external collaborations
|⚪||CCR4 inhibitor||∇||hulL agonist||∇||Cancer vaccine|
|⚪||CD20 inhibitor||∇||FAK inhibitor||∇||HDAC inhibitor|
⚪ Ongoing studies
∇ Planned studies
*Efficacy and safety of agents targeting these pathways are currently under investigation. Regulatory approval of any of these agents is dependent upon completion of the study programs and regulatory review by authorities. The clinical trial information is available at www.clinicaltrials.gov. This information is current as of April 2017.
OUR GLOBAL FOCUS
Meet the hard-working scientists behind Pfizer’s next generation of investigational IO molecules and find out what they’re working on.
The people behind the science
Pfizer Oncology researchers discuss their work.
Pfizer Talks Possibilities
Taking the temperature of immuno-oncology.
Barbra Sasu on re-engineering T-cells to fight cancer
Vice President, CAR-T
Jean-Francois Martini on harnessing the immune system to fight tumors
Senior Director, Early Development, Translational and Immuno-Oncology
We’re attempting to speed our ability to bring breakthroughs to patients with cancer by bringing forward various potential opportunities and IO combinations very rapidly.