Immue Checkpoint Inhibitors -- Cancer Therapy

Immune checkpoints are molecules in the immune system that either turn up a signal (co-stimulatory molecules) or turn down a signal. Many cancers protect themselves from the immune system by inhibiting the T cell signal. Since around 2010 inhibitory checkpoint molecules have been increasingly considered as new targets for cancer immunotherapies due to the effectiveness of two checkpoint inhibitor drugs that were initially indicated for advanced melanoma - Yervoy, from Bristol-Myers Squibb, and Keytruda, from Merck.

An example: PD-1 is a checkpoint protein on immune cells called T cells. It normally acts as a type of "off switch" that helps keep the T cells from attacking other cells in the body. It does this when it attaches to PD-L1, a protein on some normal (and cancer) cells. When PD-1 binds to PD-L1, it basically tells the T cell to leave the other cell alone. Some cancer cells have large amounts of PD-L1, which helps them evade immune attack. Monoclonal antibodies that target either PD-1 or PD-L1 can boost the immune response against cancer cells and have shown a great deal of promise in treating certain cancers.

Stimulatory checkpoint molecules

Four stimulatory checkpoint molecules are members of the tumor necrosis factor (TNF) receptor superfamily - CD27, CD40, OX40, GITR and CD137. Another two stimulatory checkpoint molecules belongs to the B7-CD28 superfamily - CD28 itself and ICOS.

CD27. This molecule supports antigen-specific expansion of naïve T cells and is vital for the generation of T cell memory. CD27 is also a memory marker of B cells. CD27's activity is governed by the transient availability of its ligand, CD70, on lymphocytes and dendritic cells.[3] CD27 costimulation is known to suppresses Th17 effector cell function. The American biotech company Celldex Therapeutics is working on CDX-1127, an agonistic anti-CD27 monoclonal antibody which in animal models has been shown to be effective in the context of T cell receptor stimulation.

CD28. This molecule is constitutively expressed on almost all human CD4+ T cells and on around half of all CD8 T cells. Binding with its two ligands are CD80 and CD86, expressed on dendritic cells, prompts T cell expansion. CD28 was the target of the TGN1412 'superagonist' which caused severe inflammatory reactions in the first-in-man study in London in March 2006.

CD40. This molecule, found on a variety of immune system cells including antigen presenting cells has CD40L, otherwise known as CD154 and transiently expressed on the surface of activated CD4+ T cells, as its ligand. CD40 signaling is known to 'license' dendritic cells to mature and thereby trigger T-cell activation and differentiation. A now-defunct Seattle-based biotechnology company called VLST in-licensed an anti-CD40 agonist monoclonal antibody from Pfizer in 2012. The Swiss pharmaceutical company Roche acquired this project when VLST was shut down in 2013.

CD122. This molecule, which is the Interleukin-2 receptor beta sub-unit, is known to increase proliferation of CD8+ effector T cells. The American biotechnology company Nektar Therapeutics is working on NKTR-214, a CD122-biased immune-stimulatory cytokine

CD137. When this molecule, also called 4-1BB, is bound by CD137 ligand, the result is T-cell proliferation. CD137-mediated signaling is also known to protect T cells, and in particular, CD8+ T cells from activation-induced cell death. The German biotech company Pieris Pharmaceuticals has developed an engineered lipocalin that is bi-specific for CD137 and HER2.

OX40. This molecule, also called CD134, has OX40L, or CD252, as its ligand. Like CD27, OX40 promotes the expansion of effector and memory T cells, however it is also noted for its ability to suppress the differentiation and activity of T-regulatory cells, and also for its regulation of cytokine production. OX40's value as a drug target primarily lies it the fact that, being transiently expressed after T-cell receptor engagement, it is only upregulated on the most recently antigen-activated T cells within inflammatory lesions ] Anti-OX40 monoclonal antibodies have been shown to have clinical utility in advanced cancer. The pharma company AstraZeneca has three drugs in development targeting OX40: MEDI0562 is a humanised OX40 agonist; MEDI6469, murine OX4 agonist; and MEDI6383, an OX40 agonist.

GITR, short for Glucocorticoid-Induced TNFR family Related gene, prompts T cell expansion, including Treg expansion. The ligand for GITR is mainly expressed on antigen presenting cells. Antibodies to GITR have been shown to promote an anti-tumor response through loss of Treg lineage stability. The biotech company TG Therapeutics is working on anti-GITR antibodies.

ICOS. This molecule, short for Inducible T-cell costimulator, and also called CD278, is expressed on activated T cells. Its ligand is ICOSL, expressed mainly on B cells and dendritic cells. The molecule seems to be important in T cell effector function. The American biotechnology company Jounce Therapeutics is developing an ICOS agonist.

Inhibitory checkpoint molecules

PD-1, short for Programmed Death 1 (PD-1) PD-1 is a cell surface receptor that belongs to the immunoglobulin superfamily and is expressed on T cells and pro-B cells. PD-1 binds two ligands, PD-L1 and PD-L2.This checkpoint is the target of Merck & Co.'s melanoma drug Keytruda, which gained FDA approval in September 2014. An advantage of targeting PD-1 is that it can restore immune function in the tumor microenvironment.

CTLA-4, short for Cytotoxic T-Lymphocyte-Associated protein 4 and also called CD152, is the target of Bristol-Myers Squibb's melanoma drug Yervoy, which gained FDA approval in March 2011. Expression of CTLA-4 on Treg cells serves to control T cell proliferation.

A2AR. The Adenosine A2A receptor is regarded as an important checkpoint in cancer therapy because adenosine in the immune microenvironment, leading to the activation of the A2a receptor, is negative immune feedback loop and the tumor microenvironment has relatively high concentrations of adenosine.

B7-H3, also called CD276, was originally understood to be a co-stimulatory molecule but is now regarded as co-inhibitory. The American biotechnology company MacroGenics is working on MGA271 is an Fc-optimized monoclonal antibody that targets B7-H3.[26] B7-H3's receptors have not yet been identified.

B7-H4, also called VTCN1, is expressed by tumor cells and tumor-associated macrophages and plays a role in tumour escape.

BTLA. This molecule, short for B and T Lymphocyte Attenuator and also called CD272, has HVEM (Herpesvirus Entry Mediator) as its ligand. Surface expression of BTLA is gradually downregulated during differentiation of human CD8+ T cells from the naive to effector cell phenotype, however tumor-specific human CD8+ T cells express high levels of BTLA.

IDO, short for Indoleamine 2,3-dioxygenase, is a tryptophan catabolic enzyme with immune-inhibitory properties. Another important molecule is TDO, tryptophan 2,3-dioxygenase. IDO is known to suppress T and NK cells, generate and activate Tregs and myeloid-derived suppressor cells, and promote tumour angiogenesis. The American biotechnology companies Newlink Genetics and Incyte are working on IDO pathway inhibitors.

KIR, short for Killer-cell Immunoglobulin-like Receptor, is a receptor for MHC Class I molecules on Natural Killer cells. Bristol-Myers Squibb is working on Lirilumab, a monoclonal antibody to KIR.

LAG3, short for Lymphocyte Activation Gene-3, works to suppress an immune response by action to Tregs[34] as well as direct effects on CD8+ T cells ] Bristol-Myers Squibb is in Phase I with an anti-LAG3 monoclonal antibody called BMS-986016.

TIM-3, short for T-cell Immunoglobulin domain and Mucin domain 3, expresses on activated human CD4+ T cells and regulates Th1 and Th17 cytokines. TIM-3 acts as a negative regulator of Th1/Tc1 function by triggering cell death upon interaction with its ligand, galectin-9.

VISTA (C10orf54). Short for V-domain Ig suppressor of T cell activation, VISTA is primarily expressed on hematopoietic cells so that consistent expression of VISTA on leukocytes within tumors may allow VISTA blockade to be effective across a broad range of solid tumors.

Approved Drugs for Checkpoint Inhibition

Monoclonal antibodies that target either PD-1 or PD-L1 can boost the immune response against cancer cells and have shown a great deal of promise in treating certain cancers.

PD-1 inhibitors: Examples of drugs that target PD-1 include: Pembrolizumab (Keytruda), Nivolumab (Opdivo)

PD-L1 inhibitors:

An example of a drug that targets PD-L1 is:

Atezolizumab (Tecentriq)-- This drug can be used to treat bladder cancer, and is also being studied for use against other types of cancer.

In the Pipeline the PD-Li/PD-L1 inhibitor called MPDL3280A, which is being developed by Roche/Genentech and received "Breakthrough Therapy" designation from the FDA for bladder cancer in June 2014. It is in phase III testing for bladder cancer and non-small cell lung cancer, and is in phase I and II trials for melanoma, kidney cancer, lymphoma, and solid tumors. See Reference 3

MEDI4736, and is being developed by AstraZeneca/MedImmune. Through its Clinical Accelerator program, CRI sparked an innovative deal with its developer to bring MEDI4736 to patients. It is part of the growing repertoire of promising immunotherapies available for testing in our global cancer immunotherapy clinical trials network. MEDI4737 is in clinical trials for a number of cancers, including brain, cervical, colorectal, head and neck, kidney, lung, and ovarian cancers. - See more at Cancer Research

Drugs that target CTLA-4

CTLA-4 is another protein on some T cells that acts as a type of "off switch" to keep the immune system in check. Ipilimumab (Yervoy) is a monoclonal antibody that attaches to CTLA-4 and stops it from working. This can boost the body's immune response against cancer cells.

Costimulatory -- coihibitory molecules

TRX518, an anti-GITR antibody, being developed by GITR, Inc. TRX518 is designed to enhance the immune response by enabling T cells to be more effective in attacking cancer cells. It is in a phase I trial that is enrolling patients with melanoma or other solid tumors at Memorial Sloan Kettering Cancer Center, University Hospitals in Cleveland, and the Cleveland Clinic (NCT01239134). TRX518 is the first treatment of its kind ever to be tested in human cancer patients. Another GITR antibody is MK-4166, which is produced by Merck. It is in a phase I trial for solid tumors, which started in June 2014. - See more at Cancer Research

4-1BB, also known as CD137, is a costimulator for activated T cells. By serving as an agonist—a chemical that binds to a receptor and activates it to produce a biological response—the anti-4-1BB antibody stimulates the first wave of the anti-tumor reaction. -

There are two 4-1BB antibodies in development for a number of cancers: urelumab (BMS-663513), being developed by Bristol-Myers Squibb, and PF-05082566 (PF-2566), being developed by Pfizer.

Readings and References

1- What is a Checkpoint Inhibitor

2-Immune checkpoint inhibitors to treat cancer

3-Immune Checkpoint Inhibitors: What's Next?

4-Cancer immunotherapy: co-stimulatory agonists and co-inhibitory antagonists