Checkpoint Inhibitor Therapy Research

From genomic biomarker discovery and verification tools to protein biology and cell analysis products

A main focus of immuno-oncology research is investigating immune checkpoint pathway functionality in effector killing cells, such as CD8+ T cell and natural killer (NK) cells, which regulate both adaptive and innate immunity. By understanding what the effects of immune checkpoints are, therapies can be developed that help to maintain or boost the body’s innate immune response to attack cancer. Through the discovery and characterization of immune checkpoints, researchers and clinicians have been able to harness their potential as immunotherapies.

Updated Immuno-Oncology (I-O) guide snapshots

Updated Immuno‑oncology (I‑O) guide

Discover key I‑O research approaches, including checkpoint inhibitor therapy research, CAR T cell therapy research, and cancer vaccine therapy research.

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What is an immune checkpoint?

Cellular homeostasis and autoimmunity are regulated by the immune system’s remarkable ability to recognize self from non-self simultaneously.[1] This complex discrimination relies on the two-signal theory of immune activation, 1) T-lymphocytes recognize antigens presented by MHC molecules and 2) CD28 on T-cells interact with B7 (CD80/CD86) molecules on antigen presenting cells (APCs).[2-4] The secondary interaction helps regulate immune cell activation pathways through molecules know as immune checkpoint proteins. Immune checkpoints have been identified as players in cell signaling pathways that are crucial for maintaining a normal immune response and protecting tissues from damage. Tumor cells manipulate immune checkpoint proteins and use this as a mechanism of immune evasion and resistance, which is why they have become the focus of targeted immune therapies.[5] Checkpoint proteins can be stimulatory or inhibitory, but those targeted for treatment of cancer have primarily been inhibitory in nature.

The first immunotherapies to market were targeted to blocking the effects of cytotoxic T-Lymphocyte antigen 4 (CTLA-4), followed programmed cell death-1 (PD-1) (Figure 1). CTLA-4 signaling is mediated by its interaction and binding to CD80/86 and is a negative regulator of T cell activation and proliferation.[6] The blockage of those inhibitory effects can enhance the T-cell response, which has been demonstrated to be effective in cancers including melanoma, non-small cell lung, and squamous cell carcinomas.[7] While CTLA-4 acts as a negative regulator of proliferation, PD-1 acts as a negative regulator of apoptosis and is instrumental in maintaining a T cell immune response.[8] Cancer cell often can bind PD-1 through the expression of its ligand, preventing PD-1 from allowing T-cell expansion. Disrupting this blockade has also been an effective in the field of antibody therapies.

The precedent set by CTLA-4 and PD-1 has propelled the research community to continue the investigation of immune checkpoint pathways and proteins. Many are in clinical trials and being used in combination therapies. Thermo Fisher Scientific products and services supports those research and clinical therapy efforts from genomic biomarker discovery, to combination therapy, and cellular analysis.

Figure 1. Stages of the adapted cancer-immunity cycle that can be impacted by checkpoint immunotherapy.

Featured products

This pan-cancer gene expression assay is designed to interrogate the tumor microenvironment to enable mechanistic studies and identification of predictive biomarkers for immunotherapy.

Simplified, robust assays for analyzing DNA replication in proliferating cells compared to traditional BrdU methods

Designed for RNA and protein expression analysis as cells change over time or in response to stimuli; assay for RNA expression when no antibody is available

Explore our checkpoint inhibitor therapy solutions and technologies

Genomic biomarker discovery

Find tools for genomic biomarker discovery by interrogating the whole transcriptome.

Antibodies

Search our extensive portfolio of antibodies to key checkpoint markers, including:

Genomic biomarker verification

Find tools for genomic biomarker verification of well-understood checkpoint inhibitors and immune related genes.

Protein expression

Learn more about protein expression systems that are easy to use and designed to deliver high protein yields.

Additional assays

  • CellTrace assays—conduct proliferation measurements based on DNA synthesis or cellular metabolism parameters. Assays can report cell health, genotoxicity, and inhibition of tumor cell growth during drug development.
  • Click-iT EdU assays—provide a simplified, more robust assay for analyzing DNA replication in proliferating cells compared to traditional BrdU methods
  • PrimeFlow RNA assays—designed for RNA and protein expression analysis as cells change over time or in response to stimuli; assay for RNA expression when no antibody is available

Quantitative protein analysis

We offer quality Invitrogen immunoassays designed to help you easily quantify checkpoint protein biomarkers with confidence.

Singleplex quantitation of proteomic biomarkers

  • Validated ELISA kits—complete and ready to use, designed to enable accurate protein quantitation of immune-related cancer targets. We also offer simplified workflow and high-sensitivity options.
  • Robust, reliable microplate readers—from the original inventors of microplate readers, choose from a lineup of tried and true Thermo Scientific dedicated and multimode readers, all powered by the same intuitive SkanIt Software.
  • ProQuantum Immunoassays—when working with very limited sample volume, this unique platform offers high-sensitivity with a streamlined workflow, available with popular targets used in I/O research.

Multiplex quantitation of proteomic biomarkers

Immune cell functionality

Learn more about immune checkpoint proteins and immune cell functionality.

References

  1. Zinkernagel RM, Doherty PC. Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system. Nature. 1974 Apr 19;248(5450):701-2.
  2. Bretscher P, Cohn M. A theory of self-nonself discrimination. Science. 1970 Sep 11;169(3950):1042-9. PMID: 4194660.
  3. Reinherz EL. Revisiting the Discovery of the αβ TCR Complex and Its Co-Receptors. Front Immunol. 2014 Nov 21;5:583. doi: 10.3389/fimmu.2014.00583. eCollection 2014.
  4. Esensten JH, Helou YA, Chopra G, Weiss A, Bluestone JA. CD28 Costimulation: From Mechanism to Therapy. Immunity. 2016 May 17;44(5):973-88. doi:10.1016/j.immuni.2016.04.020.
  5. Marin-Acevedo JA, Dholaria B, Soyano AE, Knutson KL, Chumsri S, Lou Y. Next generation of immune checkpoint therapy in cancer: new developments and challenges. J Hematol Oncol. 2018 Mar 15;11(1):39. doi: 10.1186/s13045-018-0582-8.
  6. Love PE, Hayes SM. ITAM-mediated signaling by the T-cell antigen receptor. Cold Spring Harb Perspect Biol. 2010 Jun;2(6):a002485. doi: 10.1101/cshperspect.a002485. Epub 2010 Apr 28.
  7. Siedel JA, Otsuka A, Kabashima K. Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations. Front Oncol. 2018 Mar;8:86. doi: 10.3389/fonc.2018.00086.
  8. Sun C, Mezzadra R, Schumacher TN. Regulation and Function of the PD-L1 Checkpoint. Immunity. 2018 Mar 20;48(3):434-452. doi: 10.1016/j.immuni.2018.03.014.

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