The safety and efficacy of Celgene's CAR T cell therapies are under investigation and have not been established. There is no guarantee that these agents will receive health authority approval or become commercially available in any country for the uses being investigated.

Cancer Immune Response

Refresh your knowledge about the immune response to cancer, and how cancer can evade detection

CAR T Science

Learn about the science behind CAR T cell therapies

B Cell Malignancies

Learn about unmet needs in select B cell malignancies

CAR T Process

Learn what the CAR T therapy process may involve for you and your patients

The Immune System Response to Target Cells

Immunological surveillance is a monitoring process of the immune system to detect and attack infected and neoplastically transformed cells in the body.1

Key Players in Immune Surveillance

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1 B cells -

B cell development encompasses a continuum of stages that begin in the bone marrow, with subsequent functional maturation in secondary lymphoid tissue. They form part of the adaptive immune response and mediate humoral immunity. B cells can produce high-affinity antibodies and generate immunological memory.2

2 Dendritic cells +

Dendritic cells are antigen-presenting cells located in the skin, mucosa and lymphoid tissues. Their main function is to process and present antigens to T cells to promote immunity to foreign antigens and tolerance to self antigens. They also secrete cytokines to regulate immune responses.3

3 T cells +

T cell precursors develop in the bone marrow and migrate to the thymus, where they mature and differentiate into subtypes, including CD4+ T cells and CD8+ T cells. T cells can initiate or suppress immune responses, regulate T and B cell maturation and proliferation, and kill cells bearing a specific foreign antigen.4

4 Cytokines +

Cytokines are protein, peptide and glycoprotein signaling molecules, each with its own receptor on target cells. Lymphocytes and monocytes secrete cytokines, including interleukins, interferons and chemokines to regulate immune responses, hematopoiesis and lymphocyte development.5,6

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T Cell Subsets: A Promising Focus for Adoptive Cancer Immunotherapy

A fundamental principle of cancer immunology is that cancer cells express antigens that the immune system can recognize to target for cell elimination.7

While there are a number of key players in this continual process of tumor immunosurveillance, T cells play an important role. T cells normally function to eliminate the body’s own cells that are infected or have become cancerous.8

T cell subsets are defined by the cell-surface markers and transcription factors they express and the cytokines they secrete, and are grouped by function.9 Subsets that have been used in approved or investigational CAR T cell therapies include10-12:

  • CD4+ (helper) T cells
  • CD8+ (cytotoxic) T cells
  • Natural killer T (NKT) cells
  • Regulatory T (Treg) cells
  • Gamma-delta (γδ) T cells

T cell differentiation begins in the thymus, where the majority of immature cells express an alpha-beta (αβ) T cell receptor (TCR) and both CD4 and CD8 co-receptors.13 The αβ TCR is responsible for recognizing major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells.13

Co-receptor binding with MHC determines an immature T cell’s differentiation into two main lineages13:

  • CD4+ T cells result when the CD4 co-receptor binds to MHC class II, ceasing CD8 expression
  • CD8+ T cells result when the CD8 co-receptor binds to MHC class I, ceasing CD4 expression

Naïve CD4+ and CD8+ T cells may undergo further differentiation into various memory and effector subsets upon antigen recognition in peripheral tissues.14,15

CD4+ T cells

Known as “helper” T cells because they help initiate and regulate immune responses. Each differentiated CD4+ subset releases specific cytokines that can support other immune cells and promote or suppress immune reactions.14,15 CD4+ T cells help activate B cells to secrete antibodies and macrophages to attack ingested microbes. CD4+ T cells help activate CD8+ T cells to kill target cells.16 In pre-clinical studies, CD4+ T cells were also shown to support CD8+ T cell memory functions.14,17,18

CD8+ cells

Known as “cytotoxic” T cells because they are specialized to recognize and directly attack target cells.8 As naïve CD8+ T cells differentiate from memory to effector subtypes, they trade off persistence and proliferative potential for shorter-lived cytotoxic potential.14

CD8+ T cell differentiation

Adapted from Golubovskaya V, Wu L. Cancers. 2016;8:36. doi:10.3390/cancers8030036.14

Natural killer T (NKT) cells

An uncommon T cell subset, NKT cells combine innate and adaptive immunity characteristics of natural killer cells and T cells, displaying pronounced, intrinsic anti-tumor activity.9,13,14,19

Regulatory T (Treg) cells

A subset of either immature T cells or CD4+ T cells, Treg cells are responsible for inhibiting immune responses.10,13 In preclinical studies, Treg cells and their ratio to effector T cells were shown to impact the effectiveness of anti-cancer immunotherapy.14 Conversely, the immunosuppressive properties of Treg cells are being investigated for use in transplant rejection and various autoimmune disorders.20

Gamma-delta (γδ) T cells

A minority of immature T cells express a gamma-delta TCR, and possess both innate and adaptive immune cell qualities with broad and potent anti-tumor activity, and both pro- and anti-inflammatory functions.9,21 These unconventional T cells do not require antigen presentation by MHC molecules and do not recognize the same antigens as αβ T cells.21

SEE THE CONVENTIONAL TREATMENT STATISTICS IN B CELL MALIGNANCIES

T Cell Activation

Effective T cell activation requires two concurrent signals: an activation signal and a co-stimulatory signal

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1 Activation signal -

1. T cell activation
  • Dendritic cells capture antigens and present them to T cells.22
  • Once the antigen is recognized by the T cell receptor, an activation signal is sent through the T cell.22
  • Antigens processed by dendritic cells can be presented to both CD8+ and CD4+ T cells.22
  • In addition to antigen receptor signals (antigen recognition provides the first signal), signals from proteins called costimulatory receptors are needed (provides the second signal) for lymphocyte activation.8

2 Co-stimulatory signal +

2. T cell activation
  • Dendritic cells also signal to the T cells to proliferate and differentiate with one or more co-stimulatory signals.22
  • When specific molecules on the dendritic cell interact with receptors on the T cell, the dendritic cell sends a secondary signal that fully activates the T cell, signaling the T cell to proliferate and differentiate.22
  • Once antigen-specific effector CD8+ T cells have been generated, they are able to recognize and kill target cells without co-stimulation.8
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Tumor Strategies to Evade T Cell Immune Response

Lack of immunogenic molecules

Tumor cells are heterogeneous, and some of them do not express the molecules necessary to trigger an immune response. When the immune system first begins to attack a tumor, malignant cells without these targeted molecules are able to survive and proliferate undetectable by T cells.22

Expression of negative co-stimulatory molecules

Tumors may express negative co-stimulatory molecules that inhibit T cell activation.22

Impaired antigen-presentation

Tumor cells may have genetic mutations that prevent proper antigen processing and presentation, making recognition by T cells difficult.22

Release of cytokines that impair T cell functioning

Tumor cells can establish an immunosuppressive state within the microenvironment by releasing various immunosuppressive cytokines that inhibit T cell activation.22

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Tumor Strategies to Evade T Cell Immune Response

1 LACK OF IMMUNOGENIC MOLECULES -
Tumor cells are heterogeneous, and some of them do not express the molecules necessary to trigger an immune response. When the immune system first begins to attack a tumor, malignant cells without these targeted molecules are able to survive and proliferate undetectable by T cells.22
2 EXPRESSION OF NEGATIVE CO-STIMULATORY MOLECULES +
Tumors may express negative co-stimulatory molecules that inhibit T cell activation.22
3 IMPAIRED ANTIGEN PRESENTATION +
Tumor cells may have genetic mutations that prevent proper antigen processing and presentation, making recognition by T cells difficult.22
4 RELEASE OF CYTOKINES THAT IMPAIR T CELL FUNCTIONING +
Tumor cells can establish an immunosuppressive state within the microenvironment by releasing various immunosuppressive cytokines that inhibit T cell activation.22

Tumor Evasion Strategies Can Contribute to Relapse and Treatment Resistance

In many cancer types, target cells are genetically diverse at diagnosis. Initial treatment with chemotherapy suppresses or kills the most aggressively multiplying cells but often leaves behind target cells with genetic mutations that allow them to continue multiplying despite ongoing therapy.23 While there have been significant advances in cancer treatment over the past 20 years, there is still a need for additional treatment approaches.

References:

  1. Swann JB, Smyth MJ. J Clin Invest. 2007;117:1137-1146.
  2. LeBien TW, Tedder TF. Blood. 2008;112:1570-1580.
  3. Nature. Accessed November 21, 2018.
  4. Janeway CA Jr, Travers P, Walport M, Shlomchik MJl. Immunobiology. 5th ed. 2001;258.
  5. Nature. Accessed November 21, 2018.
  6. Showalter A, Limaye A, Oyer JL, et al. Cytokine. 2017;97:123-132.
  7. Finn OJ. Ann Oncol. 2012;23:viii6-viii9.
  8. Abbas AK, Lichtman AH, Pillai S. Cellular and Molecular Immunology. 9th ed. Philadelphia, PA: Saunders Elsevier; 2018.
  9. Dong C, Martinez GJ. Nat Rev Immunol. 2010. Poster.
  10. News release. Silver Spring, MD: Food and Drug Administration; October 18, 2017. Accessed January 11, 2019.
  11. ClinicalTrials.gov. Accessed September 29, 2018.
  12. News release. Osaka, Japan: TC BioPharm; February 7, 2018. Accessed September 29, 2018.
  13. ThemoFisher. Accessed September 29, 2018.
  14. Golubovskaya V, Wu L. Cancers. 2016;8:36. doi:10.3390/cancers8030036.
  15. Luckheeram RV, Zhou R, Verma AD, et al. Clin Dev Immunol. 2012;2012:925135.
  16. Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th ed. 2002;1589.
  17. Shedlock DJ, Shen H. Science. 2003;300:337-339.
  18. Laidlaw BJ, Craft J, Kaech SM. Nat Rev Immunol. 2016;16:102-111. doi:10.1038/nri.2015.10.
  19. Simon B, Wiesinger M, März J, et al. Int J Mol Sci. 2018;19:2365.
  20. News release. Richmond, CA: Sangamo Therapeutics; October 1, 2018. Accessed February 12, 2019.
  21. Wu YL, Ding YP, Tanaka Y, et al. Int J Biol Sci. 2014;10:119-135.
  22. Maus MV, Levine BL. Oncologist. 2016;21:608-617.
  23. Hunger SP, Mullighan CG. N Engl J Med. 2015;373:1541-1552.

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