elsaid - cancer immunotherapy

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24 Terms

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cell-based immune response against tumors

  • concept of immune system activated by antigens presented on surface of cancer cells

  • dendritic cells (DC) are professional antigen presenting cells and when they encounter cancer cells with antigens presented on their surface, they take up the tumor antigens

  • dendritic cells enter lymphatic tissues and mature —> mature DCs present antigens to T-cells

  • activated T-cells leave lymph nodes and migrate to tumor bearing antigens to destroy tumor cells

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mechanisms of immune evasion by tumors

tumors acquire immune tolerance

  • early in tumorigenesis, tumor cells can be classified as highly immunogenic or poorly immunogenic

  • immune response (innate and adaptive) removes the highly immunogenic cells and the remaining poorly immunogenic cells evade the immune system by:

    • downregulating genes encoding for proteins involved in antigen presentation on tumor cells

    • upregulating genes encoding for proteins that provide an immunosuppressive environment e.g. TFG-beta, IL-10

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types of tumor antigens

knowt flashcard image
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tumor-specific antigens

  • completely absent from normal cells

  • present in cancer cells from oncogenic viral proteins or as a result of a mutation

  • examples:

    • HPV-associated cancer of the cervix

    • KRAS mutations in different cancers (pancreatic, lung, and other cancers)

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tumor-associated antigens

  • low expression on normal cells

  • disproportionately expressed on tumor cells

  • examples:

    • EGFR and HER-2 over-expressing cancers

    • prostate cancers overexpressing prostate acid phosphate (PAP)

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classification of cancer immunotherapy

  • immune checkpoint inhibitors

  • monoclonal antibodies against cell surface markers

  • cell-based immunotherapy (adoptive cell transfer)

  • cytokines

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immune checkpoint: CTLA4

  • CTLA-4 is an immune checkpoint that prevents excessive stimulation of effector T-cells

  • effector T-cells express a number of co-stimulatory and co-inhibitor receptors

    • CTLA4 is a co-inhibitory receptor on T-cells

      • signal 1 (priming) is initiated when TAAs attached to MHC on APCs bind to the TCR

      • signal 2 (activating) is initiated by binding of B7 molecules on the APC to CD28 receptors on the T cell

      • signal 3 (inhibitory) results from CTLA-4 expression on the T-cell surface, where it competes with CD28 for binding to B7 on APCs

  • CTLA-4 limits T-cell responses early in an immune response, primarily in lymphoid tissues

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weak TCR signal

with a weak TCR signal, CD28:B7 binding predominates and a net positive activating signal, IL-2 production, cell proliferation, and enhanced survival

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strong TCR signal

with a strong TCR signal, CTLA4:B7 binding predominates and results in a net negative signal, reduced IL-2 production, reduced cell proliferation and cell survival

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Ipilimumab

  • CTLA-4 antibody — binding to CTLA-4 results in its neutralization and subsequent inhibition of effector T-cell inactivation

  • indicated for treatment of melanoma

    • well characterized family of melanoma associated antigens (MAGE) expressed in melanoma tissue and absent in normal tissues

  • ADEs and toxicity:

    • immune related adverse effects in the skin and GI due to immune enhancement

    • response to Ipilimumab can NOT be predicted based on objective biomarker level

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immune checkpoint: PD-1

  • Programmed Death 1 (PD-1) expressed on T-cells and bind to Programmed Death Ligands (PDL-1 or PDL-2)

  • PD-1 pathway regulates previously activated T cells at the later stages of an immune response, primarily in peripheral tissues

  • PD-1/PDL-1/2 is a co-inhibitory signal that results in inhibition of T cell activation, proliferation, and reduces T-cell survival

  • PD-1 ligands can be inducibly expressed by non immune cells, including tumor cells

  • tumors that over-express PDL-1/2 may be able to evade the immune response by inhibiting T-cell function at the level of the tumor microenvironment

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mechanisms of immune system evasion by tumors

  • ineffective presentation of tumor antigens to the immune system

  • recruitment of immunosuppressive cells

  • release of immunosuppressive factors

    • factors/enzymes directly or indirectly suppress immune response

  • T-cell checkpoint dysregulation

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PD-1/PD-L1 pathway

  • prolonged TCR (T cell receptor) stimulation during an ongoing immune response can cause upregulated PD-1 expression of T-cells

  • release of proinflammatory cytokines by T-cells upregulates PD-L1 expression by tumor cells or through oncogenetic mutations

  • PD-1/PD-L1 binding results in reduced T-cell proliferation, reduced proinflammatory cytokine production and reduced survival

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PD-1 inhibitors

  • Nivolumab (Opdivo)

  • Pembrolizumab (Keytruda)

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PD-L1 inhibitors

Durvalumab (Imfinzi)

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predictive marker for response to PD-1 and PDL-1 inhibitors

  • tumor PD-L1 expression can be used a s a predictive marker for response to the use of PD-1 and PD-L1 inhibitors

  • PD-L1 is used as a marker to determine patient eligibility to receive these treatments

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immune related ADEs — CTLA-4 vs PD-1 and PD-L1

higher prevalence w/ CTLA-4 b/c it’s non-specific in stimulating immune response in lymph nodes at cancer cells and other normal cells

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combined CTLA-4 and PD-1/PD-L1 treatment

  • CTLA-4 pathway blockade allows more activation of T-cells in the lymph nodes and inhibits T-reg function

  • PD-1 pathway blockade restores the activity of anti-tumor T-cells at tumor site

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monoclonal antibodies against cancer cell surface markers

Rituximab (chimeric) and Ofatumumab (fully human)

  • binding to CD20 on surface of malignant B-cell results in:

    • apoptosis

    • antibody-dependent cell-mediated cytotoxicity (ADCC)

    • complement-dependent cytotoxicity

  • Rituximab: the R in R-CHOP for B cell Non-Hodgkin’s Lymphoma

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combining immunotherapy and radiotherapy: antibody-radionuclide conjugates

90Y-Ibritumomab

  • Ibritumomab — mouse monoclonal antibody against CD20 (similar target of Rituximab)

  • Tiuxetan — a linker-chelator that is covalently attached to the Mab and provides a high affinity chelating site for 90Y

  • 90Y (Yttrium-90) — pure β radiation/particle emitter with a half-life of 64 hrs

    • β rays can penetrate soft tissues up to 4 mm

    • β radiation is a class of ionizing radiation that damages DNA resulting in DNA strand breaks

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adoptive cell transfer — engineered T-cells

Tisagenlecleucel — cell based therapy for diffuse large B cell lymphoma

  • extracellular domain — antigen-recognition (antibody to antigen)

  • intracellular domain — when antigen binds to the extracellular domain, signaling by intracellular domain results in T cell activation and cancer cell destruction

  • CAR-T (Chimeric Antigen Receptor)-T cells:

    • re-engineer patient’s own T-cells to recognize a specific cancer antigen

  • transduction of the engineered antigen receptor into the patient's T cell is achieved using a virus

    • patient’s T-cells now express a CAR against CD19

    • when cells are re-infused into the patient, cells are now programmed to recognize CD19 and destroy CD19 bearing cells

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interleukin-2 (IL-2)

produced primarily by Th1 subset and induces activation and proliferation of cytotoxic T cells

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Alesleukin (Proleukin)

  • recombinant human interleukin-2 (IL-2)

  • endogenously produced by NK and T-cells (T helper cells)

  • major physiologic role: promote activation and proliferation of T and NK cells in autocrine and paracrine manner

  • toxicity — capillary leak syndrome

    • increase in leakiness of small blood vessels

    • characterized by hypotension, tachycardia, swelling of arms, legs, and other parts of the body and pulmonary edema

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interferons (IFNs)

  • type I: IFN𝜶, IFNβ

  • type II: IFNɣ

  • IFNs activate dendritic cells, natural killer cells, and cytotoxic T cells and suppresses the function of myeloid derived suppressor cells (MDSC)

  • side effects:

    • flu-like symptoms, fatigue, neuropsychiatric