Cancer Immunotherapy Notes

Cancer Immunotherapy Learning Outcomes

  • Target cancer by manipulating the immune system.
  • Therapeutic strategies:
    • Chimeric T cells (CAR-T)
    • Cancer vaccines (limited examples)
    • Checkpoint inhibitors (PD-1/CTLA-4 inhibitors)
  • Awareness of opportunities, complexity, and challenges within immuno-oncology.

Overview: Therapeutics & Immunology

  • Themes:
    1. Principles of immunology
    2. Allergy and hypersensitivity
    3. Autoimmunity
    4. Therapeutics that activate the immune system
    5. Transplantation and immunosuppression
    6. Cancer Immunotherapy

5 Core Concepts

  • Innate & Adaptive
  • Antigen Specificity
  • Lymphocytes
  • Effector Mechanisms
  • Focus: Interventions
    • Infection: Vaccines, Immune stimulators
    • Hypersensitivity: Antihistamines, Glucocorticoids + Symptom management
    • Transplantation: Glucocorticoids, Antiproliferatives, Calcineurin inhibitors, Other immunosuppressants
    • Autoimmunity: Analgesics, Glucocorticoids, Antiproliferatives, Calcineurin inhibitors, Other immunosuppressants + Symptom management
    • Cancer: Checkpoint inhibitors, Cancer vaccines, T cell immunotherapy

Summary Themes 1-5

  • Trade-off between the seriousness of the condition and the severity of the intervention.
  • More serious autoimmune conditions justify more severe immunosuppression.
  • Cancer is the next frontier for immunopharmacology.

How to treat cancer?

  • Surgery - excision
  • Radiation
  • Cytotoxic drugs

Cancer Immunotherapy: Approaches

  • Tumor phenotypes are linked to possible therapeutics.
  • Key Types:
    • mAbs against specific Ag
    • Checkpoint blockade (mAbs)
    • Cancer Vaccine
    • Transferred T cells (e.g., CAR-T)
    • Cytokines
    • Oncolytic viruses

Cancer Immunotherapy: Three Conceptual Approaches

  • Antigen-specific approach
    • Cancer vaccines
    • Attempt to deliberately cause ‘autoimmune’ disease?
    • “CAR-T cell therapy”
    • mAbs against specific tumor Ag
  • Exploit natural “immune defense” against cancer
    • “Checkpoint inhibitors”
    • Also cytokines
  • Preferential infection and killing of tumor cells
    • Oncolytic viruses

Antigen-specific Approach

  • Attempt to deliberately cause autoimmunity against tumor.
  • Need to prime an adaptive immune response to tumor.
  • Cancer Vaccine
    • Pro: Simple
    • Con: New technology, not well established yet
  • T cell immunotherapy
    • Pro: Can be effective
    • Con: Personalized, Expensive

Tumour Antigens

  • Tumor cells are ‘self’ but can express specific antigens detectable by the immune system.
  • The immune system has different ways to control, including immune surveillance, and a number of endogenous mechanisms to inhibit cancer.
  • Examples of tumor antigens:
    • e.g., HER-2 (breast cancer), PSA/PAP (prostate)
    • e.g., Some HPV antigens (cervical cancer)

Autoantigen in Autoimmune Disease (TAA)

  • Research has identified a range of autoantigens.
  • Not just any old protein/peptide from the body.
  • Each disease has its own specific autoantigen(s) that is characteristic for that condition - presumably the disease cause.

Tumour-associated Antigens (TSA)

  • Research has identified a range of antigens (peptides and antibody targets) which seem to be found only in certain tumor cells.
  • Not just any old protein/peptide from the body.
  • Challenge: is it really tumor-specific?
  • Each tumor may have its own specific autoantigen(s) that is characteristic for that condition or that individual: related e.g., to mutations and cellular origin of that tumor.

Cancer Vaccines

  • Identify tumor-specific antigen.
  • These can be targeted by cancer vaccines.
  • Vaccine combines: ANTIGEN + ADJUVANT

How do Vaccines Protect?

  • Millions of T & B cells and antibodies that recognize pathogenic microbes.
  • Remember: Lymphocyte clonal expansion
  • Immunization drives clonal expansion

Vaccine Types

  • Live attenuated: Whole virus or bacteria, weakened to not cause disease (MMR, Rotarix, Nasal Flu vaccine, Zostavax)
  • Inactivated: Whole virus or bacteria that has been ‘killed’ (Polio vaccine (part of the 6 -in-1 vaccine))
  • Subunit: Part of a virus or bacterium, e.g., protein (recombinant protein) (Gardasil 9 (recombinant protein and VLP), Influenza VLP)
  • VLP: Virus-like particle (HepB (see also Gardasil9))
  • OMV: Outer membrane vesicle (MenB)
  • Polysaccharide-conjugate: Polysaccharide with ‘carrier’ (HiB, MenC, MenACWY (polysacch. joined to tetanus toxoid))
  • Toxoid: Inactive toxins (toxoid vaccine) (Diptheria/Tetanus/Pertussis (toxoid – all in 6 -in-1))
  • Viral Vector: Virus that doesn’t cause disease to deliver pathogen gene (Oxford-Astra- Zeneca COVID-19 vaccine (ChAdOx1 vector))
  • DNA-based: DNA encoding antigen (None in UK (ZyCoV-D in India))
  • RNA-based: mRNA in lipid envelope (Pfizer-BioNTech and Moderna COVID-19 vaccine)
  • Newer technologies + whole cell and protein/peptide + dendritic cell vaccines

Cancer Vaccines 2

  • Identify tumor-specific antigen
  • These can be targeted by cancer vaccines (???)
  • PROBLEMS:
    • Human adjuvants are not very effective
    • Tumors seem to ‘resist’ adaptive immune response
    • May need different vaccine for each patient
  • What about peptide antigens and T cell responses?
  • Mostly in development/trial (e.g., BNT116 non-small cell lung cancer)
  • Some examples have been introduced in clinical settings e.g., Provenge – uses dendritic cells present (antigen) for metastatic prostate cancer [ATMP]
  • Prophylaxis: Gardasil9, HepB vaccines

Recent Developments in Expanding Tumor-specific T cells

  • Immunisation
  • Culture conditions drives clonal expansion (e.g., IL-2)

Recent Developments in T Cell Immunotherapy: CAR-T – Chimeric Antigen Receptor T-cells

  • Kymriah
  • Use: Refractory B cell acute lymphoblastic leukemia
  • Immunization drives clonal expansion
  • CULTURE + GENE THERAPY drives clonal expansion
  • USE artificial T cell receptor in patients own cells
  • Example: Kymriah – Tisagenlecleucel [ATMP]

Monoclonal Abs vs Antigens

  • AIMS:
    • Deliver ‘toxin’ to tumor or elicit an immune response
    • Many clinical examples with different targets, indications, mechanisms
    • Some examples (including checkpoint inhibitors – see later):
      • mAb: Ipilimumab
      • Cancer: Melanoma, colorectal, non-small cell lung, renal cell carcinoma…
      • Target: CTLA-4
      • mAb: Pembrolizumab
      • Cancer: Wide range cancers e.g., melanoma, cervical, gastric…
      • Target: PD-1
      • mAb: Rituximab
      • Cancer: Non-Hodgkin’s Lymphoma and CLL
      • Target: CD20
      • mAb: Trastuzumab
      • Cancer: Breast and gastric
      • Target: HER2

T Cell Priming Tumour Cells: Recap

  • Immune response against ‘self’ is tightly regulated to block immunopathology (e.g., tolerance, inhibitory checkpoint proteins, e.g., CTLA-4, PD-1)
  • Recall T-cells can be activated by recognition presented tumor antigens
  • Cancer can exploit checkpoints to evade immune response (e.g., upregulate PD-L1 – binds PD-1 on T-cell and inhibits activation)

Checkpoint Inhibitors

  • Can exploit existing immune response to tumors which are ‘switched off’
  • Evidence tumors can be attacked by various immune effector mechanisms
  • SOLUTION: REMOVE the brakes “CHECKPOINT INHIBITORS”
    • Pro: Seems to work…
    • Con: …BUT Only works for some people, but very harmful for others!
  • Checkpoint inhibitors currently becoming mainstream treatment, with expanding list of cancers

Nobel Prize for Medicine 2018

  • Allison and Honjo discoveries of inhibition of negative immune regulation: inhibition of CTLA-4 and PD-1
  • Main targets:
    • CTLA-4: Ipilimumab (Yervoy)
    • PD-L1: Atezolizumab
    • PD-1: nivolumab (Opdivo), pembrolizumab (Keytruda)

Use of Cytokines

  • A range of cytokines is used for cancer immunotherapy, mimicking endogenous mechanisms.
  • Examples include IFNs (a,b,g) – not used much, IL2
  • Aldesleukin (IL-2) – renal cell carcinoma

Oncolytic Viruses

  • Virus infects and preferentially kills tumor cells.
  • Example Imlygic – modified HSV to target melanoma [ATMP]
  • Not yet many clinical examples but lots of ongoing research and examples in trials.
  • Can be engineered to deliver a variety of ‘other’ proteins/mechanisms.

Current Cancer Immunotherapy

  • Trade-off between autoimmunity and immunopathology vs tumor reduction
  • Unclear immunology within tumors
  • Diverse tumor types
  • Genetic variation within tumors and between individuals

Summary Theme 6

  • Antigen-specific priming
    • Cancer vaccines prime adaptive immunity against tumor
  • Antigen-specific effector functions
    • CAR-T 汽車
      REMOVE INHIBITION “Checkpoint inhibitor”
    • PD-1 inhibitor
    • CTLA-4 blockade
  • Artificial generation of anti -cancer T cell response
    • Mainly development/trials
  • Also cytokines
  • Monoclonal Abs

Summary Themes 1-5 And others!

  • Experimental gene therapy (SCID)
  • Vaccines activate pathogen-specific adaptive immune responses
  • Recombinant cytokines and synthetic innate stimulatory drugs activate inflammation
  • Anti-histamines, glucocorticoids, and biopharmaceuticals block inflammatory signals
  • Three classes of immunosuppressant drugs block adaptive immune priming: calcineurin inhibitors, non-CNI, proliferation blockers, and mAbs block signals or kill
    lymphocytes
  • Analgesics block pain, providing insulin / thyroid hormones gives symptomatic relief from immunopathology

Core Concepts - Recap

  • Innate & Adaptive
  • Antigen Specificity
  • Lymphocytes
  • Effector Mechanisms
  • Focus: Interventions
    • Infection: Vaccines, Immune stimulators
    • Hypersensitivity: Antihistamines, Glucocorticoids + Symptom management
    • Transplantation: Glucocorticoids, Antiproliferatives, Calcineurin inhibitors, Other immunosuppressants
    • Autoimmunity: Analgesics, Glucocorticoids, Antiproliferatives, Calcineurin inhibitors, Other immunosuppressants + Symptom management
    • Cancer: Checkpoint inhibitors, Cancer vaccines, T cell immunotherapy

Learning Outcomes: Recap

  • It may be possible to target cancer by deliberately manipulating the immune system
  • Know different therapeutic strategies and identify clinical examples of those that have succeeded to date, e.g.:
    • Chimeric T cells (CAR-T)
    • Cancer vaccines (limited examples … yet)
    • Checkpoint inhibitors (PD-1/CTLA-4 inhibitors)