Immunotherapy and Cancer Treatment

Cancer Immunotherapy Overview

  • Focus on advancements in immunotherapy, particularly for cancers.

Bispecific T-cell Engaging Antibodies

  • Definition: Antibodies with two different antigen binding domains.
    • One binds to a tumour antigen.
    • The other binds to CD3ε, which engages and activates cytotoxic T-cells.
  • Immunological Synapse: Triggered by the binding of these antibodies, leading to T-cell activation.

Role of CD3ε

  • Component of the T-cell receptor complex.
  • Contains signaling domains crucial for T-cell activation.
  • T-cell receptor does not have its own signaling domains; they rely on CD3ε!

Redirecting T-cells to Tumour Antigens

  • Mechanism: Insert a new receptor into a T-cell that recognizes a tumour antigen.
    • This enables T-cells to attack cancer cells expressing the target antigen.
  • Technology in Use: Chimeric Antigen Receptor (CAR) design creates CAR-T cells used in cancer immunotherapy.

Chimeric Antigen Receptor Design

  • Based on antigen-binding domains of monoclonal antibodies.
  • Does not require MHC for antigen presentation.
  • Components:
    • Antibody hinge region
    • Transmembrane domain
    • Intracellular signaling and costimulatory domains, including CD3 and other T-cell signaling molecules.

CAR-T Cell Process

  1. Collect T-cells from the patient.
  2. Introduce CAR into these T-cells in vitro (ex vivo).
  3. Expand the CAR-T cells.
  4. Infuse the CAR-T cells back into the patient.
  • Outcome: These CAR-T cells then actively target and attack cancer cells.

Armoured CARs

  • Enhanced CAR-T cells designed to produce beneficial molecules for stimulating the tumour immune microenvironment.
  • Example: TRUCKs (T-cells Re-directed towards Universal Cytokine Killing) that secrete cytokines to boost immune response.

Clinical Use: CD19 CAR-T Cells

  • Application: Treatment of chemorefractory childhood acute B-cell leukemia.
  • Outcome: Significant, enduring remissions in most patients and potential curative effects on other aggressive B-cell malignancies.

Side Effects of CAR-T and Bispecific Antibodies

  • Cytokine Release Syndrome: Result of widespread T-cell activation, leading to excessive secretion of cytokines, particularly IL-6.
  • Symptoms: Severe immune response similar to a critical infection.
  • Treatment: Use of immunosuppressive medications (i.e., corticosteroids) and IL-6 receptor-blocking monoclonal antibodies.

Immune Checkpoint Inhibitors

  • Represent significant advancements in treating cancers, especially blood cancers.
  • Not as effective against solid tumors compared to checkpoint inhibitors, which have shown potential for curative treatments.

Immune Checkpoint Proteins

  • Serve as T-cell surface receptors inhibiting T-cell activity when bound to specific ligands.
  • Important for maintaining immune tolerance and homeostasis, but can aid in tumour evasion.

Mechanism of Inhibition in Cancer Treatment

  • T-cell activation can be inhibited by the PD1-PDL1 interaction.
  • Therapeutic Targeting: Blocking this interaction enhances T-cell activity against tumour cells.

Available Immune Checkpoint Inhibitors

  • Utilize monoclonal antibodies targeting T-cell surface receptors or their ligands.
  • Major Inhibitors:
    • CTLA4 (Ipilimumab)
    • PD-1/PD-L1 (Pembrolizumab, Durvalumab)
    • LAG-3 (Relatlimab)
  • Combination therapies are being explored for greater effect.

Adverse Effects of Immune Checkpoint Inhibitors

  • Potential for autoimmunity resulting from lowered self-tolerance due to enhanced T-cell activation.

Resistance Mechanisms to Immunotherapy

  • Primary Resistance: Immunotherapy fails from the onset.
  • Secondary Resistance: Effectiveness diminishes with time.
  • Factors: Loss of target antigens, tumor heterogeneity, and lack of immune response triggers.

Summary of Types of Cancer Immunotherapy

  • Antigen-targeted, T-cell based:
    • Bispecific T-cell engaging antibodies
    • Chimeric Antigen Receptor T-cells (CAR-T)
  • Antigen-agnostic, T-cell based:
    • Immune checkpoint inhibitors
  • Resistance Mechanisms: Important to understand for treatment efficacy.