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.