NK cell immunotherapy

NK Cell Immun



otherapy Class Lecture Notes

Basic Information

  • Course: Year 2 BSc ATT, Module: Biologics and Immunotherapeutics (BIT)

  • Title: NK Cell Immunotherapy

  • Date: 26th September 2025

  • Lecturer: Dr. Chiara De Santi

  • Institution: RCSI Royal College of Surgeons in Ireland / Coláiste Ríoga na Máinleá in Éirinn

Structure and Content Overview

  • Lectures:

    • Anti-inflammatories II

    • Biologics: Cytokines

    • Biologics: Interferons

    • Biosimilars

    • Introduction to Cancer Immunology

    • Introduction to Cancer & Cancer Cell Immunogenicity

    • Cancer Immunotherapy I

    • Cancer Immunotherapy II

    • Natural Killer Cell Immunotherapy

    • Pathology & Treatments of Breast Cancer

    • Pathology & Treatments of Esophageal & Stomach Cancer (Guest Lecturers)

    • Novel Technologies in Immunotherapeutics: Concepts (CRISPR, CAR-T, Metabolism)

    • Disorders of Immune System and Treatments: Cancer Immunotherapy

    • Immunodiagnostics Overview

    • Introduction to Biotechnology (Drug Parentals I, II, III)

    • Biotech Drugs: Proteins, Interferons, Monoclonal Antibodies

    • Vaccination Overview (Traditional Vaccinations, Latest Advancements, Spotlight on COVID)

  • Tutorials:

    • Based on Lectures 1-12

    • Based on Lectures 13-21

    • Based on Lectures 22-31

    • Group Discussion with a Patient from MS Ireland (Guest Lecturer)

    • Based on Lectures 32-36

    • Biotechnology and Immunodiagnostics

Learning Outcomes

  • Describe how NK cells mediate anti-tumour mechanisms

  • Discuss the NK cell-based approaches to cancer immunotherapy

  • Describe an example of CAR-NK cell therapy in clinical trials

  • Outline the immunotherapeutic potential of NK cell-based immune checkpoint inhibitors

Cancer Immunotherapy Concepts

Role of NK Cells in Cancer Immunity

  • Circulation and Response:

    • NK cells circulate in the blood and are recruited to tumors by a cytokine called interferon-gamma (IFN-γ).

    • Cancer cells can express ligands (e.g., MIC-A, MIC-B) that are recognized by activating receptors on NK cells like NKG2D.

    • Tumors may downregulate MHC Class I molecule expression, making them vulnerable to NK cell attacks.

  • Mechanisms of Action:

    • NK cells kill tumor cells using perforin and granzymes.

    • They can also mediate cell death via antibody-dependent cellular cytotoxicity (ADCC) when tumor cells are coated with antibodies.

Immune Challenges in Tumor Microenvironment

  • Tumor-derived factors can create an immunosuppressive environment:

    • Inhibition of tumor-specific effector T cells.

    • Dendritic cells can be conditioned by tumors to stimulate tumor growth instead of immune response.

  • Various immune cells like regulatory T cells and myeloid-derived suppressor cells may facilitate tumor survival.

Immunotherapeutic Approaches Using NK Cells

  • NK Cell-Based Therapies:

    • Passive immunotherapy:

    • Monoclonal antibodies (mAbs), including bi- and tri-specific killer engagers (BiKEs and TriKEs) used to recruit NK cells to tumors.

    • Example: TriKEs recruit NK cells through CD16 to tumor antigens.

    • Clinical trials are underway for agents like AFM13 (lymphoma) and GTB-3550 (leukemia).

  • Active immunotherapy: Includes checkpoint inhibitors to unleash NK cell action.

Breakdown of Immunotherapeutics

  • Passive Immunotherapy:

    • Monoclonal Antibodies - Engagers designed to enhance NK cell activity against cancer (e.g., BiKEs, TriKEs).

    • Cytokines: IL-2 and IL-15 (e.g., Anktiva for bladder cancer) promote NK cell proliferation but can have severe side effects.

  • Active Immunotherapy:

    • Checkpoint inhibitors targeting PD-1, LAG-3, TIM-3, and TIGIT to enhance NK cell response.

    • Specifically, anti-KIR and anti-NKG2A antibodies may also improve NK activation against tumors.

Future Directions

Challenges in NK Cell Therapies

  1. Lifespan and Efficacy: BiKEs and TriKEs’ short in vivo persistence necessitates optimizations in administration and design.

  2. Source of NK Cells: Allogeneic NK cell transfers from various sources provide advantages but present challenges such as patient matching and production time.

  3. Clinical Trials and Innovations: Continuous optimization of CAR NK cell therapy, with trials like QUILT-106 assessing the efficacy and safety of innovative approaches.

Summary of Key Points

  • NK cells are intrinsic to anti-cancer immunity with unique activation methods determined by the balance of inhibitory and activating receptors.

  • The development of NK cell-based therapies presents a promising avenue in cancer treatment with potential for lower side effects compared to traditional treatments.

  • Ongoing investigations into passive and active immunotherapies leverage NK cell biology to develop more effective treatments against cancers.