Cancer Immune Surveillance and Immunotherapy

Cancer Immunology

  • Cancer Interaction with the Immune System: Understanding how cancer cells evade immune detection and the immune response.

  • Immune Cancer Surveillance: The immune system's ability to detect and eliminate nascent cancers via tumor antigens.

  • Cancer Escape from Surveillance: Mechanisms by which cancer cells evade immune recognition.

  • Types of Cancer Immunotherapy:

    • Allows harnessing the immune system to fight cancer.

  • Mechanisms of Action: How immunotherapies induce immune responses against cancer.

  • Mechanisms of Resistance: Understanding how cancers can resist immune attacks.

Historical Context of Immune Cancer Theory

  • Coley’s Hypothesis (1891):

    • Suggested that infections could induce cancer regression through an immune response.

  • Burnet and Thomas (1950s):

    • Independently proposed immune surveillance theory, positing that the immune system eradicates early cancers by recognizing tumor-associated antigens (TAAs).

    • Questions remain on how to prove the existence of these early cancers.

Evidence Supporting Anti-Tumor Immunity

  • Circumstantial Evidence:

    • Higher cancer incidence in immunocompromised individuals suggests immune surveillance.

    • Tumor transplants are rejected in immunocompetent mice, indicating potential immune recognition of tumors.

    • Improved prognosis correlating with higher immune cell infiltrates in tumors.

Key Clinical Observations

  • Melanoma:

    • Instances of spontaneous regression suggest immune-mediated responses.

Key Experimental Evidence

  • Schreiber et al. (2001):

    • Found immunodeficient mice demonstrate a higher propensity for cancer; tumors from immunodeficient mice provoke immune responses in syngeneic, immunocompetent mice.

  • Three E's of Cancer Immunity:

    • Elimination: Immune cells destroy cancer cells.

    • Equilibrium: Cancer cells remain present but are controlled by the immune system.

    • Escape: Cancer cells that evade immune recognition proliferate.

Basis of Cancer Immune Response

  • Tumor-Associated Antigens (TAA):

    • Unique antigens on tumor cells recognized by the immune system, inducing an immune response.

    • Important for the development of targeted cancer therapies.

Harnessing the Immune System for Treatment

  • Immune Evasion: Understanding how tumors escape immune detection is crucial for treatment.

Early Approaches to Cancer Immunotherapy

  • Utilization of bacteria to induce immune responses despite a lack of understanding of specific tumor antigens.

  • Bacillus Calmette-Guérin (BCG):

    • Used to reduce recurrence of superficial bladder cancers.

Cytokines in Immunotherapy

  • Immunostimulatory Cytokines:

    • Essential signaling molecules, including interferons and interleukins, used to provoke immune responses.

    • Indicated improvement in advanced melanoma cases, but limited by side effects.

Bone Marrow Transplantation

  • Concept:

    • Originally aimed to eradicate bone marrow cancer but primarily effective through transplantation of donor immune systems.

    • Risk of graft versus host disease alongside potential significant cancer cures.

Tumor-Infiltrating Lymphocytes (TIL)

  • A promising treatment for melanoma through the isolation, expansion, and reinfusion of TILs.

Antigen-Targeted Approaches

  • Cancer Vaccines and Monoclonal Antibodies:

    • Techniques targeting specific tumor antigens, including antibody-drug conjugates (ADCs) and CAR-T cells.

Dendritic Cell Vaccines

  • Involves loading dendritic cells with tumor antigens for effective immune presentation, aiming for immune response generation.

Monoclonal Antibodies

  • Mechanisms of Action:

    • Can induce cancer cell death through various mechanisms, including ADCC (antibody-dependent cellular cytotoxicity).

  • Example Treatments:

    • Herceptin (Trastuzumab): Targets HER2 in breast cancer; has improved patient outcomes.

    • Rituximab: Targets CD20 in B-cell lymphomas, enhancing response rates but with potential side effects.

Antibody-Drug Conjugates (ADCs)

  • Mechanisms: Combine targeting with drug delivery to cancer cells selectively, yielding localized treatment effects.

  • Example: Trastuzumab emtansine (Kadcycla): HER2 targeting with a chemotherapy component.

Summary of Immune Cancer Surveillance and Immunotherapy

  • Evidence for immune responses against cancer and the significance of identified TAAs.

  • The three E’s: Elimination, Equilibrium, Escape frame immune response dynamics.

  • Overview of immunotherapeutic strategies including:

    • Antigen-agnostic approaches: Cytokines, TIL, and stem cell transplantation.

    • Antigen-targeted strategies: Therapeutic vaccines, monoclonal antibodies, and ADCs.