Cancer Immunotherapy Overview

Reduced Expression of Class I MHC Molecules

• Tumor cells can reduce Class I MHC expression to avoid T cell recognition.

Cancer Immunotherapy

• Cancer treatment options include surgery, radiation, and anti-neoplastic agents.
• Cancer immunotherapy aims to stimulate the body's immune response against cancer cells.
• Cancer immunotherapy includes:
  • Therapeutic cancer vaccines
  • Oncolytic immunotherapy
  • Adoptive T cell therapy
  • Antibody-based therapies
  • Cytokines
  • Non-specific therapies (e.g., BCG vaccine)

Therapeutic Cancer Vaccines

• Dendritic cell-based vaccination uses patient's dendritic cells pulsed with tumor antigens.
• Antigen-pulsed DCs activate tumor-specific T cells.
• Sipuleucel-T (Provenge®) is an FDA-approved vaccine for advanced prostate cancer.
• Provenge uses patient's DCs incubated with a fusion protein containing GM-CSF and the tumor-associated antigen PAP (prostatic acid phosphatase).

Oncolytic Viral (OV) Therapy

• Genetically-engineered oncolytic viruses replicate only in cancer cells and produce GM-CSF.
• Infected cancer cells lyse, releasing tumor antigens and GM-CSF to stimulate dendritic cells.
• Activated DCs promote an anti-tumor immune response by activating T cells.
• Imlygic (talimogene laherparepvec or T-VEC), a modified herpesvirus, is the first FDA-approved OV therapy for melanoma.

Adoptive T Cell Therapy

• Transfer of tumor-specific T cells:
  • TIL therapy: tumor-infiltrating lymphocytes (TILs) are isolated from the tumor, cultured with IL-2, and infused back into the patient.
  • Genetically-engineered T cells: T cells are isolated from the blood, genetically modified with a tumor-specific TCR or CAR, cultured with IL-2, and infused back into the patient.

Clinical Application: CAR-T Cell Therapy

• KymriahTM (tisagenlecleucel) was the first FDA-approved CAR-T cell therapy for certain B cell leukemias.
• PD-1 binds PD-L1/L2 on various cells, inhibiting effector T cell function.

Antibody-Based Therapies

• Immune checkpoint inhibitors:
  • Block inhibitory receptors/ligands, stimulating antitumor responses by enhancing T cell activation.
  • Enhance the patient's own immune response to tumors.
  • Examples:
    • Anti-CTLA4 mAbs: Ipilimumab (Yervoy®)
    • Anti-PD-1 mAbs: Pembrolizumab (Keytruda), Nivolumab (Opdivo)
    • Anti-PD-L1 mAbs: Atezolizumab (Tecentriq®)
• Anti-tumor monoclonal antibodies:
  • Induce antibody-dependent cellular cytotoxicity (ADCC).
  • Activate complement.
  • Block growth or activation signals.
  • Deliver radiation, toxins, or chemotherapy drugs to tumor cells (immunoconjugates).
  • Many monoclonal antibodies have been developed for treating various cancers.