Cancer Immunotherapy

•  Current Approaches (many are experimental)

  • Active nonspecific immune stimulation (e.g.,ECG)

  • Active specific immune stimulation (e.g.,melacine melanoma vaccine)

  • Immunomodulators (e.g. levamisole)

  • Cytotoxic cytokines (e.g., IMF_a)

  • Immunostimulatory cytokines (e.g., IL-2)

  • Adaptive cellular immunotherapy (e.g. lymphokine activated killer cells {LAK cells}; tumor infiltrating lymphocytes{TILs})

  • Monoclonal antibodies

  Gene Therapy

• Gene transfer

  • Replace missing gene

  • Replace inactivated gene (mutation)

  • Introduce extra copies of a normally expressed gene

  • Introduce a new gene, not normally present

•   Purpose

  • Replace missing functions

  • Increase existing functional capability

  • Introduce a new function/capability

•   Management of immunologic disease Example:

  •  Severe combined immunodeficiency syndrome (SCID) -- ADA deficiency

    • Repair by retroviral ADA gene-transfer into patient lymphocytes

•  Approaches for gene therapy and management of cancer

  • Cytokine gene transfer for effectors such as:

    • TNF_a into effector lymphocytes (e.g. lymphokine activated killer cells (LAK cells) or tumor-infiltrating cells (TILs))

  • DNA vaccines:

    • Genes encoding tumor rejection antigens -- injected & expressed to induce tumor immunity

  • Gene-modified tumor cells as vaccines

    • Tumors are transduced or transfected in vitro (for later vaccination) or

    • Tumors are transduced or transfected in vivo (tumor becomes more immunogenic)

    • Potentially useful genes -- encoding IL-1, IL-2, IL-4, IL-6, IL-7, IL-10, IL-12,; TNF-a, IFN-a, IFNg, B7.1, B7.2

  • Carrier cells (transduced with genes noted above) injected into the tumor or mixed with tumor cells for vaccination.

    • Rationale: immunostimulatory gene product is provided near the immunizing tumor cells