Personalized Cancer Immunotherapy
The basic premise of immunotherapy for cancer is to stimulate the immune system to recognize and destroy cancerous cells. Historical data show that the immune system clearly plays a role in cancer progression. For example, immunosuppression is associated with cancer development (Nephrol Dial Trans 2007 22 Sup. 1 i.4-10). In contrast, heightened antitumor activity of the immune system has been associated with spontaneous cancer regression (Acta Oncol 1990 29 (5) p. 545-50).
When cells become cancerous, they sometimes, but not always, express proteins that are recognized as foreign by the immune system. So, if a cancer cell does express an immunogenic marker, why is it not eliminated by the immune response? Several possible mechanisms may explain this observation. A suboptimal immune response may arise due to a lack of helper T cells, non-activated antigen presenting cells (APCs), or active suppression by CD4+ CD25+ regulatory T cells. There may be an inadequate number of CD8+ cytotoxic T lymphocytes (CTLs), or signaling from CTLs may be impaired. The effector phase of the immune response may not function properly because of CTL apoptosis or a failure of CTLs to migrate to the tumor site. Finally, the tumor cells may evade the immune response through several mechanisms including loss of or lowered expression of tumor antigen, loss of human-leukocyte antigen (HLA) expression, or loss of the ability to undergo apoptosis (Nat Rev 2003 3 (9) p. 666-75).
Some of the antigens identified in multiple solid tumors include: MAGE 1, 2, & 3, gp100, carcino-embryonic antigen (CEA), HER-2, mucins (e.g., MUC-1), and prostate-specific antigen (PSA). Viral proteins that are also immunogenic – from hepatitis B (HBV), Epstein-Barr (EBV), and human papilloma (HPV) viruses – are expressed during the development of hepatocellular carcinoma, lymphoma, and cervical cancer, respectively. Several phase III clinical trials are ongoing to test whether targeting of these tumor antigens has any therapeutic benefit. Most tumor antigens, however, are “self” proteins that do not elicit a robust immune response because of self-tolerance. Therefore, some outside help to boost the immune system’s response is warranted.
Immunotherapy for cancer is achieved by stimulation of the immune system via a variety of reagents such as vaccines, infusion of T cells, or cytokines. These reagents act through one of several mechanisms:
1) by stimulating the antitumor response, either by increasing the number of effector cells or by producing one or more soluble mediators such as lymphokines,
2) by decreasing suppressor mechanisms,
3) by altering tumor cells to increase their immunogenicity and make them more susceptible to immunologic defense, and
4) by improving tolerance to cytotoxic drugs or radiotherapy, such as stimulating bone marrow function with granulocyte colony-stimulating factor (G-CSF).
One technique for stimulating the immune system to destroy cancer cells is called Adoptive-Cell-Transfer Therapy (ACT). Also called T cell infusions, ACT therapy involves infusion of T cell subsets. Use of CD8+ T cells for adoptive therapy has several advantages, including the facts that T cells can specifically target tumor cells, T cells have a long clonal life span which can result in tumor treatment and immunosurveillance, and T cells can be genetically manipulated with ease (J Clin Invest 2007 117 (5) p.1204-12).
In one approach to ACT therapy, polyclonal ex vivo activation and expansion of the T cells is performed. The T cells are then infused back into the patient with the assumption that these T cells will react against tumor antigens directly or via antigen presenting cells. The rationale for this approach is strengthened by the idea that many patients already elicit a tumor immune response that is simply not robust enough on its own to clear the cancerous cells (J Clin Invest 2007 117 (5) p.1204-12).
Biocytics™ is currently exploring ways to expand T cells ex vivo to be used for immunotherapy.
