University of Pittsburgh Cancer Institute (UPCI)

Vaccines for Immunotherapy

Dendritic CellAdvanced melanoma is difficult to treat. Historically, chemotherapy, immunotherapy, and molecularly targeted therapy have demonstrated limited benefits and sometimes significant toxicities for melanoma patients. Clinical trials of new immunotherapies and molecularly targeted agents have demonstrated improved survival and rapid, dramatic, and predictable improvements in symptomology and tumor burdens. However, the contrasting limitations of each (i.e., ability to predict patient responders and low response rates for immunotherapy, and lack of durable responses for molecularly targeted therapy, respectively) have proven to be substantial challenges and subsequently spurred an international effort to develop therapeutic combinations to
surmount these obstacles by capitalizing on the strengths of
each and countering their weaknesses.

Our increasing understanding of tumor immunobiology and the complexity of interactions between host T cells and cancer has led to novel treatment approaches with vaccines, especially in combination with new, more potent stimulants of the immune system. Immunization offers the hope to induce durable immune protection against melanoma and other cancers, and reduce or eliminate substantial toxicities that have historically characterized and limited the use of chemotherapy and less specific immunotherapy approaches.

Since 1985, the MP has conducted studies that have demonstrated the potential role of vaccines in the induction of more potent and specific serum antibody and CTL (cytotoxic or killer T lymphocyte) responses and which utilize the body's system of immune instruction to effectively present tumor antigens (or markers) through dendritic cells (DCs) and trigger durable and specific immunity to cancer without the toxicity that has accompanied less specific forms of immunotherapy as well as chemotherapy and molecularly targeted therapies for melanoma. These studies have provided significant insights into the nature of damping influences on the immune system, the elucidation of which has led to the development of new therapies that block immune ‘checkpoints’ that contribute to the failure of specific and effective immune recognition and response in melanoma patients.

Anti-CTLA4 blocking antibodies such as ipilimumab, which was recently FDA-approved for the treatment of advanced metastatic melanoma, and anti-PD-1 blocking antibodies, which are currently under active study to evaluate their efficacy in stimulating more effective vaccination immunotherapy, represent two promising therapeutic approaches towards not only curtailing potential hinderers to anti-tumor immunity, but also in generating more robust and less toxic immune responses to melanoma.

Selected Publications

  • Natural killer (NK) cells mediate immunoregulatory helper functions in addition to their cytolytic activity. The NK cell-mediated type-1 polarization of dendritic cells (DCs) enhances the efficacy of DCs by inducing tumor-specific cytotoxic T lymphocytes. (Wong JL, et. al., J Immunother. 2011, 34:270-8).
  • Ipilimumab is an antibody that blocks the cytotoxic T-lymphocyte antigen-4, which is a critical regulator of the antitumor T-cell response. Ipilimumab treatment prolongs median overall survival of patients with melanoma, but it does have immune-related toxicities that require particular attention and care. (Tarhini A, et.al., Cancer Biother Radiopharm. 2010, 25:601-13).
  • Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. Tim-3-Tim-3L blockade together with PD-1-PD-L1 blockade can be used to reverse tumor-induced T cell exhaustion/dysfunction in patients with advanced melanoma. (Fourcade J, et. al., J Exp Med. 2010, 207:2175-86).

Members

Butterfield, Lisa, PhD
Medicine
Rao, Uma, MD
Pathology
Falo, Louis, MD, PhD
Dermatology
Storkus, Walter, PhD
Dermatology
Ferris, Laura Korb, MD, PhD
Dermatology
Tarhini, Ahmad, MD, PhD
Medicine
Ho, Jonhan, MD
Dermatology and Pathology
Zarour, Hassane, MD
Medicine
Kirkwood, John M., MD
Medicine