Immunology and Immunotherapy of Melanoma
Advanced 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, and anti-PD-1 blocking antibodies, 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.
- Cancer patients frequently exhibit a deficiency in Type-1 (but not Type-2 or regulatory) CD4(+) T cell responses against tumor-associated antigens (TAA), which may limit protection against disease progression or responsiveness to immunotherapy in these individuals. Since such deficiency was acutely evident in patients with active disease (AD), where chronic stimulation of anti-tumor CD4(+) T cells would be expected and activation-induced cell death may be prevalent, MHC Class II-peptide tetramers were employed to characterize the frequency and apoptotic status of TAA- vs. influenza (FluM1) virus-specific CD4(+) T cells in the peripheral blood of HLA-DR*0401(+) patients with melanoma or renal cell carcinoma. Results suggested that the preferential sensitivity of TAA (but not viral)-specific CD4(+) Th1 cells to apoptosis in melanoma patients with AD will need to be overcome for optimal clinical benefit of immunotherapeutic approaches to be realized. (Wesa et. al., Front Oncol. 2014 Sep 29;4:266.)
- Although melanoma vaccines stimulate tumor antigen-specific CD8(+) T cells, objective clinical responses are rarely observed. In patients with metastatic melanoma who were administered tumor vaccines, rapid tumor antigen-specific CD8(+) T-cell responses were stimulated, and a vast majority of these cells upregulated PD-1 and a minority also upregulated Tim-3. Levels of PD-1 and Tim-3 expression by vaccine-induced CD8(+) T cells at the time of vaccine administration correlated inversely with their expansion in vivo. Dual blockade of PD-1 and Tim-3 enhanced the expansion and cytokine production of vaccine-induced CD8(+) T cells in vitro. Collectively, our findings support the use of PD-1 and Tim-3 blockades with cancer vaccines to stimulate potent antitumor T-cell responses and increase the likelihood of clinical responses in patients with advanced melanoma. (Fourcade et. al., Cancer Res. 2014 Feb 15;74(4):1045-55.)
- Neoadjuvant ipilimumab was evaluated in patients with surgically operable regionally advanced melanoma in order to define markers of activity in the blood and tumor as assessed at baseline (before ipilimumab) and early on-treatment. This study revealed a significant immunomodulating role for ipilimumab on Treg, MDSC and effector T cells in the circulation and tumor microenvironment that warrants further pursuit in the quest for optimizing melanoma immunotherapy. (Tarhini et. al., PLoS One. 2014 Feb 3;9(2):e87705.)
- Dasatinib (DAS) is a potent inhibitor of the BCR-ABL, SRC, c-KIT, PDGFR, and ephrin tyrosine kinases that has demonstrated only modest clinical efficacy in melanoma patients. MP members demonstrated the superior immunotherapeutic benefit of a combination treatment of DAS with a dendritic cell-based vaccine against the OVA257-264 peptide epitope in a melanoma mouse model. This combination more potently inhibited tumor growth and extended overall survival as compared with treatment with either single modality. The culmination of this bimodal approach was a profound "spreading" in the repertoire of tumor-associated antigens recognized by CD8+ TILs, in support of the therapeutic superiority of combined DAS + vaccine immunotherapy in the melanoma setting. (Lowe et. al., Oncoimmunology. 2014 Jan 1;3(1):e27589.)
| Butterfield, Lisa, PhD
| Kirkwood, John, MD|
|Davar, Diwakar, MD
| Storkus, Walter, PhD|
|Falo, Louis, MD, PhD
|Zarour, Hassane, MD|
| Fuschiotti, Patrizia, PhD