JOURNAL OF THE LOUISIANA STATE MEDICAL SOCIETY
Figure 3. Six months post initiation of therapy, the patient’s axillary and liver masses showed continued improvement
EPIDEMIOLOGY
Developments in the understanding of the tumor micro- environment allowed for the ultimate development of more targeted immune mediating drugs. Melanomas are often found to contain tumor-infiltrating lymphocytes (TIL). These cytotoxic T-lymphocytes (CTL) are capable of inducing tumor cell lysis and studies in the 1980s demonstrated the ability of IL-2 to mediate these cells to cause tumor regression in melanomas. 9,10 Tumors infiltrated with T cells were found to have better long-term patient survival. The mechanismbehind a response was thought to be secondary to an active antitumor response by the patient’s immune system. This discovery led to therapeutic approaches using recombinant high-dose IL-2 to induce immune-mediated tumor cell lysis in patients with metastatic melanoma. 9 Several studies demonstrated objective responses in 10-16% of patients treated with high dose IL-2.9,10 However, high dose IL-2 treatment is associated with severe toxicity such as vascular leak syndromes, requiring inpatient management. While these factors have limited its generalized use, high dose IL-2 served as proof-of-principle that immunotherapies can be effective. When grown ex-vivo, TILs exhibit potent antitumor activity. However, in patients, TILs often have a diminished capacity for proliferation, tumor lysis, and cytokine production. 11 This implies that the immune climate within the tumor micro-environment (TME) can dampen CTL activity, the result being limited efficacy of IFN-α2b and IL-2. Understanding of the micro-environment has led to the expansion of today’s drug armamentatium.
Melanoma is a life threatening form of skin cancer that is most commonly associated with excessive ultraviolet light exposure. It affects roughly onemillion Americans and is projected to claim over 10,000 lives in 2016. 1 Stage IV, or metastatic melanoma, is thought to be incurable. 2 Historically, alkylating chemotherapy agents such as dacarbazine and temozolomide have been used with limited efficacy. 3,4 Interferon-α2b (IFN-α2b) and high dose interleukin-2 (IL-2) therapy were mainstays in the treatment of metastatic melanoma; surgical resection is reserved for cases of limited metastatic tumor. 5 Advances in tumor genomics have recently improved survival rates in patients with metastatic melanoma. For example, a mutation of BRAF is found in half of all melanomas: the V600E BRAF mutation causes unregulated cell proliferation via the MAP kinase pathway. 6,7 Metastatic melanomas positive for BRAF mutation can be treated with the BRAF inhibitors, vemurafenib or dabrafenib, and can result in a relative reduction of death by 63%. 3,6 Concurrent inhibition of the BRAF and MEK of the MAP kinase pathway can result in a higher rate of tumor responses and longer duration of responses. Treatment with the MEK inhibitor trametinib combined with dabrafenib has been shown to have an objective response of 76%, with amedian progression free survival (PFS) of 9.4 months vs 5.8 months for patients who received dabrafenib monotherapy alone (HR 0.39, P<0.001). 7
RATIONALE FOR IMMUNOTHERAPY
INHIBITION OF CTLA-4
Recent advances in immunotherapy have provided patients with more durable responses and longer survivals. Metastatic melanomas with and without BRAF mutations may be treated by new immune checkpoint inhibitors, such as nivolumab (anti- PD1 antibody) and ipilimumab (anti-CTLA4 antibody), used in our case patient. Historically, traditional cytotoxic chemotherapy produced modest benefit. For example, dacarbazine resulted in a low response rate (10-15%) and an overall survival (OS) of eight months. 8 Interestingly, the immune mediating cytokines also were shown to result in some long-termobjective response rates in a limited number of patients. These results suggested that melanoma could be an ideal target for immune manipulation. But, the crude, non-targeted nature of these therapies often resulted in unacceptable toxicities for many patients.
One mechanism by which T-cells self-regulate is through expression of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), a receptor found only on T cells. It functions as a negative co-stimulatory molecule for the T cell. 12 CTLA-4 binds to CD80 and CD86 on antigen-presenting cells and by outcompeting CD28 for binding to CD80 and CD86, CTLA-4 can present the co-stimulation needed to maintain T-cell activation (Figure 4). 13 Ipilimumab is a fully human IgG-1 monoclonal antibody that blocksCTLA-4, resultinginincreasedT-cell activityandpromoting antitumor activity. 14 Two phase-III trials have evaluated ipilimumab in the treatment of metastatic melanoma. 14,15 In the first trial of patients with treated unresectable stage III or IV melanoma, ipilimumab demonstrated an improved OS versus
J La State Med Soc VOL 169 MAY/JUNE 2017 79
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