Claim: Immune-Focused Drug May Be New Weapon Against Advanced Melanoma
Verdict: SUPPORTS

Retrieved passages:
title: Melanoma
text: Clinical Oncology Conference in June 2010, the Bristol-Myers Squibb pharmaceutical company reported the clinical findings of their drug ipilimumab. The study found an increase in median survival from 6.4 to 10 months in patients with advanced melanomas treated with the monoclonal ipilimumab, versus an experimental vaccine. It also found a one-year survival rate of 25% in the control group using the vaccine, 44% in the vaccine and ipilimumab group, and 46% in the group treated with ipilimumab alone. However, some have raised concerns about this study for its use of the unconventional control arm, rather than comparing the drug against

title: Melanoma
text: a placebo or standard treatment. The criticism was that although Ipilimumab performed better than the vaccine, the vaccine has not been tested before and may be causing toxicity, making the drug appear better by comparison. Ipilimumab was approved by the FDA in March 2011 to treat patients with late-stage melanoma that has spread or cannot be removed by surgery. In June 2011, a clinical trial of ipilimumab plus dacarbazine combined this immune system booster with the standard chemotherapy drug that targets cell division. It showed an increase in median survival for these late stage patients to 11 months instead of

title: Melanoma
text: this disease in a small percentage of people with melanoma. Intralesional IL-2 for in-transit metastases has a high complete response rate ranging from 40 to 100%. Similarly, IFN-a has shown only modest survival benefits and high toxicity, limiting its use as a stand alone therapy. Immune check point inhibitors include anti-CTLA-4 monoclonal antibodies (ipilimumab and tremelimumab), toll-like receptor (TLR) agonists, CD40 agonists, anti-PD-1 (pembrolizumab, pidilizumab and nivolumab) and PDL-1 antibodies. Evidence suggests that anti-PD-1 antibodies are more effective than anti-CTLA4 antibodies with less systemic toxicity. A therapeutic approach that includes the combination of different therapies improves overall survival and progression-free

title: Melanoma
text: BRAF and MEK inhibitors may create a fast and lasting melanoma therapy response. A number of treatments improve survival over traditional chemotherapy. Biochemotherapy (chemotherapy with cytokines IL-2 and IFN-α) combined with BRAF inhibitors improved survival for people with BRAF positive melanoma. Biochemotherapy alone did not improve overall survival and had higher toxicity than chemotherapy. Combining multiple chemotherapy agents (polychemotherapy) did not improve survival over monochemotherapy. Immunotherapy is aimed at stimulating the person’s immune system against the tumor, by enhancing the body's own ability to recognize and kill cancer cells. The current approach to treating melanoma with immunotherapy includes three broad

title: Melanoma
text: of virotherapy, where oncolytic viruses are used to treat diseases; viruses can increase metabolism, reduce anti-tumor immunity and disorganize vasculature. Talimogene laherparepvec (T-VEC) (which is a herpes simplex virus type 1–derived oncolytic immunotherapy), was shown to be useful against metastatic melanoma in 2015 with an increased survival of 4.4 months. Melanoma Melanoma, also known as malignant melanoma, is a type of cancer that develops from the pigment-containing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye. In women, they most commonly occur on the legs, while in men they

title: H. Lee Moffitt Cancer Center & Research Institute
text: Adam Comprehensive Melanoma Research Center at Moffitt, and researchers at Moffitt Cancer Center discovered two monotherapy drugs – Mekinist (trametinib) and Tafinlar (dabrafenib) – can be safely combined to overcome or delay treatment resistance for a large percentage of melanoma patients with a specific gene mutation. Approved by the FDA in January 2014, Mekinist in combination with Tafinlar is one of the biggest advancements in melanoma treatment in the past 30 years. In August 2011, the U.S. Food and Drug Administration (FDA) approved the drug vemurafenib (Zelboraf) for metastatic melanoma patients who test positive for a specific gene mutation. Moffitt

title: Tumor antigen vaccine
text: suggest that they induce targeted immune responses in patients treated with the vaccines. The article also discusses 19 clinical trials that were initiated in the same time period. These trials are targeting solid tumors, glioma, glioblastoma, melanoma, and breast, cervical, ovarian, colorectal, and non-small lung cell cancers and include antigens from MUC1, IDO1 (Indoleamine 2,3-dioxygenase), CTAG1B, and two VEGF receptors, FLT1 and KDR. Notably, the IDO1 vaccine is being tested in patients with melanoma in combination with the immune checkpoint inhibitor ipilimumab and the BRAF (gene) inhibitor vemurafenib. The following table, summarizing information from another recent review shows an example

title: B16 Melanoma
text: B164A5, B16GMCSF, and B16FLT3. Today, B16 melanoma remains indispensable for metastasis studies. Current research projects focus on the cells’ immunological response to vaccines, microRNA mediated metastatic properties, especially miR-21, a noted aggressor of tumor suppressors and anti-proliferative factors. B16 is also used as a pre-clinical model to study immunotherapy. Those are just a few examples, but the undergirding idea is that the B16 melanoma model is a powerful research tool, and a staple for metastasis studies, and its development as such can be considered a huge benefit to the cancer research community. B16 Melanoma B16 melanoma is a murine tumor

title: Treatment of cancer
text: an immune response against tumours include intravesical BCG immunotherapy for superficial bladder cancer, and use of interferons and other cytokines to induce an immune response in renal cell carcinoma and melanoma patients. Cancer vaccines to generate specific immune responses are the subject of intensive research for a number of tumours, notably malignant melanoma and renal cell carcinoma. Sipuleucel-T is a vaccine-like strategy in late clinical trials for prostate cancer in which dendritic cells from the patient are loaded with prostatic acid phosphatase peptides to induce a specific immune response against prostate-derived cells. Allogeneic hematopoietic stem cell transplantation ("bone marrow transplantation"

title: Melanoma
text: Plexxicon's vemurafenib could lead to substantial tumor regression in a majority of patients if their tumor contain the B-Raf mutation. In June 2011, a large clinical trial confirmed the positive findings from those earlier trials. In August 2011 Vemurafenib received FDA approval for the treatment of late-stage melanoma. In May 2013 the US FDA approved dabrafenib as a single agent treatment for patients with BRAF V600E mutation-positive advanced melanoma. Some researchers believe that combination therapies that simultaneously block multiple pathways may improve efficacy by making it more difficult for the tumor cells to mutate before being destroyed. In October 2012

title: Avax Technologies
text: the cancer cells. Started May 2007. Currently in a Phase III trial for Stage IV Melanoma. MVax’s Phase II response rate of 35% (CR + PR) in combination with low-dose IL-2 compares favorably to the Phase II results of other melanoma cancer vaccines such as Vical’s Allovectin-7 (11% CR + PR) and BioVex’s OncoVex (28% CR + PR), both of which are given as stand alone therapy. Due to the Financial crisis of 2007–2010 and recent cancer vaccine failures in other companies like Favrille and Cell Genesys, Avax has had trouble attracting investors. In an effort to conserve cash, enrollment

title: Melanoma
text: therapies work by blocking the genes involved in pathways for tumor proliferation and survival. The main treatments are BRAF, C-Kit and NRAS inhibitors. These inhibitors work to inhibit the downstream pathways involved in cell proliferation and tumour development due to specific gene mutations. People can be treated with small-molecule targeted inhibitors if they are positive for the specific mutation. BRAF inhibitors, such as vemurafenib and dabrafenib and a MEK inhibitor trametinib are the most effective, approved treatments for BRAF positive melanoma. Melanoma tumors can develop resistance during therapy which can make therapy no longer effective, but combining the use of

title: Melanoma
text: categories of treatments including cytokines, immune check point inhibitors, and adoptive cell transfer. These treatment options are most often used in people with metastatic melanoma and significantly improves overall survival. However, these treatments are often costly. For example, one immune check point inhibitor treatment, pembrolizumab, costs $10,000 to $12,000 USD for a single dose administered every 3 weeks. Cytokine therapies used for melanoma include IFN-a and IL-2. IL-2 (Proleukin) was the first new therapy approved (1990 Europe, 1992 USA) for the treatment of metastatic melanoma in 20 years. IL-2 may offer the possibility of a complete and long-lasting remission in

title: BRAF (gene)
text: well-understood, high yield target. Vemurafenib (RG7204 or PLX4032) was licensed by the US Food and Drug Administration as Zelboraf for the treatment of metastatic melanoma in August 2011 based on Phase III clinical data. Improved survival was seen, as well as a response rate to treatment of 53%, compared to from 7-12% with the former best chemotherapeutic treatment, dacarbazine. In clinical trials, B-Raf increased metastatic melanoma patient chance of survival. In spite of the drug's high efficacy, 20% of tumors still develop resistance to the treatment. In mice, 20% of tumors become resistant after 56 days. While the mechanisms of

title: Cancer vaccine
text: cancers. Another approach is to generate an immune response "in situ" in the patient using oncolytic viruses. This approach was used in the drug talimogene laherparepvec, a version of herpes simplex virus engineered to selectively replicate in tumor tissue and to express the immune stimulatory protein GM-CSF. This enhances the anti-tumor immune response to tumor antigens released following viral lysis and provides a patient-specific vaccine. In a phase III trial of follicular lymphoma (a type of non-Hodgkin's lymphoma), investigators reported that the BiovaxID (on average) prolonged remission by 44.2 months, versus 30.6 months for the control. On April 14, 2009,

title: Ipilimumab
text: cancer. One of the three studies failed to meet its primary goal of shrinking tumors in at least 10.0% of the study's 155 patients. Side effects included rashes, diarrhea, and hepatitis. In 2010, a study was presented that showed a median survival of 10 months in advanced melanoma patients treated with ipilimumab, compared with 6 months for those treated with , an experimental vaccine (n=676). The one year survival rate was 46% in those treated with only ipilimumab, compared with 25% in those treated with gp100, and 44% for those receiving both. The Phase III clinical studies on the drug

title: Cancer vaccine
text: of a phase III clinical trial. The approval is for a subset of kidney cancer patients who are at intermediate risk for disease recurrence. It awaits approval in the US and EU. but will need a new trial for FDA approval. Interim results from a phase III trial of talimogene laherparepvec in melanoma showed a significant tumour response compared to administration of GM-CSF alone. Oncophage was approved in Russia in 2008 for kidney cancer. It is marketed by Antigenics Inc. Sipuleucel-T, Provenge, was approved by the FDA in April 2010 for metastatic hormone-refractory prostate cancer. It is marketed by Dendreon

title: CancerVax
text: signaling. Since this treatment is very general it has many complicated side effects. -Specific Active Immunotherapy: The generation of cell-mediated and antibody immune responses focused on specific antigens expressed by the cancer cells. Canvaxin is an example of this therapy. CancerVax partnered with Serono and released Canvaxin in 2004; a therapeutic polyvalent cancer vaccine. It was an antigen-rich, allogeneic whole-cell vaccine developed in 1984 from three melanoma cell lines and is the most extensively studied melanoma vaccine to date. However, on October 3, 2005, CancerVax announced the discontinuation of its Phase 3 clinical trial of Canvaxin in patients with Stage

title: Vemurafenib
text: has efficacy against the rarer BRAF V600K mutation. Melanoma cells without these mutations are not inhibited by vemurafenib; the drug paradoxically stimulates normal BRAF and may promote tumor growth in such cases. Three mechanisms of resistance to vemurafenib (covering 40% of cases) have been discovered: In a phase I clinical study, vemurafenib (then known as PLX4032) was able to reduce numbers of cancer cells in over half of a group of 16 patients with advanced melanoma. The treated group had a median increased survival time of 6 months over the control group. A second phase I study, in patients with

title: Cancer immunotherapy
text: locally advanced or metastatic urothelial carcinoma who: Ipilimumab (Yervoy) is a human IgG1 antibody that binds the surface protein CTLA4. In normal physiology T-cells are activated by two signals: the T-cell receptor binding to an antigen-MHC complex and T-cell surface receptor CD28 binding to CD80 or CD86 proteins. CTLA4 binds to CD80 or CD86, preventing the binding of CD28 to these surface proteins and therefore negatively regulates the activation of T-cells. Active cytotoxic T-cells are required for the immune system to attack melanoma cells. Normally inhibited active melanoma-specific cytotoxic T-cells can produce an effective anti-tumor response. Ipilumumab can cause a