Michael R. Page, PharmD, RPh

Cytotoxic T-lymphocyte-Associated Protein-4,

from notable researchers at Memorial Sloan Kettering reported a case of complete remission of metastatic melanoma in a patient treated with single doses of ipiliumab and nivolumab.

The complete remission occurred in a patient enrolled in an early phase I trial. Overall results of the 13-patient trial (NCT02186249) showed that more than half (53%) of patients experienced tumor shrinkage of 80% or more.

The best response in the trial, reported in the letter, occurred in a women aged 49 years who had an ulcerated lesion of melanoma skin cancer. The cancer had been removed surgically from an area on her back 4 years prior to the phase I study.

Before treatment, the cancer had metastasized through a large portion of underside of the woman's chest, yet 3 weeks later there was no evidence of disease, including no masses visible on CT scan.

Regarding the response, researchers wrote, &ldquo;We wish to bring this to the attention of our colleagues&hellip;as an example of the potential of immunotherapy to mediate dramatic and rapid antitumor effects.&rdquo; However, such rapid responses might also carry safety concerns, the researchers noted, &ldquo;Such an antitumor effect occurring in a transmural metastasis in the small bowel or myocardium, common sites of metastatic melanoma, could have grave consequences. It is ironic that we are now concerned about the possibility of overly vigorous antimelanoma responses.&rdquo;

The results of this case report, and the small phase I study from which it originated, bode well for the combination of nivolumab and ipilimumab in treatment of advanced cases of metastatic melanoma. With several immunotherapies in development, finding optimal combinations for a variety of patient types and cancer types will likely include a combination of intensive research with results from exceptional cases such as this one.

------------------------------------------

Chapman PB, D'Angelo SP, Wolchok JD. Rapid eradication of a bulky melanoma mass with one dose of immunotherapy.

Articles

A letter to the editor in the New England Journal of Medicine from notable researchers at Memorial Sloan Kettering reported a case of complete remission of metastatic melanoma in a patient treated with single doses of ipiliumab and nivolumab.

Case Shows Dramatic Antitumor Effects With Immunotherapy in Melanoma

Radix ginseng is the dried root of Panax ginseng.

, ginseng polysaccharides may affect the balance of T-helper cells in patients with non-small cell lung cancer (NSCLC).

Research teams at several locations in China and Taiwan recruited a total of 96 patients with NSCLC to participate in the study. Patients received either dendritic cell therapy alone or dendritic cell therapy with ginseng polysaccharides.

Both dendritic cells and the ginseng extract were administered through a thoracoscope directly into the lungs to target the tumor site. Dendritic cells were administered at a dose of 60,000 cells per kg, and ginseng polysaccharides were administered at a dose of 0.5 mg/kg. Treatments were repeated every week for 1 month.

Before and after treatment, investigators assessed each patient&rsquo;s functional status using the Functional Assessment of Cancer Treatment-Lung (FACT-L) questionnaire. Investigators also measured levels of serum interferon-gamma, several interleukins (ILs) including IL-2, -4, and -5, and markers of T-helper cell activity.

A total of 48 patients were assigned to each group. All patients in the trial had either stage IIIA or IIIB cancer and had received between 3 and 6 cycles of prior chemotherapy and stopped using chemotherapy for at least 1 month before entering the study. The youngest and oldest patients enrolled in the trial were aged 30 years and 70 years, respectively.

The expression of both Th1 cytokines and the ratio of Th1 to Th2 cytokines were increased, while levels of Th2 cytokines decreased. Because Th1 expression is important in cell-mediated immunity and inhibition of tumor cell proliferation, and because Th2 expression may promote tumor cell proliferation, these changes suggest an improved anticancer immune response with dendritic cell therapy and ginseng versus dendritic cell therapy alone.

All changes in cytokine levels were significantly different from changes in the control group at the 1% significance level. In addition, changes in total FACT-L scores on physical, community/family, emotional, functional, and total status were significantly improved in patients receiving ginseng polysaccharides versus comparator patients, also at the 1% significance level or lower.

Ginseng is a compound with immunomodulatory effects. Although it is known to have a stimulatory effect, which may account for some of the improvement in quality of life scores, changes in cytokine levels in association with ginseng treatment indicate a possible synergistic antitumor effect of ginseng polysaccharides with dendritic cell therapy.

As more and more treatments harness the power of the immune system, treatments that work to potentially enhance the effectiveness of these immunologic agents may have a future role in the management of some patients with NSCLC.

1. Ma J, Liu H, Wang X. Effect of ginseng polysaccharides and dendritic cells on the balance of Th1/Th2 T helper cells in patients with non-small cell lung cancer.

2. Ru W, Wang D, Xu Y, et al. Chemical constituents and bioactivities of Panax ginseng (C. A. Mey.).

Ginseng polysaccharides may affect the balance of T-helper cells in patients with non-small cell lung cancer.

Ginseng May Enhance Dendritic Cell Therapy in NSCLC

In a study published by Chang Xia, MD, PhD, and colleagues affiliated with several hospitals and treatment centers in the Midwestern United States, investigators reported results of an early trial using a triple therapy strategy of temozolomide plus panobinostat and decitabine for patients with resistant metastatic melanoma.

Because this was an early trial, investigators focused on safety and tolerability.

For the first week of therapy, patients received subcutaneous injections of decitabine 3 times weekly. During the second week of therapy, patients received 3 weekly injections of decitabine in addition to oral doses of panobinostat (administered every 4 days) and daily oral doses of temozolomide. Although each treatment cycle lasted 6 weeks, patients received treatment on the first 2 weeks of each cycle. In the trial, patients received up to 6 cycles of treatment or up to 36 weeks of therapy.

About 65% of patients enrolled in the trial were male, and the remaining third were female. Patients enrolled in the trial had a median age of 56 years. Of all 17 patients treated, efficacy was not evaluable in nine patients because of disease progression before completion of 2 treatment cycles. Of the remaining eight patients who were considered evaluable, two patients did not respond to therapy, five patients had stable disease, and one patient experienced a complete response. In the patient with a complete response, the patient&rsquo;s response continued for 8 months before relapse occurred (

Figure 1. Result of combination therapy with panobinostat, decitabine, and temozolomide in patients with metastatic melanoma.

No dose-limiting toxicities or maximum tolerable medication doses were identified in the trial. However, investigators identified several adverse events (AEs) that were considered related to treatment, including grade 3 lymphopenia, anemia, neutropenia, and fatigue, as well as grade 2 leukopenia, neutropenia, nausea, and lymphopenia. Although treatment is associated with several AEs, the five cases of stable disease and one case of a complete response to therapy indicate an early positive result that may lead to further development of targeted therapies to alter epigenetic signaling in melanoma.

Although no indications for epigenetic therapies in melanoma have been secured, therapies that are active on epigenetic targets have recently gained approvals in the treatment of some types of cancers, including multiple myeloma and cutaneous T-cell lymphoma. Among these agents, the HDAC inhibitor panobinostat has been considered a strong candidate for treatment of melanoma because of its direct cytotoxicity against melanoma cells in vitro and its immunostimulant properties of the immune system on tumor cells.

For instance, in early 2013, Woods and colleagues published a study supporting the efficacy of panobinostat in an animal model of melanoma. In mice implanted with melanoma cells, panobinostat significantly improved survival, but only in mice that were not treated with immunosuppressive medications. The fact that survival advantages in mice treated with panobinostat were eliminated in immunocompromised mice further supports the immunomodulatory effects of panobinostat as its anticancer mechanism. Research has confirmed that programmed cell death ligand 1 (PD-L1) inhibitors and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors augment the innate anticancer activity of tumor-infiltrating lymphocytes. Now emerging evidence indicates that panobinostat may be similarly active in enhancing tumor-infiltrating lymphocyte activity against melanoma cells.

Considering the preclinical evidence of the immunomodulatory effect and potentially synergistic effect of panobinostat with immunotherapies, it is not surprising that researchers at the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, are recruiting participants for a clinical trial to test the combination of panobinostat and ipilimumab in patients with melanoma (NCT02032810).

is recruiting adult patients with stage III and stage IV metastatic melanoma who have had up to 3 prior treatments, have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and have laboratory values within certain parameters.

Epigenetic-active agents have already been approved for the treatment of certain types of cancer. Although use of these agents as a monotherapy is unlikely, use of treatments such as HDAC inhibitors may enhance the effectiveness of other treatments, such as CTLA-4 inhibitors and PD-L1 inhibitors. By finding more agents to enhance the effectiveness of existing treatments and new combinations of treatments, scientists are making headway in the fight against metastatic melanoma.

1. &nbsp;&nbsp; Xia C, Leon-Ferre R, Laux D, et al. Treatment of resistant metastatic melanoma using sequential epigenetic therapy (decitabine and panobinostat) combined with chemotherapy (temozolomide).

2. &nbsp;&nbsp; Woods DM, Woan K, Cheng F, et al. The antimelanoma activity of the histone deacetylase inhibitor panobinostat (LBH589) is mediated by direct tumor cytotoxicity and increased tumor immunogenicity.

3. &nbsp;&nbsp; National Institutes of Health. Phase I of Histone Deacetylase (HDAC) Inhibitor Panobinostat With Ipilimumab With Unresectable III/IV Melanoma. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02032810. Accessed April 2015.

Using treatments that target epigenetic pathways, including the DNA methyltransferase inhibitor decitabine and the histone deacetylase (HDAC) inhibitor panobinostat, investigators hoped to improve the sensitivity of melanoma cells to the alkylating agent temozolomide.

Michael R. Page, PharmD, RPh | Authors

Articles

Case Shows Dramatic Antitumor Effects With Immunotherapy in Melanoma

Ginseng May Enhance Dendritic Cell Therapy in NSCLC

Epigenetic-Active Agents May Improve Sensitivity to Temozolomide in Melanoma