An update on recent news, research and treatment trends for skin cancer.

UCLA Researchers Genetically Engineer Blood Stem Cells To Fight Melanoma

Researchers from the University of California, Los Angeles, have engineered melanoma-specific T cells that target a specific antigen of the deadly skin cancer that resulted in both a reduction in tumor size and complete elimination of tumors.

Building on previous work in which the researchers generated engineered T cells, Jerome Zack, senior author and professor of medicine and microbiology, immunology and molecular genetics in the UCLA Life Sciences division, and colleagues used a T-cell receptor cloned from a cancer patient that seeks out an antigen expressed by a certain type of melanoma. Human blood stem cells were then genetically engineered by importing genes from the T-cell receptor into the stem cell nucleus with a viral vehicle.

These engineered blood stem cells were placed into human thymus tissue that had been implanted into mice in order to examine the human immune system’s response to melanoma in a living organism. Over the course of about 6 weeks, the engineered blood stem cells grew into a large population of mature, melanoma-specific T cells that targeted the correct cancer cells.

To determine the impact of these stem cells in melanoma, the researchers induced two types of melanoma tumors in mice, one of which expressed the antigen complex that attracts the engineered T cells and another that did not attract these T cells. The engineered cells specifically went after the antigen-expressing melanoma, ignoring the control tumor, according to the researchers. Of the nine mice included in the study, four experienced complete elimination of the antigen-expressing melanomas and five had their tumors decrease in size. Response was measured by physical tumor size and the metabolic activity of the cancer, which was evaluated with positron emission tomography.

The researchers are hopeful this strategy can be tested in clinical trials. One approach to such a trial would be to engineer both the peripheral T cells and the blood stem cells that give rise to T cells. The peripheral T cells would serve as the front-line cancer fighters and the blood stem cells would be a second line of defense as the function of the first wave of T cells wanes, according to the researchers.

Vatakis DN, Koya RC, Nixon CC, Wei L, Kim SG, Avancena P, et al. Antitumor activity from antigen-specific CD8 T cells generated in vivo from genetically engineered human hematopoietic stem cells. PNAS, 2011, doi: 10.1073/pnas.1115050108

Mechanism of Resistance to Vemurafenib Identified

The identification of a mechanism of resistance to vemurafenib, the melanoma drug approved in August 2011, could enable researchers to develop additional treatments and recommend combinations of vemurafenib (Zelboraf) and other drugs that can overcome this resistance.

Drug resistance is common with most targeted inhibitors, according to Dr. David Solit, an attending physician at Memorial Sloan-Kettering Cancer Center and senior author on the study. Dr. Solit and colleagues examined a subset of cells that are resistant to vemurafenib, PLX4032 and RG7204, and found that these cells express a 61-kDa variant form of BRAF (V600E), p61BRAF (V600E), a region that encompasses the RAS-binding domain and lacks exons 4-8; p61BRAF (V600E) shows enhanced dimerization in cells with low levels of RAS activation in comparison to full length BRAF (V600E), according to the article on the study published in Nature.

Vemurafenib is a BRAF inhibitor that blocks the function of the V600E-mutated BRAF protein. The examination of these cells that are resistant to the drug revealed that, in cells that express p61BRAF (V600E) endogenously or ectopically, ERK signaling is resistant to the RAF inhibitor. In addition, a mutation that abolishes the dimerization of p61BRAF (V600E) restores its sensitivity to vemurafenib, according to the Nature article. The researchers also identified BRAF (V600E) splicing variants in the tumors of six of 19 patients taking vemurafenib who had acquired resistance to the drug.

These results “identify a novel mechanism of acquired resistance in patients: expression of splicing isoforms of BRAF (V600E) that dimerize in a RAS-independent manner,” the authors conclude in the Nature article.

Poulikakos PI, Persaud Y, Janakiraman M, Kong X, Ng C, Moriceau G, et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF (V600E). Nature, 2011, doi: 10.1038/nature10662

P-Rex1 Protein Plays Key Role in Spread of Melanoma

The P-Rex1 protein, a Rac-specific Rho GTPase guanine nucleotide exchange factor, has been identified as a key player in the spread of melanoma.

Researchers from the Beatson Institute of Cancer Research made the discovery in the course of examining melanoblasts, which are involved in the early development of the skin. As the research went on, the team, led by Owen J. Sansom of the Beatson Institute, found that mice who lacked the gene that makes P-Rex1 had skin cancers that did not spread. Upon discovering this, the team tested human melanoma cells and tumor tissue, which revealed raised levels of PRex-1, suggesting that the protein was involved in the movement of the cells.

This discovery implies that P-Rex1 is downstream of BRAF, significant because it could mean that drugs targeting P-Rex1 could help the 20% of people with melanoma who do not have a faulty BRAF gene. The researchers believe that this new knowledge will provide a better understanding of how the cells work, enabling them to better select a target for new melanoma treatments.

Lindsay CR, Lawn S, Campbell AD, Faller WJ, Rambow F, Mort RL, etal. P-rex1 is required for efficient melanoblast migration and melanoma metastasis. Nature Communications, 2011, doi: 10.1038/ncomms1560

Monoclonal Antibody for Malignant Melanoma Demonstrates Positive Results in Clinical Trials, Though Researchers Report Concern About Adverse Events

Ipilimumab (Yervoy), a monoclonal antibody developed by Bristol-Myers Squibb for malignant melanoma (MM), is demonstrating positive results so far in clinical trials, according to a recent study in Dermatology Research and Practice (DRP).

Ipilimumab is a fully humanized IgGI monoclonal antibody directed to cytotoxic T-lymphocyte antigen 4 (CTLA-4). In clinical trials, objective response rates combining complete response (CR) and partial response (PR) were in the 5% to 20% range. Disease control rates (CR + PR + stable disease) averaged between 15% and 30%. In comparison, high-dose interleukin-2 and dacarbazine — two FDA-approved therapies for melanoma — were associated with response rates of only 10% to 20% and a small percentage of CR, according to the article in DRP. These therapies are not thought to improve overall survival, according to the study authors

Although higher doses of ipilimumab were associated with higher response rates, increased dosage was also associated with increased toxicity. According to the authors, the drug is the first to show prolonged overall survival (OS) in patients with metastatic melanoma (median OS, 10.1 months); this is in comparison to other current therapies that lead to a median OS of 6 to 9 months.

Adverse events (AEs) in patients taking ipilimumab were dose-dependent, schedule-regulated and cumulative; the majority of AEs were autoimmune, affecting the skin, gastrointestinal tract and endocrine glands. Grade 3 and 4 AEs — severe and life-threatening AEs, respectively, according to an appendix in the World Health Organization (WHO) Toxicity Grading Scale from 2003 — were reported in 20% to 30% of patients. Life-threatening immune-related adverse events (irAEs) were reported long term at the 2-year follow-up point in Phase III trials and included dermatologic problems (rash, vitiligo and pruritus), colitis/diarrhea and endocrine-related AEs. Life-threatening irAEs — bowel perforation due to immune colitis — were reported in about 2% of patients treated with ipilimumab. Up to 50% of treatment-related deaths were associated with irAEs.

The researchers acknowledge the severity of these AEs in the conclusion of the article in DRP: “It seems essential to tailor treatment options to those patients most likely to benefit, especially because the treatment is associated with frequent and sometimes life-threatening irAEs.”

However, despite these significant risks, they also write: “Ipilimumab is the first agent demonstrating promise in the treatment of metastatic MM. The positive but modest OS benefit requires more investigations.”

Piérard GE, Aubin F, Humbert P. Ipilimumab, a promising immunotherapy with increased overall survival in metastatic melanoma? Derm Research and Practice, 2012, doi: 10.1155/2012/182157

Decreased Antioxidant Levels May Explain Higher Rates of Squamous Cell Carcinoma in Men

Decreased levels of the antioxidant catalase may be the reason that men are three times more likely to develop squamous cell carcinoma, according to researchers at Ohio State University Comprehensive Cancer Center (OSUCCC).

Catalase, a protein, halts the development or progression of skin cancer by “mopping up” hydrogen peroxide and other DNA-damaging reactive-oxygen compounds that form during exposure to UVB light, according to the researchers, co-led by Gregory Lesinski and Tatiana Oberyszyn, both of the OSUCCC. Lesinski, Oberyszyn and the team found that male mice produced lower levels of catalase than female mice and had increased amounts of certain cancer-linked inflammatory cells compared to female mice.

“The findings suggest that women may have more natural antioxidant protection in the skin than men,” the researchers explain. “As a result, men may be more susceptible to oxidative stress in the skin, which may raise the risk of skin cancer in men compared to women.”

The study also revealed that exposure to UVB initiated a unique population of inflammatory white blood cells called myeloid-derived suppressor cells to move from the bone marrow into the UVB-exposed skin; higher numbers of these cells migrated in male mice than female mice.

“To our knowledge, we’ve shown for the first time that UVB exposure causes a migration of systemic myeloid-derived suppressor cells, and it suggests that these cells might be a novel source of UVB-induced immune suppression,” explains Nicholas Sullivan, a researcher in the Oberyszyn lab and first author of the article on the study published in the Journal of Investigative Dermatology.

After establishing these findings, the researchers treated mice with topical catalase, which inhibited the migration of the suppressor cells into UVB-exposed skin; male mice with UVB-induced skin tumors had 55% more of the suppressor cells in the skin than the female mice. This suggests, according to the researchers, that the influx of these cells in males might be because of the relatively low skin-catalase activity.

“This is the first report to our knowledge of a sex discrepancy in this group of inflammatory cells in tumor-bearing mice, and it suggests that our findings might translate to other types of cancer,” Oberyszyn, an associate professor of pathology, says. “Men face a higher risk of numerous types of cancers and relatively higher levels of inflammatory myeloid cells might contribute to this susceptibility.”

Sullivan NJ, Tober KL, Burns EM, Schick JS, Riggenbach JA, Mace TA. UV light B-mediated inhibition of skin catalase activity promotes Gr-1+CD11b+ myeloid cell expansion. Jour Invest Derm, 2011, doi: 10.1038/jid.2011.329

Patients With Inflammatory Bowel Disease Have Increased Risk Of Skin Cancer, Especially Those Taking Thiopurine

Patients with inflammatory bowel disease (IBD) who are currently taking or who have taken thiopurines, a frequently used class of immunosuppressants for the treatment of IBD, may be at an increased risk of skin cancer.

The researchers, who were from a number of organizations around the world, performed two studies with patients who were currently taking or had taken thiopurines and control patients. In the first study, the researchers determined that past and present exposure to the immunosuppressant drug significantly increased an individual’s risk of non-melanoma skin cancer (NMSC), even before age 50. The second study revealed that certain individuals with IBD may have a baseline increased risk of basal cell carcinoma (BCC) and an increased risk of squamous cell carcinoma (SCC) with the use of thiopurines.

In the article on the study published in Gastroenterology, the authors report that, before age 50, “crude incidence rates of NMSC among patients currently receiving or who previously received thiopurines were 0.66/1000 and 0.38/1000 patient-years, respectively.” These values were 2.59/1000 and 1.96/1000 patient-years for patients 50 to 65 years of age and 4.04/1000 and 5.70/1000 patient-years for patients older than 65, according to the Gastroenterology abstract. Patients who had never received thiopurines were at zero risk for NMSC before age 50, 0.60/1000 for patients 50 to 65 years of age and 0.84/1000 for individuals older than 65 years.

The researchers also performed a multivariate Cox regression model stratified by propensity score quintiles, which revealed that ongoing thiopurine treatment (hazard ratio [HR], 5.9; 95% confidence interval [CI], 2.1–16.4; P = .0006) and past thiopurine exposure (HR, 3.9; 95% CI, 1.3–12.1; P = .02) were risk factors for NMSC. Age per one-year increase was also identified as a risk factor (HR, 1.08; 95% CI, 1.05–1.11; P < .0001).

The researchers conclude that any exposure to thiopurines, past and present, significantly increases a patient’s risk for NMSC, even before the age of 50. They also recommend diligent protection against UV exposure for these patients and lifelong dermatologic screening.

Peyrin-Biroulet L, Khosrotehrani K, Carrat F, Bouvier AM, Chevaux JB, Simon T, et al. Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease. Gastroenterology 2011; 141(5):1621-1628

Idera Pharmaceuticals Regains Rights to Investigational Drug for Squamous Cell Carcinoma

Idera Pharmaceuticals has regained its global rights to IMO-2055, an agonist Toll-like Receptor (TLR) 9, as part of the termination agreement with its oncology partner Merck KGaA, Damstadt, Germany.

The agreement allows Merck KGaA to complete an ongoing randomized Phase II trial of IMO-2055 in patients with squamous cell carcinoma of the head and neck (SCCHN) and gives Idera rights to the data from that trial. When this trial is complete, Idera will be the sole party responsible for conducting continued research on IMO-2055.

In regard to the monetary aspects of the agreement, Idera will reimburse Merck KGaA approximately 1.8 million Euros for expenses during the course of the Phase II trial and make milestone payments of 1 million Euros each upon entering into any future partnership for IMO-2055, upon initiating the next clinical trial of the drug that is Phase II or III and upon the regulatory submission of IMO-2055 to any country.

According to Idera, the following data from clinical trials should be available shortly:

• A Phase Ib clinical trial of IMO-2055 in combination with Tarceva® and Avastin® in patients with advanced non-small cell lung cancer (NSCLC).

• The NSCLC Phase Ib clinical trial evaluated four dose levels of IMO-2055 in combination with Tarceva and Avastin. Thirty-six patients have been recruited in this trial and data analysis is ongoing.

• A Phase Ib clinical trial of IMO-2055 in combination with Erbitux and FOLFIRI (5-fluorouracil/leucovorin/irinotecan) in patients with metastatic colorectal cancer (CRC).

• The CRC Phase Ib clinical trial evaluated three dose levels of IMO-2055 in combination with Erbitux and FOLFIRI. Twenty-two patients have been recruited and data analysis is ongoing.

• A randomized Phase II clinical trial of IMO-2055 in combination with Erbitux versus Erbitux alone as a second-line treatment in patients with recurrent and/or metastatic SCCHN.

The design of the Phase II study provides for the enrollment of 104 patients, 52 in each of the two arms. Crossover of patients from Erbitux alone to IMO-2055 in combination with Erbitux is permitted under specified circumstances. The primary endpoint of the trial is progression-free survival. This study is fully enrolled and patient treatment and follow-up are ongoing.