Translational medicine provides new insight for treating cutaneous lymphomas

Key Points

Boston - Clinical observations from the use of immune modulators and histone deacetylase (HDAC) inhibitors are providing researchers with clues into the mechanism of cutaneous T-cell lymphoma (CTCL), an expert says.

The classical understanding of translational medicine begins in the laboratory, where the biology of a disease is studied and this knowledge is used to create new drugs for the clinic, says Rachael Clark, M.D., Ph.D., assistant professor of dermatology, Brigham and Women's Hospital, Boston.

"But knowledge can also flow in the other direction. For example, when patients were given biologic tumor necrosis factor (TNF) inhibitors for the treatment of arthritis, patients with psoriasis experienced clearing of their skin. This gave us a key insight into the biology of psoriasis," Dr. Clark says.

With CTCL and other cancers, "We used to believe that cells became cancerous simply by accumulating mutations in their DNA," Dr. Clark says. However, the emerging field of epigenetics has shown that although gene mutations can contribute to carcinogenesis, dysregulation of gene expression also plays a critical role. "In other words," Dr. Clark says, "it is not only your genes that are important, it is what you do with them. Modification of gene expression plays a critical role in cancer."

Genes can be silenced by adding methyl groups to the DNA itself, or by modifying the histones that the DNA is coiled around, Dr. Clark says. The acetyl groups on histone proteins determine whether the chromatin is in an open configuration, allowing transcription, or in a closed configuration, preventing transcription, she adds.

"Epigenetic changes in gene expression are an early event in cancer progression. Cancer cells of many types, including CTCL, have aberrant HDAC activity and therefore have decreased transcription of multiple genes important for suppressing cancer progression," Dr. Clark says. HDAC inhibitors block histone deacetylation and therefore shift the DNA to a more open configuration, allowing gene expression. "When one treats tumor cells with HDAC inhibitors in vitro, effects include tumor cell differentiation, growth arrest and tumor cell death," she says.

HDAC inhibitors approved by the Food and Drug Administration include Zolinza (vorinostat, Merck), Istodax (romidepsin, Gloucester) and panobinostat (LBH589, Novartis). These drugs achieve partial responses in about 30 percent of patients and may work best in combination with other drugs, Dr. Clark says.

Immune modulation

Immunomodulatory therapies for CTCL include extracorporeal photopheresis (ECP), which involves removing blood, exposing it to psoralen and UVA light and then re-infusing it. ECP is also effective in the treatment of autoimmune and inflammatory disorders, including graft vs. host disease and allograft rejection, Dr. Clark says. "In these diseases, ECP appears to work by inducing tolerance - particularly by enhancing the development of regulatory T cells," she says.

Findings from the lab of Madeleine Duvic, M.D., professor of internal medicine and dermatology and deputy chairwoman of dermatology, MD Anderson Cancer Center, Houston, demonstrate that ECP probably works via a similar mechanism in CTCL (Duvic M, Chiao N, Talpur R. J Cutan Med Surg. 2003 Jul-Aug;7(4 Suppl):3-7). In particular, Dr. Clark notes, researchers have shown in vitro that ECP induces tolerogenic dendritic cells (DCs) that enhance regulatory T-cell function and shift T cells toward a Th2 phenotype.

"There appear to be both good and bad types of inflammation in CTCL," Dr. Clark says. She notes that the study of CTCL can be confusing, because both the cancer and the immune response to the cancer involve T cells. There are T cells in which inflammation is pathogenic and may lead to progression; for example, stimulation of the malignant CD4 T cells. "On the other hand, stimulation of tumor-specific CD8 T cells with interferon can improve CTCL," she says.

As for regulatory T cells, Dr. Clark says the picture is again confusing. A subset of patients with leukemic CTCL have a true malignancy of regulatory T cells, but these patients are a minority. "In most patients, studies have shown that maintenance of a normal, benign regulatory T-cell population in the blood and skin is associated with better prognosis. This is consistent with the idea that ECP improves disease by increasing regulatory T cells," she says.

TLR agonists

Toll-like receptor (TLR) agonists approved or under study for CTCL include imiquimod (TLR7) and resiquimod (TLR8). TLR7 agonists primarily stimulate plasmacytoid DCs, a cell type found primarily in inflamed skin and in skin cancers, Dr. Clark says. TLR7 agonists stimulate plasmacytoid DCs (PDCs) to produce type 1 interferons, which leads to activation of endothelial cells, innate immune cells and T cells. Thus, treatment with imiquimod leads to inflammation only in skin in which PDCs are present.

"This is why we see inflammation of subclinical actinic keratoses (AKs) in our patients treated with imiquimod. The AKs contain PDCs, but normal skin does not," Dr. Clark says.

However, resiquimod has the capacity to stimulate all of the DCs in skin, which express TLR8, and thus resiquimod can induce inflammation in both normal and inflamed or precancerous skin, Dr. Clark says. Therefore, resiquimod is more useful than imiquimod for single-application adjuvant cancer treatment or immune system boosting. "It's not a problem-seeking molecule like imiquimod," she says.

Dr. Clark and colleagues used daily topical imiquimod therapy to treat a patient with refractory Sézary syndrome which had recurred with mycosis fungoides (MF)-like lesions following stem cell transplantation. "The lesions got bigger, then they cleared from the center outward. What this pattern says about CTCL biology is not yet clear, but it's trying to teach us something," she says.

Alemtuzumab

Dr. Clark, Thomas Kupper, M.D., and their colleagues have been achieving exciting results with alemtuzumab, an anti-CD52 humanized antibody that depletes T and B cells. Dr. Kupper is Thomas B. Fitzpatrick Professor of Dermatology, Harvard Medical School, and chairman, dermatology, Brigham and Women's Hospital.

When used at 30 percent of the dose previously used to treat chronic lymphocytic leukemia, alemtuzumab induced complete responses in nine of 11 patients with highly refractory leukemic CTCL (Clark R, Watanabe R, Fisher DC, et al. Poster 278. Society for Investigative Dermatology Annual Meeting, Atlanta, 5-8 May 2010). One patient achieved partial clearance, and another patient's treatment was ongoing at press time, Dr. Clark says. Furthermore, although alemtuzumab depleted T and B cells from the blood, it produced no severe infectious complications.

Biopsies of normal-appearing skin in treated patients showed that despite the lack of circulating T cells, "There were a significant number of T cells in the skin," Dr. Clark says. "Interestingly enough, both the skin and blood T cells all expressed CD52, but it appeared that only T cells that entered the bloodstream were depleted by alemtuzumab. T cells remaining in the skin of these patients were similar to those found in normal skin, except that the malignant clone and the population of central memory cells had been depleted.

"We now realize that during the immune response, effector memory cells are generated that home to the skin and do not migrate," she says. Central memory cells are also generated, and these cells recirculate between the blood and lymph nodes, and a subset can also enter the skin. "In normal skin, 20 to 25 percent of T cells are migratory central memory T cells, and the remainder are skin-resident, nonmigratory effector cells."

Drs. Clark and Kupper and James Campbell, Ph.D., have found that MF and leukemic CTCL likely represent malignancies of two different T-cell subsets. Dr. Campbell is assistant professor of dermatology, Harvard Medical School and Brigham and Women's Hospital.

In MF, Dr. Clark explains, "Nonmigratory skin-resident T cells appear to be the culprit, whereas it is the migratory central memory T cells that undergo malignant transformation in leukemic CTCL and Sézary syndrome."

Alemtuzumab is effective in leukemic CTCL because the malignant T cells are migratory and are depleted by alemtuzumab when they enter the blood, Dr. Clark says. Conversely, alemtuzumab spares skin-resident T cells because they are nonmigratory. "This also explains why this medication does not appear to work in MF. The malignant cells in this disease do not migrate and are not depleted by the medication.

"This is a perfect example of the patients teaching us something important about the disease. Although previously shown in mice, this is the first demonstration in humans that these two T-cell subsets have different abilities to migrate," she says.

Disclosures: Dr. Clark previously served on the scientific advisory board for Therakos.