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Seventh Annual T-Cell Lymphoma Forum January 29-31, 2015 The seventh annual T-Cell Lymphoma Forum was held in San Francisco at the end of January. This annual scientific meeting provides a forum for researchers, scientists and clinicians from around the world to come together to share updates and latest findings related to the biology of T-cell lymphoma as well as information about treatment options using existing therapies along with new therapies on the horizon. Although the meeting covers all T-cell lymphomas, there were several presentations specific to cutaneous T-cell lymphoma and posters presented by experts in the field. Drs. Pierluigi Porcu, Youn Kim, Madeleine Duvic, Christiane Querfeld and Miles Prince were among the cutaneous lymphoma presenters. The major take-away from this meeting was research to understand the molecular basis of T-cell lymphomas is ongoing and is essential to help ensure that new drugs and other therapies being developed specifically target the different types of T-cell lymphomas. Synopsis of Cutaneous T-Cell Lymphoma Presentations Biology of Cutaneous Lymphoma Understanding the molecular pathogenesis of Sézary syndrome There continues to be discussion among the clinical community in cutaneous lymphoma whether or not Sézary syndrome (SS) and mycosis fungoides are different stages of the same primary cutaneous T-cell lymphoma or distinct diseases with similar cellular tissue, immune system response and genetic features. Although significant advances are now being made in mapping the underlying cell biology of CTCL, the molecular development of Sézary syndrome is still poorly understood. In order to learn more about the overlap between MF and SS, as well as their distinct differences, additional studies are needed. Requirements for these new studies should include multi-institutional collaborations, the adoption of standardized approaches in patient selection and longitudinally-acquired samples from the same patients to detect changes in the mutational biology. Rare subtypes of T-cell lymphoma Primary cutaneous gamma-delta T-cell lymphoma (PCGD-TCL) is a very rare but aggressive form of T-cell lymphoma. Despite the very low incidence of these lymphomas, they are important to study because their extremely aggressive clinical course typically responds poorly to chemotherapy-based treatments. The effectiveness of newer therapies on these disorders is not well studied and long-term remissions have been achieved with stem cell transplantation. Additional studies to understand the biology of these rare subtypes are needed including international collaborative efforts to learn how to improve outcomes for these patients worldwide. Some responses have been seen using brentuximab vedotin and other non-chemotherapy agents. Microenvironment of CTCL Many factors contribute to the microenvironment of the cells that form cutaneous lymphoma. Researchers currently do not understand what stimulates the cancerous cells. Work is being done to understand the program death (PD-1) pathway in restoring the immune response to cancer cells. The normal immune system recognizes cancer cells and can mount an active anti-cancer cell response. One way the cancer cells can evade this normal immune response is to inhibit these cancer-fighting T-cells, deactivating them which allows the cancer cells to proliferate. By finding ways to reactivate this specific pathway with new therapies, the immune system might be restored and become active again in targeting the cancer cells and eliminating them. New Treatment Therapies in Cutaneous Lymphoma Therapeutic immune system approaches in CTCL A new drug that supports the immune system in doing its job to kill the cancerous cutaneous lymphoma cells (pembrolizumab) focuses on blocking the expression of PD1 and PD-L1 (program death) pathways that may play a significant role in blocking the growth of MF/SS cancer cells. Two cases of patients with relapsed MF were treated with this new targeted therapy in clinical trial and responded to the treatment. Phase II clinical trials are currently recruiting for this study at Stanford University Cancer Institute and the University of Pennsylvania. Comparative study chemotherapy vs biologics in MF/SS Numerous systemic treatment options exist for patients with mycosis fungoides and Sézary syndrome but no large comparative studies of the treatments have been published. In order to study the effectiveness of treatments, specifically the timing of treatment regimens, a retrospective analysis of data from the Peter MacCallum Cancer Centre in Australia was performed. The study reviewed 198 MF/SS patients undergoing systemic therapies, comparing chemotherapy regimens with interferon and histone deacetylase inhibitor therapies (HDACi - romidepsin and vorinostat are examples of the HDACi therapies). It showed that all the chemotherapy regimens assessed had very modest effectiveness when compared directly with interferon and HDACi therapies. Additionally, the non-chemotherapy regimens had a greater time lapse before the next treatment was required. The recommendation is that chemotherapy use be restricted until other options are exhausted. Brentuximab Vedotin (brand name Adcetris) in combination with other therapy Promising activity has been seen in a variety of T-cell lymphomas that express CD30 proteins on the cells. Multiple studies are in progress testing brentuximab vedotin in combination with different types of biologic and immune therapies as well as in combination with radiation therapy. The challenge in testing these combinations will be to minimize toxicity to the patient while optimizing the therapeutic benefit. A number of these trials are currently being undertaken in several cancer centers. Information on specific clinical trials for cutaneous lymphoma can be found on www.clinicaltrials.gov or by asking your treatment team about options that may be available at their center. Treatment review for CTCL Several therapies are approved for the treatment of mycosis fungoides and Sézary syndrome, although skin-directed therapies for early disease are still limited and options to treat advanced stage or large-cell transformation successfully remain challenging. New topical approaches currently in the development pipeline (i.e. topical resiquimod and vorinostat) may offer new options for treating early stage disease. Combination therapies along with new targeted therapies that treat the cancer cells with less toxicity are showing some promise. Because the malignant cells that cause cutaneous lymphoma are not uniform in structure (being somewhat unique to each person), future therapies need to target a variety of cell markers and pathways in order to improve overall survival. There is still a huge unmet need for safer, more effective and affordable agents for CTCL patients based on understanding individual molecular makeup. As identifying patient’s specific disease information becomes possible, we will be able to have better therapeutic outcomes. New agents in the pipeline for CTCL: ◦ ◦ ◦ ◦ ◦ ◦ ◦ ◦ SGX301 (synthetic hypericin) is a first-in-class potent photosensitizer which utilizes safe visible light for activation. Phase 2 clinical trial. SHP141 topical histone deacetylase inhibitor. Phase 2 clinical trial. Topical resiquimod. Phase 1 clinical trial. Topical sirolimus (rapamycin) in the treatment of early stage CTCL. E777 (improved purity denileukin diftitox). Phase 1 clinical trial. Topical Stat and JAK signaling pathway inhibitors in the wings. Electron beam - lower dose as palliative therapy. IPH4102 a first-in-class anti-KIR3DL2 antibody granted Orphan Drug Designation in Europe for the treatment of CTCL and has shown potent anti-cancer cell properties in early non-human models. A Phase 1 trial is in development. Diagnostic Updates in Cutaneous Lymphoma High throughput T-cell receptor sequencing Diagnosis of early stage cutaneous T-cell lymphoma is challenging due to skin lesions containing a mixture of both benign and malignant T-cells. High throughput T-cell receptor sequencing is a new method for identifying both the total malignant T-cells in a biopsy sample as well as the breadth of diversity of cell types. This type of diagnostic testing for cutaneous T-cell lymphoma can provide important quantitative data about the number of benign versus malignant cells, extent of disease and disease response to treatment. Cutaneous Lymphoma International Consortium (CLIC) Study The goal of the CLIC is large-scale scientific collaboration to study cutaneous lymphoma worldwide. The initial study undertaken by CLIC evaluated prognostic parameters in advanced stage MF/SS in a retrospective fashion. The pilot study demonstrated the intrinsic flaws of a retrospective analysis and the need for a prospective study. A collaborative, world-wide prospective study is currently being developed to capture an unprecedented large-scale collection of data, employing welldefined criteria with the hope that it may enable the building of a prognostic index model to augment the current clinical staging system. In Summary The T-Cell Lymphoma Forum provided an ideal venue for the exchange of clinical and research information. While progress in the development of new and effective therapies for T-cell lymphomas may seem slow, great strides are being made in gaining a better understanding of what is happening at the molecular level that will, in turn, lead to better and more targeted therapies resulting in longer remissions and less treatment toxicity for patients.