Alternative Splicing of the Inhibitory Immune Checkpoint Receptor SLAMF6 Generates a Dominant Positive Form, Boosting T-cell Effector Functions.

SLAMF6 is a homotypic receptor of the Ig-superfamily associated with progenitor-exhausted T cells. Here we show that in humans, SLAMF6 has three splice isoforms involving its V-domain. Although the canonical receptor inhibited T-cell activation through SAP recruitment, the short isoform SLAMF6Δ17-65 had a strong agonistic effect. The costimulatory action depended on protein phosphatase SHP1 and led to a cytotoxic molecular profile mediated by the expression of TBX21 and RUNX3. Patients treated with immune checkpoint blockade showed a shift toward SLAMF6Δ17-65 in peripheral blood T cells. We developed splice-switching antisense oligonucleotides (ASO) designed to target the relevant SLAMF6 splice junction. Our ASOs enhanced SLAMF6Δ17-65 expression in human tumor-infiltrating lymphocytes and improved their capacity to inhibit human melanoma in mice. The yin-yang relationship of SLAMF6 splice isoforms may represent a balancing mechanism that could be exploited to improve cancer immunotherapy.

Widespread morbilliform rash due to sorafenib or vemurafenib treatment for advanced cancer; experience of a tertiary dermato-oncology clinic.

BACKGROUND: In the literature, there are minimal data for the treatment of grade 2 or 3 morbilliform/atypical target lesion rashes secondary to sorafenib or vemurafenib given for patients with advanced stage cancer. This poses a dilemma for clinicians, particularly in patients with advanced neoplastic disease for whom other optional treatments are limited. METHODS: The cohort included data on all patients attending the dermato-oncological clinic at a tertiary medical center that presented in 2011-2014 with a widespread rash following treatment with sorafenib or vemurafenib. All patients were prospectively followed. RESULTS: Eight patients met the study criteria. Five, under sorafenib, aged 50-65 years, presented with an extensive grade 2 (involving 20-30% of the body surface area, two patients) or grade 3 (three patients) morbilliform rash, 5-10 days after onset of the drug. Two had atypical target lesions. The dosage was temporarily reduced in only two patients, and oral steroids were added in four. Under vemurafenib, three patients presented with an extensive grade 3 morbilliform rash 5-10 days after onset of treatment. Two had atypical target lesions. The dose was temporarily reduced in one, and another patient stopped the drug at her own initiative; both also received steroids. The rash subsided after 2-3 weeks in all eight patients, allowing continuation of the treatment at the regular dose. CONCLUSION: Our cohort suggests that not all cases of widespread morbilliform rash or atypical erythema multiforme, which occur under treatment with sorafenib or vemurafenib, given for advanced cancer, require discontinuation of therapy.

An open trial of climatotherapy at the Dead Sea for patch-stage mycosis fungoides.

BACKGROUND: Climatotherapy at the Dead Sea (CDS) is a well-established therapeutic modality for moderate to severe psoriasis vulgaris, resulting in sustained remissions. It has also been found to be effective for atopic dermatitis, another T-cell-mediated dermatosis. OBJECTIVE: We sought to prospectively evaluate the efficacy of CDS in patch-stage mycosis fungoides. METHODS: A total of 12 patients with patch-stage mycosis fungoides (6 with stage IA and 6 with stage IB) were treated with CDS as monotherapy for 28 consecutive days according to the protocol for psoriasis, ie, a gradual increase of sun exposure to a maximum of 3 hours daily. RESULTS: A total of 9 patients achieved a complete clinical response (CCR), defined as no disease activity present; 2 achieved an almost CCR, defined as the reduction by more than 90% of disease activity; and 1 achieved a partial response, ie, reduction by more than 50% of disease activity. A CCR was achieved in all the patients with stage IA disease and in 3 of the 6 patients with stage IB disease. Of the 9 with a CCR, 6 also showed histopathologic clearing. Duration of the remissions, during which no therapy was allowed except for emollients, lasted from 2 to 9 months (mean: 5 months). No serious short-term side effects were recorded. CONCLUSION: CDS appears to be an effective, well-tolerated therapy for patch-stage mycosis fungoides.