ALBERT

Description: Introduction: MAVORIC was an open-label, multicenter, randomized phase 3 study evaluating the safety and efficacy of mogamulizumab (moga) compared to vorinostat (vori) in patients with mycosis fungoides (MF) or Sézary syndrome (SS) who had failed at least one prior course of systemic therapy (NCT01728805). Primary results have been reported (Kim et al. Lancet Oncol 2018) and were based on a data cutoff date of December 31, 2016. The primary endpoint was progression-free survival (PFS); patients in the moga treatment arm experienced significantly longer PFS compared to patients in the vori treatment arm (median 7.7 months vs 3.1 months; p

Description: Treatment of advanced mycosis fungoides (MF)/Sézary syndrome (SS) remains difficult as virtually all pts become refractory to most standard therapies. The CD52 monoclonal antibody alemtuzumab is a new therapeutic option. We report from a clinical trial as well as clinical use in E-CTCL. Alemtuzumab was IV administered at a dose of 30 mg three times per week (t.i.w.) for 4 weeks (Dose 1 and 2: 3 mg and 10 mg, respectively) followed by SQ administration of 30 mg for an additional 8 weeks t.i.w. All pts received prophylactic treatment with TMP-SMZ, acyclovir, and fluconazole until immune reconstitution. 19 pts with E-CTCL have been treated to date. 15 pts have been enrolled into the study; while 4 pts who did not meet the pre-study criteria were treated off study (including second malignancy without recurrence diagnosed within 5 years prior study entry in 2 pts and living too remote from study center in 2 pts). Median age was 63 yrs, (39 to 88 years). Clinical stages were: 8 (42%) stage III; 10 (53%) stage IVA; 1 (5%) stage IVB. All pts were heavily pretreated with a median of 5 prior treatments. The ORR was 79% (15 pts.) with CR in 47% (9 pts) and PR in 32 % (6 pts) with effective clearing of circulating Sézary cells in 100%. Four pts (21%) developed PD with the development of cutaneous tumors in one patient despite complete clearing of circulating Sézary cells. Median response duration was 7 months (1–39 months). We have analyzed minimal residual disease (MRD) by PCR of γ/δ TCR after treatment in skin and/or blood samples in 11 pts who achieved CR and PR. MRD was detected in 8 pts with subsequent relapse in 5 pts after a median time of 6 months. Only 3 pts had negative blood samples tested with histologic evidence of cutaneous residual disease in 2 pts (PR). Patients remained in remission for 17, 4, and 5 months, respectively. Another patient with CR had negative skin, but a positive blood sample tested and relapsed after 3 months. The median overall survival of all pts. was 18 months (1–50 months). Ten pts (53%) have died, 7 (37%) attributable to MF. One patient developed a second B-cell lymphoma approximately 6 months after completing alemtuzumab. One patient died of aplastic anemia. None of the pts died of infectious complications. In general, treatment was well tolerated, with the majority of toxicities being Grade 2 in severity and transient. The major hematologic side effect was T-cell depletion (lymphopenia Grade 4) with infectious complications in 4 pts (including PICC line infection in 2 pts, and Herpes zoster infection and neck abscess formation in one pt each) and neutropenic fever in one patient without documented infection. 6 pts developed grade 3 or 4 leukopenia with prolonged cytopenias in 2 pts requiring withholding and/or discontinuation from treatment. No patient manifested reactivation of CMV infection. One patient developed a fungal otitis externa remote from study during the terminal phase of CTCL. In conclusion, alemtuzumab has shown impressive responses in patients with refractory E-CTCL and could be considered for first-line therapy. The persistence of MRD suggests that a longer duration of therapy or sequential use of other biologic agents may enhance responses or improve durability.

Description: Abstract 2643 Background: Granulomatous mycosis fungoides (GMF) is a variant of MF/cutaneous T-cell lymphoma characterized by a prominent granulomatous infiltrate in addition to the malignant lymphoid infiltrate. The diagnosis of GMF remains challenging due to variable clinical and histopathologic features. The significance of granuloma formation in CTCL is unclear and whether patients with GMF have a distinct prognosis compared to patients with classic type of MF is controversial. Data are scarce and long term results are not available. Objectives: To evaluate the clinical, histopathologic, prognostic significance and therapeutic responses of patients with GMF and to compare results to age and stage-matched patients with classic type of MF. Methods: A single center retrospective case-case study was performed at Memorial Sloan-Kettering Cancer Center of 430 patients with a diagnosis of MF between January 1981 and April 2012. Available histopathology slides were reviewed for the presence of granulomas or histiocytes comprising ≥ 25% of the atypical lymphoid infiltrate. Each identified case was matched with two classic MF cases via age and TNMB stage. For each case meeting criteria, the medical records, photographs, and histopathology slides were reviewed. Results: Twenty-seven patients with GMF were identified representing 6.3% of all MF patients at our center. Patient demographics were similar between the GMF group and case-control classic MF group, with a male-to-female ratio of 2.1:1 and a median age of 57. Most GMF patients (69%) present at early stages (IA-IIA). Patients with GMF had a longer onset of disease prior to diagnosis (median, 4.5 years vs 3.0 years). Skin manifestations of granulomatous MF showed a great variability, but were not distinguishable from those of classic MF. Histological findings showed an atypical predominantly CD4+ lymphocytic infiltrate with either granuloma formation or histiocytes with giant cells. TCR rearrangement was positive in 70% of cases. Features of GMF were present at initial diagnosis in 17 patients. In 10 patients, granulomatous infiltrates appeared at an average of 5.4 years after MF diagnosis. Secondary malignancies developed in 38% of patients with GMF compared to 23% of patients in the case-control classic MF group. Among the GMF patients, there was a trend towards fewer CRs to any treatment (38% vs 54%; p = 0.21); fewer PRs or CRs with topical therapy (57% vs 83%; p = 0.002) and with UV-light therapy (62% vs 90%; p = 0.008). Significantly more GMF patients received systemic therapy (66.7%) compared to classic MF patients (32.7%; p = 0.006). They also required a longer time to achieve best response (median 35 months vs 9 months, p = 0.002) compared to the control group. Disease progression to higher stage was seen in 46% of cases in the GMF group compared to 30% of cases in the classic MF group (p = 0.23). The 5-year and 10-year progression-free survival rates were significantly lower in the GMF group (59% and 33%, respectively) compared to the control group (84% and 56%, respectively; p = 0.02). However, the 5-year and 10-year overall survival rates were similar between GMF (86% and 72%, respectively) and classic MF patients (85% and 85%; p = 0.54). Conclusion: Our study presents the largest series on GMF in the United States. Most patients with GMF show similar clinical features when compared to patients with conventional MF. The clinical features do not reflect the histologic findings of granulomas. More frequent disease progression and poorer response to skin-directed therapies are seen in GMF patients compared to classic MF; however, overall survival is not significantly different. The majority of GMF patients present with granulomatous features at initial diagnosis and in subsequent biopsies suggesting that this entity has a unique relationship with its microenvironment. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Mycosis Fungoides (MF) and its leukemic variant Sezary syndrome (SS) are disorders of malignant, skin homing helper/memory T-cells. MF presents with patches, plaques, or tumors, while SS presents with generalized erythroderma and blood involvement. Either can involve lymph nodes, blood, and viscera. A multi-center, open label, single arm clinical trial previously demonstrated the safety and efficacy of ECP as a monotherapy in the treatment of patients with advanced/refractory MF/SS (Edelson, et al, 1987, N Engl J Med, 316:297–303). The primary endpoint of this study was a ≥25% improvement in skin score maintained for at least 4 weeks. We present a long-term, secondary analysis of these patients to further evaluate clinical outcomes and predictors of response for ECP as a monotherapy in MF/SS. Partial (≥50%) and complete (≥90%) skin score responses, extent of skin disease, number of ECP treatments administered, and the time required to achieve 50% and 90% improvement in skin involvement were evaluated. Patients and Methods: Thirty-nine patients (pts) who met eligibility criteria were included in the secondary efficacy analysis as the intent-to-treat (ITT) patient population. Thirty-one pts with generalized erythroderma (GE) and 8 pts with extensive patch plaque (EPP) were treated with ECP on 2 consecutive days every 4–5 weeks for 3 months. No concomitant systemic medications for MF/SS were allowed on study; however, topical steroids could be applied to the hands and feet. Patients had received an average of 3.7 (range 0–13) prior therapies (systemic and topical). Immediately prior to undergoing ECP, all pts received oral doses of methoxsalen in order to achieve blood level concentrations ≥50 ng/mL. Skin improvement was calculated by comparing baseline skin score to skin scores on all subsequent treatment dates. The mean baseline skin score of the 39 ITT patients was 262 (median = 291) based on a maximum possible skin score of 400 points. Results: The median follow-up of the 39 ITT pts was approximately 4 years (range 9 days–7.8 years). Twenty-nine pts (74%) achieved at least a ≥50% improvement in skin score, and 16 pts (41%) achieved ≥90% improvement on ECP monotherapy. The type and extent of skin disease (GE vs. EPP) prior to the start of treatment did not predict response. Patients received a median of 12 (range 4–65) or 30.0 (range 12–109) individual ECP treatments to achieve a ≥50% or ≥90% response, respectively. The mean times to reach a ≥50% or ≥90% response were 8.4 ± 6 months (median=6.5) or 25.2 ±14.9 mos (median=19.6), respectively. The mean duration of a ≥50% response was 32.5 ± 28.6 mos, which included a median of 20 (range 0–153) ECP treatments. Median survival from date of diagnosis and from date of first ECP treatment was 10.6 yrs and 5.4 yrs, respectively. Conclusions: In this long-term, follow-up analysis, ECP monotherapy was associated with a significant and durable improvement in skin score in the majority of patients with MF/SS.

Description: Background CD47 is an immune checkpoint that binds signal regulatory protein alpha (SIRPα) and delivers a "do not eat" signal to suppress macrophage phagocytosis. Tumor cells, including T-cell lymphomas, frequently overexpress CD47 to escape immune surveillance. TTI-621 (SIRPαFc) is a fusion protein consisting of the CD47 binding domain of human SIRPα linked to the Fc region of human IgG1, designed to enhance phagocytosis and antitumor activity by blocking the CD47-SIRPα interaction between malignant cells and macrophages, and engaging activating Fcγ receptors. It is hypothesized that direct intralesional (IL) administration of TTI-621 may enhance both local and systemic antitumor activity. Methods A multicenter, open-label Phase 1 study is ongoing to characterize the safety, tolerability, pharmacokinetics, pharmacodynamics and antitumor activity of IL injections of TTI-621 (NCT02890368) in adult patients with relapsed/refractory (R/R) percutaneously accessible solid tumors and mycosis fungoides (MF) who have progressed on standard anticancer therapy or for whom no other approved therapy exists. The current report analyzed a cohort of R/R MF/Sézary syndrome (SS) patients enrolled by the data cut-off date. Patients received induction therapy consisting of a single IL injection (1, 3 or 10 mg), three 10 mg injections over one week, or six 10 mg injections over two weeks distributed across one to three lesions. The protocol was recently amended to enable weekly post-induction IL maintenance dosing and to explore IL TTI-621 administration in combination with subcutaneous pegylated interferon-α2a. Responses were evaluated using the Composite Assessment of Index Lesion Severity (CAILS) score a week after induction therapy and at later time points in some patients. Serial biopsies were collected to assess the impact of TTI-621 on the tumor microenvironment. Results Twenty-two patients (16 M/6F, median age 65.5 years, range 32-85) were enrolled as of June 15, 2018. Primary diagnosis included MF (n=18), MF with transformation (n=3) and SS (n=1). Clinical stages included stage IA (n=2), IB (n=3), IIA (n=1), IIB (n=13), IVA (n=2) and IVB (n=1). Patients received a median of 3 prior systemic therapy regimens. Twenty-one patients were treated with TTI-621 monotherapy and one patient with TTI-621 in combination with pegylated interferon-α2a. Single and multiple IL injections of up to 10 mg TTI-621 have been well tolerated. The most frequently reported treatment-related adverse events (AEs) were chills (n=8), injection site pain (n=7) and fatigue (n=6). All treatment-related AEs were Grade 1 or 2 in severity. No treatment-related serious AEs or dose-limiting toxicity have been observed. CAILS scores for injected lesions obtained after the last injection were available for 17 patients: 15 (88%) had measurable improvement; 7 (41%) exhibited ≥50% decrease from baseline (Figure 1). Responses were rapid and in some patients occurred after a single injection of varying doses of TTI-621. CAILS scores continued to decrease in 5/5 (100%) monotherapy patients for which post-induction therapy assessments were conducted. Seven patients with reduced CAILS of varying degree (-14% to -67%) in the injected lesions had paired assessments available in adjacent, non-injected lesions. In 6/7 patients, a reduction in CAILS was observed in the non-injected lesions (-12% to -67%), indicating that TTI-621 could induce local-regional responses that were not confined to the site of injection. Additionally, one patient with transformed MF exhibited clear evidence of abscopal effects with rapid resolution of lesions on the abdomen, left flank/back and arms less than two weeks after receiving IL TTI-621 injections in lesions on the foot and leg. The only SS patient on study achieved a reduction in circulating Sézary cells after a single 3 mg local injection of TTI-621. Conclusions Preliminary data from this ongoing study indicate that IL TTI-621 administration is well-tolerated and has single agent activity in heavily pre-treated MF/SS patients across various disease stages. The rapid responses observed occurred in both injected and non-injected lesions indicating a local-regional effect with initial evidence of distant abscopal or systemic effects. Enrollment in this study is continuing to evaluate the impact of weekly maintenance dosing and further characterize the systemic effect and durability of responses. Disclosures Querfeld: Kyowa: Membership on an entity's Board of Directors or advisory committees; Acelion: Membership on an entity's Board of Directors or advisory committees; Bioniz: Membership on an entity's Board of Directors or advisory committees; Medivir: Membership on an entity's Board of Directors or advisory committees; Trillium Therapeutics: Membership on an entity's Board of Directors or advisory committees. Thompson:Trillium Therapeutics: Research Funding. Taylor:Trillium Therapeutics: Research Funding. Johnson:Trillium Therapeutics: Employment. Catalano:Trillium Therapeutics: Employment. Petrova:Trillium Therapeutics: Employment. Thompson:Trillium Therapeutics: Employment. Uger:Trillium Therapeutics: Employment. Shou:Trillium Therapeutics: Employment. Akilov:Kyowa Kirin: Consultancy; Pfizer: Research Funding; Seattle Genetics: Consultancy; Trillium Therapeutics: Research Funding; Actelion Pharmaceuticals: Consultancy.

Description: Cutaneous T-cell Lymphoma (CTCL) is a heterogeneous group of diseases, derived from skin resident or skin homing T-cells, with Mycosis Fungoides (MF) and Sezary Syndrome (SS) being the most common subtypes. Although CTCL is the best-studied group among T-cell malignancies, our understanding of its pathogenesis remains limited, due to the paucity of comprehensive, large-scale genomic studies. Recent whole exome and targeted sequencing approaches have primarily elucidated mutations in genes affecting immune synapse signaling (PLCG1, CD28, JAK3) and epigenetic modulation (ARID1A, DNMT3A) in both MF and SS. In search of novel genetic alterations, we applied deep targeted sequencing in 71 freshly cryopreserved skin or peripheral blood samples derived from 61 patients with CTCL, including patients with MF, SS, primary cutaneous anaplastic large cell lymphoma (pcALCL), pleomorphic small/medium sized CD4+ CTCL and CD8+ CTCL. Genomic DNA was sequenced for the entire coding region of 585 known cancer-related genes on a HiSeq2500 Illumina instrument with a mean depth of 1000X. Sequences were analyzed for base substitutions, in-frame or frameshift insertions and deletions and splicing variants. Known germline variants reported at dbSNP and the 1,000 Genomes Project data were excluded, while confirmed somatic variants previously reported at the COSMIC database were included. Only variants with an allele frequency above 2% were further analyzed, in order to eliminate false positive data. Recurrent mutations were identified in genes responsible for tumor suppression (TP53, FAT1, FAT3), DNA damage response (ATM, MDC1), DNA mismatch repair (MSH3), chromatin remodeling (ARID1B), histone methylation (MLL2, MLL3, KDM6A) and DNA methylation (DNMT1). Moreover recurrent mutations pointed to robust activation of the three following signaling pathways: Receptor Tyrosine Kinase (IRS2, FOXO3) JAK/STAT (JAK3, STAT5A/B, SOCS1) and NOTCH (NOTCH1, NOTCH2). Finally, at a subclonal level we paradoxically identified mutations of the Androgen Receptor (AR) gene. Interestingly, the presence of large cell features correlated with a higher accumulation of molecular events, since transformed MF and pcALCL had a significantly higher number of genetic alterations compared to untransformed MF (Figure 1). In sum, the genomic landscape occurring from our targeted sequencing approach highlights the pathologic complexity of these neoplasms, suggesting multiple non-redundant mechanisms leading to lymphomagenesis. The characterization of this cohort is expected to provide an opportunity to comprehend intra-CTCL molecular heterogeneity and offer a better classification of CTCL entities along with novel potential therapeutic targets. Figure 1. Figure 1. Disclosures Levine: Foundation Medicine: Consultancy; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; Loxo Oncology: Membership on an entity's Board of Directors or advisory committees. van den Brink:Merck: Honoraria; Boehringer Ingelheim: Consultancy, Other: Advisory board attendee; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria; Tobira Therapeutics: Other: Advisory board attendee. Palomba:Janssen: Consultancy.

Description: Background: Cutaneous T-cell lymphoma (CTCL), collectively known as mycosis fungoides (MF) and Sézary syndrome (SS), is characterized by the accumulation of neoplastic memory T- cells in the skin in a background of chronic inflammation. This observation suggests that chronic inflammation fosters the growth of CTCL cells, and may impair successful anti-tumor responses mediated by the CD8+ tumor-infiltrating T-cells. T-cell exhaustion plays an important role in the pathogenesis of CTCL. PD-1 and other inhibitory immune checkpoints are overexpressed in exhausted T-cells (Cancer Immunol Res 6; 2018). Their binding to corresponding ligands like PD-L1 on dendritic cells (DCs), macrophages and tumor cells in the microenvironment directly reduces the functional and proliferative capabilities of T-cells by repressing T-cell receptor signaling and inducing genes that impair T-cell function. As a result, malignant CTCL cells escape immune surveillance and are not eliminated. The miRNA profile of CTCL correlates with a dysfunctional/exhausted immunophenotype, suggesting that epigenetic regulation is involved in the regulation of immune checkpoints. Signaling pathways such as JAK-STAT are constitutively active in CTCL and may also be involved in immune checkpoint regulation. At present, the exact role of miRNAs in regulating the expression of PD-L1 in CTCL has yet to be elucidated. Therefore, the goal of this project is to understand how PD-L1 is regulated, how this regulation contributes to T-cell exhaustion, and how this regulation is altered to contribute to the development of CTCL. To this end, we set out to test the hypothesis that PD-L1 is regulated by oncogenic miRNAs in CTCL. Methods: We first conducted a high-throughput miRNAseq analysis to assess the miRNA profile of 50 CTCL patient tumor samples. Library preparation, miRNA sequencing, and correlation calculation of miRNAs with PD-L1 mRNA expression was performed by the City of Hope Integrative Genomics Core. Next, we verified the expression of 2 highly upregulated miRs-miRs-21and -130- from the miRNAseq analysis in 5 CTCL cell lines and tumor samples using qRT-PCR and in situ hybridization (ISH). Finally, we transfected the CTCL cell line Hut78 with anti-miR-21, -130 or Scramble (Scr) control using the Lonza nucleofection kit and nucleofector machine. Cell lysates were prepared 72 hours after transfection and then subjected to Western Blot analysis. We probed the blot with antibodies against PD-L1, pSTAT3 and GAPDH as a loading control. Results: The miRNAseq data revealed that miRs-21 and -130 had the highest correlation with PD-L1 mRNA. qRT-PCR and ISH revealed that miRs-21 and -130 were upregulated in all 5 CTCL cell lines and primary tumor samples. There was a drastic decrease in PD-L1 and pSTAT3 expression in Hut78 cells transfected with anti-miRs-21 or -130, compared to cells transfected with Scr. Conclusions: PD-L1 expression in CTCL is regulated by miRs-21 and -130. miRs-21 and -130 may be regulating PD-L1 indirectly by silencing negative regulators of STAT signaling such as the SOCS family of proteins. This would explain the decrease in pSTAT3 levels in Hut78 cells transfected with anti-miRs. Taken together, these results demonstrate the ability of miRNAs to regulate immune checkpoints and ligands like PD-L1, and pave the way for the creation of miRNA therapeutics to reverse T-cell exhaustion and slow CTCL disease progression. Disclosures Querfeld: Acelion: Membership on an entity's Board of Directors or advisory committees; Kyowa: Membership on an entity's Board of Directors or advisory committees; Bioniz: Membership on an entity's Board of Directors or advisory committees; Medivir: Membership on an entity's Board of Directors or advisory committees; Trillium Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Description: Background: T cells in CTCL are functionally exhausted and are characterized by the expression of immune inhibitory molecules such as PD1 and PD-L1 (Cancer Immunol Res 6; 2018). These findings justify the evaluation of immune checkpoint inhibition to reverse T cell exhaustion in CTCL. We initiated a phase 1/2 clinical trial of lenalidomide and durvalumab to determine the safety and efficacy of this regimen. Durvalumab is a human monoclonal antibody with high affinity and selectivity for PD-L1, targeting exhausted T cells and distinct cells within their environment. Lenalidomide, an oral immunomodulatory drug (IMiD) and analog of thalidomide, has previously shown activity in CTCL (Blood 123; 2014). Durvalumab may restore an anti-tumor immune response, and the combination of durvalumab and lenalidomide may enhance immune checkpoint blockade-induced immune responses. Associations between immune checkpoints, gene expression profile and the clinical efficacy of durvalumab/lenalidomide combination were evaluated. The primary objectives were to determine the recommended phase 2 dose of lenalidomide in combination with durvalumab and safety with primary endpoint of toxicity (using CTCAE 4.03). Secondary end points included objective response rate (ORR) and median duration. Relationships between gene expression profile (GEP), PD-L1 expression, and antitumor activity were exploratory end points. Methods: A Phase 1 portion (NCT03011814) is ongoing to evaluate the safety and tolerability of the durvalumab and lenalidomide combination. Pts are enrolled in sequential cohorts to receive durvalumab (fixed dose at 1500 mg) and dose escalation of lenalidomide (dose level 1 = 10 mg for all cycles; dose level 2 = 10 mg for cycle 1, 15 mg for all subsequent cycles; dose level 3 =10 mg for cycle 1, 15 mg for cycle 2, and 20 mg for all subsequent cycles) to characterize safety, efficacy and antitumor activity. Serial skin samples were collected to assess the impact on the tumor microenvironment and anti-tumor activity. Results: Ten pts. were evaluable for toxicities. Nine patients were evaluable for response with three patients at each dose level. 8 males/2 females, age 29-59 y, with refractory/advanced CTCL, clinical stages IB (1), IIA (3), IIB (4), IIIA (1), and aggressive epidermotropic CD8+ CTCL (1) and a median of prior systemic treatments of 3 (range, 2-4) have been enrolled. Median follow up time was 12 (range, 3-24+) months. No serious AEs or DLTs were observed during the DLT evaluation period (cycles 1-3). The most frequently reported AEs were fatigue (n=7), skin pain (n=4), chills (n=3), anemia (n=3), and leukopenia (4). One grade 3 maculopapular rash (possibly due to lenalidomide) was observed, all other treatment-related AEs were grade 1/2 in severity. Median cycles of treatment were 7 (range, 3-20+) months. Median duration of response was 4 (range, 1- 21+) months. Six pts achieved PR, while 3 pts maintained stable disease. Three pts remain on treatment. Expression panels of several checkpoints (PD1, PD-L1 & ICOS) (Cycle1 Day1 vs Cycle 2 Day15) were analyzed. Detectable levels of PD-L1 but low levels of ICOS are observed in responding pts vs. high PD-L1 and ICOS levels in non-responders. GEP highlights downregulation of TNF-alpha signaling via NFkB, IFN-gamma, and PI3-AKT-mTOR signaling pathways among other pathways. Conclusions: Durvalumab/lenalidomide has significant clinical activity in refractory/advanced CTCL, which will be formally evaluated in the Phase 2 portion. Responses were durable and ongoing, and treatment was well tolerated. Dose escalation is up to lenalidomide 20 mg daily. Our preliminary results from pts on trial demonstrated that immune signatures on skin biopsies at baseline may be predictive of response to checkpoint blockade and yield insights into mechanisms of therapeutic resistance. Disclosures Querfeld: Bioniz: Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Soligenix: Other: Investigator; Celgene: Other: Investigator, Research Funding; City of Hope Cancer Center and Beckman Research Institute: Employment; Medivir: Consultancy; Trillium: Consultancy, Other: Investigator, Research Funding; miRagen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Kyowa: Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Eisai: Other: Investigator; Elorac: Other: Investigator, Research Funding; Helsinn: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Investigator. Palmer:Gilead Sciences: Consultancy. Zain:Spectrum: Consultancy; Seattle Genetics: Consultancy.

Description: Key Points Lenalidomide is effective in refractory advanced cutaneous T-cell lymphoma, with an overall response rate of 28%. Patients demonstrate a transient flare reaction in skin, blood, and/or lymph nodes that may be associated with improvement in disease burden.

Description: Background: In CTCL, intratumoral T cells are functionally exhausted and are characterized by the expression of immune inhibitory molecules such as PD1 and PD-L1 (Cancer Immunol Res 6; 2018). These findings justify the evaluation of immune checkpoint inhibition to reverse T cell exhaustion in CTCL. To this end, we initiated a phase 1/2 clinical trial of lenalidomide and durvalumab to determine the safety and efficacy of this regimen. Durvalumab is a human monoclonal antibody with high affinity and selectivity for PD-L1, with mechanisms of action that target the exhausted T cells and distinct cells within their environment. Lenalidomide, an oral immunomodulatory drug and analog of thalidomide, has previously shown activity in CTCL (Blood 123; 2014). Durvalumab may restore an anti-tumor immune response, and the combination of durvalumab and lenalidomide may enhance immune checkpoint blockade-induced immune responses. Methods: A Phase 1 portion is ongoing to characterize the safety and tolerability of durvalumab and lenalidomide combination. Patients (pts) are enrolled in sequential cohorts to receive durvalumab (fixed dose at 1500 mg) and dose escalation of lenalidomide (cohort 1 = 10 mg; cohort 2 = 15 mg; subsequent planned dose increments of 5 mg) to evaluate safety, efficacy and antitumor activity. Serial skin and blood samples were collected to assess the impact on the tumor micro-environment. We examined the correlation between clinical response and resistance and the following biological factors: PD1 clustering at the single molecule level using super-resolution microscopy, and expression of PD-L1 and ICOS at the tissue level by means of multiplex immunohistochemistry on pre-treatment primary cells (migrated from skin explants), and skin tissue (formalin-fixed and paraffin-embedded) from clinical trial subjects. Results: Six patients (5 males/1female, age 32-57 years) with refractory/advanced CTCL (mycosis fungoides/Sezary syndrome subtype), clinical stage IB (1), IIA (1), IIB (3), IIIA (1) have been enrolled as of July 2018. Duration time on treatment was 4 to 13+ months. Four patients showed improvement of skin disease with 2 patients achieved partial response with 〉 90% improvement of skin disease by mSWAT. Two patients developed progressive disease. No serious adverse events (AEs) were observed. The most frequently reported AEs were fatigue (n=6), skin pain (n=4), anemia (n=3) chills (n=4), and decreased appetite (n=3). All treatment-related AEs were Grade 1 or 2 in severity. One grade 3 fatigue occurred in one patient. No dose limiting toxicity has been observed to date. Using multispectral microscopy, we analyzed expression panels of several checkpoints: PD1, PD-L1, and ICOS on lesional skin biopsies at baseline. Strong PD-L1 and ICOS expression is observed from non-responders. Detectable levels of PD-L1, but low levels of ICOS is observed in responding patients. Quantitative super-resolution microscopy detected nanoscale clusters of PD1 in T cells from responders and no PD1 clustering was observed in T cells from non-responders. Conclusions: Durvalumab/lenalidomide has significant clinical activity in patients with refractory/advanced CTCL, which will be formally evaluated in the Phase 2 portion of this trial. Responses were durable and ongoing, and treatment was well tolerated with a low toxicity profile. Dose escalation is planned up to lenalidomide 20 mg daily. Our preliminary results from patients on trial demonstrated that immune signatures on skin biopsies at baseline may be predictive of response to checkpoint blockade and yield insights into mechanisms of therapeutic resistance. Disclosures Querfeld: Acelion: Membership on an entity's Board of Directors or advisory committees; Kyowa: Membership on an entity's Board of Directors or advisory committees; Bioniz: Membership on an entity's Board of Directors or advisory committees; Medivir: Membership on an entity's Board of Directors or advisory committees; Trillium Therapeutics: Membership on an entity's Board of Directors or advisory committees.