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PURPOSE To assess the efficacy of pembrolizumab in patients with advanced relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS). PATIENTS AND METHODS CITN-10 is a single-arm, multicenter phase II trial of 24 patients with advanced MF or SS. Patients were treated with pembrolizumab 2 mg/kg every 3 weeks for up to 24 months. The primary end point was overall response rate by consensus global response criteria. RESULTS Patients had advanced-stage disease (23 of 24 with stage IIB to IV MF/SS) and were heavily pretreated with a median of four prior systemic therapies. The overall response rate was 38% with two complete responses and seven partial responses. Of the nine responding patients, six had 90% or more improvement in skin disease by modified Severity Weighted Assessment Tool, and eight had ongoing responses at last follow-up. The median duration of response was not reached, with a median response follow-up time of 58 weeks. Immune-related adverse events led to treatment discontinuation in four patients. A transient worsening of erythroderma and pruritus occurred in 53% of patients with SS. This cutaneous flare reaction did not result in treatment discontinuation for any patient. The flare reaction correlated with high PD-1 expression on Sézary cells but did not associate with subsequent clinical responses or lack of response. Treatment responses did not correlate with expression of PD-L1, total mutation burden, or an interferon-γ gene expression signature. CONCLUSION Pembrolizumab demonstrated significant antitumor activity with durable responses and a favorable safety profile in patients with advanced MF/SS.

2500 Background: People with HIV have been excluded from immuno-oncology (IO) studies. Anti- PD-1/PD-L1 therapies are approved for a growing number of cancers. We evaluated pembrolizumab (pembro) in people with HIV and cancer. Methods: CITN-12 is a multicenter phase 1 trial. Key eligibility: advanced cancer; ECOG ≤1; CD4 ≥100 cells/μL; ≥4 weeks antiretroviral therapy (ART), HIV viral load (VL) < 200 copies/mL. Exclusion: uncontrolled HBV/HCV, autoimmune disease. Participants (pts) accrued into CD4 based cohorts (C): C1 100-199; C2 200-350; C3 > 350 CD4 cells/μL. Pembro 200 mg IV administered Q3W for up to 35 doses. Adverse events (AE) evaluated by CTCAE. Immune related AE ≥ grade (Gr) 2 were events of clinical interest (irECI). Clinical benefit (tumor shrinkage or stable disease [SD] ≥24 weeks) was estimated. Data were locked for safety analysis and publication once C2 and C3 completed accrual and all pts completed ≥2 cycles. Accrual continued for 6 C1 pts and a new phase 1b Kaposi sarcoma (KS) cohort (C4). Results: 30 pts, characteristics: C1 (6), C2 and 3 (12 each), median (med) age 57 years (range 39-77), 28 men, 2 women, 60% White, 30% Black, 10% Hispanic. Med CD4 285 cells/μL (132 - 966). Cancers: KS (6), non-Hodgkin lymphoma (NHL) (5), non-AIDS defining (19) – most common: anal (6) and squamous cell skin (3). Prior radiation (19), med prior systemic therapies 2 (0-8). Safety observed over 183 cycles, med 5 (1-32). Treatment emergent AE ≥ possibly attributed to pembro mostly Gr 1-2, with 20% of pts having Gr 3. irECI: hypothyroidism (6), elevated AST/ALT (1), pneumonitis (3), rash (2), musculoskeletal (1).1 KS pt developed KSHV-associated multicentric Castleman disease (KSHV-MCD) and died of the AE. HIV was controlled and increasing CD4 counts were observed. Best response: complete (lung, 1), partial (NHL, 2), SD ≥24 weeks (KS, 2), SD < 24 weeks (13), progressive disease (10), not evaluable (2). Conclusions: Pembro has acceptable safety in cancer pts with HIV on ART and > 100 CD4 cells/µL, similar to patients without HIV. Anti-PD-1 may unmask KSHV-MCD and such KSHV-viremic patients should be excluded. Clinical benefit was noted in several tumor types. Anti-PD1 is appropriate for FDA-approved indications in this population. Patients with HIV meeting appropriate eligibility criteria should be included in IO studies. Clinical trial information: NCT02595866.

e14008Background: EGFRvIII is the most prevalent tumor-specific variant of the EGFR family and represents an attractive tumor target such as in glioblastoma, head and neck or lung cancer. EGFRvIII ...

e14012Background: AFM13 is an NK-cell engaging TandAb in Ph. 2 development in Hodgkin Lymphoma (HL) and CD30+ malignancies. As immune checkpoint modulators have demonstrated clinical efficacy in a various cancers we were prompted to investigate the combination of AFM13 with several immunomodulatory antibodies. In previous experiments, we demonstrated higher efficacy of AFM13 than such antibodies and strong synergy between AFM13 and an anti-PD1 antibody in vitro, and in vivo PDX models with human HL tumors. Methods: To further investigate the immunological mechanisms we used an autologous PDX mouse model with donor-matched tumors and PBMCs from HL patients. Animals were treated with AFM13 and in combination with anti-PD1. Tumor size, tumor-infiltrating human lymphoid cells, myeloid cells and intra-tumoral cytokines were evaluated at several time-points after treatment start. Results: While monotherapy with AFM13 was reproducibly more potent than anti-PD1 in controlling tumor growth, significant synergy was...

e14007Background: The epidermal growth factor receptor (EGFR) is an important and established target for the treatment of several solid tumors, including colorectal, head and neck and lung cancer. ...

3075 Background: The clinical successes of BTK inhibitor Ibrutinib and Ofatumumab (GA101), a humanized, glycoengineered mAb against CD20, suggests that a combination therapy may have clinical poten...

TPS3089 Background: REGN1979 is a human bispecific antibody based on an IgG4 isotype modified to reduce Fc binding, designed to bridge CD20-expressing cells to cytotoxic T-cells by binding to the C...

3031 Background: Immunotherapy with PD-1/PD-L1 axis blockade shows encouraging activity in head and neck squamous cell carcinoma (HNSCC). T-cell inflammation and gamma interferon driven gene expres...

3078 Background: Between 1996-2014, the FDA approved 175 drugs for the treatment of various indications of oncology and despite the progress that has been made in other forms of cancer therapy, Pro...

3004 Background: 4-1BB agonists enhance cytotoxic T-cell and NK cell responses, including antibody-dependent cellular cytotoxicity, resulting in anti-tumor activity in preclinical models. PF-050825...

6078 Background: Immunotherapy with PD-1/PD-L1 axis blockade has shown promising preliminary results in patients with head and neck squamous cell carcinomas (HNSCC) (Seiwert ASCO 2014). Using a 12-...

6079 Background: Anti-PD-1/PD-L1 blockade is active in patients (pts) with head and neck squamous cell carcinoma (HNSCC) (Seiwert ASCO 2014). The T-cell inflamed phenotype (TCIP)/INF-g driven gene ...

TPS7098 Background: Acquired mutations in oncogenic kinases remains an obstacle between valid therapeutic hypotheses and meaningful patient benefit. The inhibition of FLT3 can be efficacious in AML...

TPS8604 Background: Immunotherapy is a promising treatment modality for low grade non-Hodgkin’s lymphomas. SD-101 (Dynavax Technologies) is an immunostimulatory synthetic CpG molecule that activate...

7606 Background: Thymomas (T) contain lymphocytic infiltrates, and as they arise from an immune organ confer a unique tumor microenvironment. Tumor expression of the immune checkpoint ligand, PD-L1...

3007 Background: 4-1BB agonists markedly enhance cytotoxic T-cell responses, resulting in anti-tumor activity in several models. PF-05082566 is a fully humanized IgG2 agonist monoclonal antibody ta...

3017 Background: Anti-CD137 antibody was shown in both murine cancer models and in a first-in-human, phase I trial (Sznol et al., 2008) to increase peripheral activated CD8 T cells and IFN-inducibl...

3622 Background: PD-L1 has been reported to be expressed broadly in human cancer and can lead to inhibition of anti-tumor T-cell responses. MPDL3280A, a human monoclonal antibody containing an engineered Fc-domain designed to optimize efficacy and safety, targets PD-L1, blocking PD-L1 from binding its receptors, including PD-1 and B7.1. Pts with a broad range of tumors were examined in an expansion study with MPDL3280A. Methods: Pts with locally advanced or metastatic tumors received MPDL3280A administered IV q3w. Pts were treated for up to 1 y. Response was assessed by RECIST v1.1. Results: As of Jan 10, 2013, 20 pts with tumor types other than NSCLC, RCC and mM were evaluable for safety and treated at doses of 0.01-20 mg/kg (≤1 [n=3], 3 [n=1], 10 [n=3] and 20 mg/kg [n=13]). Median pt age was 67 y (range 26-80 y), 100% were PS 0-1, 90% had prior surgery and 45% had prior radiotherapy. 95% of pts received prior systemic therapy. Pts received MPDL3280A treatment for a median of 96 days (range 22-330). The incidence of all G3/4 AEs, regardless of attribution, was 50%. No G3-5 pneumonitis or diarrhea was reported. Confirmed RECIST responses were observed in several tumor types, including CRC, GC and SCCHN. Additionally, antitumor activity (tumor shrinkage that has not yet met criteria for a RECIST response) has been observed in sarcoma and lymphoma. Analysis of biomarker data from archival tumors revealed that all pts reported to have RECIST response had baseline tumors that were PD-L1 positive. Updated data will be presented. Conclusions: Treatment with MPDL3280A was well tolerated, with no pneumonitis-related deaths. Rapid responses were observed in pts with CRC, GC and SCCHN. PD-L1 tumor status appears to correlate with responses to MPDL3280A. These data suggest that PD-L1 is a conserved mechanism for mediating tumor immune escape across a range of tumor types. MPDL3280A may be broadly active as anti-cancer therapy in PD-L1–expressing tumors, supporting further investigation. Clinical trial information: NCT01375842.

3015 Background: Cetuximab therapy results in beneficial, yet limited, clinical improvement for patients with KRAS wildtype (WT) colorectal (CRC) and head and neck (HN) cancer. The efficacy of cetuximab, an IgG1 monoclonal antibody against EGFR, is due in part to antibody-dependent cell-mediated cytotoxicity (ADCC) by natural killer (NK) cells. CD137 is a costimulatory molecule expressed following activation on NK and memory, antigen-specific, CD8 T cells. Methods: We investigated the hypothesis that the combination of cetuximab with anti-CD137 mAb will enhance innate and adaptive immunity, thereby improving cetuximab’s anti-tumor efficacy in preclinical models and a prospective trial, NCT01114256. Results: NK cells increased their expression of CD137 by a factor of 30-40 when exposed to cetuximab-coated, EGFR-expressing HN and CRC cell lines. An agonistic anti-CD137 mAb enhanced NK cell degranulation and cytotoxicity 2-fold (~45 to 90% tumor lysis assayed by chromium release). The combination of cetuximab and anti-CD137 mAbs was synergistic in a syngeneic, human-EGFR-transfected murine tumor leading to complete tumor resolution and prolonged survival. NK cell depletion, significantly, and CD8 T cell depletion, partly, abrogated the anti-tumor efficacy of this combination. A series of HN and both KRAS WT and mutant CRC xenotransplant models demonstrated synergy with cetuximab and anti-CD137 mAbs. In our clinical trial, 54 patients with HN cancer receiving cetuximab therapy, circulating and intratumoral NK cells upregulated CD137 with amplitude influenced by duration post-cetuximab and host FcyRIIIa polymorphism. Interestingly, in 10 HLA-A2+ patients, following cetuximab, an increase in EGFR-specific, CD137-expressing, CD8 T cells directly correlated with the percent increase in CD137-expressing NK cells. Conclusions: Our results demonstrate the synergy of combining an agonistic mAb, anti-CD137, augmenting ADCC and T cell memory following a tumor-targeting mAb, cetuximab, in HN and KRAS mutant and WT CRC cancer. These results support a novel, sequential antibody approach by targeting first the tumor and then the host innate and adaptive immune system. Clinical trial information: NCT01114256.

TPS3108 Background: CD137 (4-1BB) is a costimulatory molecule that belongs to the TNF superfamily. It is upregulated on activated lymphocytes, NK cells and dendritic cells and plays an important role in the potentiation of antigen-specific immune responses as well as in antibody-dependent cell-mediated cytotoxicity (ADCC). Urelumab is an agonistic antibody targeting the CD137 receptor. Preclinical evidence has shown that there is modulation of CD137 expression on NK cells after exposure to rituximab. Anti-CD137 agonist monoclonal antibody has been shown to have single-agent anti-lymphoma activity and to potentiate the anti-lymphoma activity of rituximab through enhancing ADCC. We hypothesized that upregulation of CD137 on NK cells by rituximab followed by urelumab could afford a mechanism-based approach to achieve enhanced biologic and/or clinical activity compared to either single agent alone. Here we describe a phase Ib study to investigate the clinical and biologic effects of combined treatment with urelumab and rituximab in patients with relapsed/refractory B-cell malignancies. Methods: This phase I study (n=100) will include dose escalation (Part 1) using a 3+3+3 design and cohort expansion (Part 2). In Part 1, successive cohorts of patients with relapsed/refractory B-NHL will be treated as follows: Cohort 1 (0.1 mg/kg q3weeks) and Cohort 2 (0.3 mg/kg q3weeks) with both cohorts in combination with rituximab 375 mg/m2 given weekly for the first 4 weeks of each 12 week cycle. In Part 2, cohorts of CLL (n=30), follicular lymphoma (FL) (n=30), and diffuse large B-cell lymphoma (DLBCL) (n=20) will be treated at the dose level found to be safe for the urelumab/rituximab combination. The primary objective of the study is to evaluate the safety and define a safe and effective dose of the urelumab/rituximab combination. Secondary objectives include assessment of the antitumor activity, pharmacokinetics, and immunogenicity. Exploratory objectives include investigation of the immunoregulatory activity of this combination in peripheral blood and paired tumor biopsy specimens and the association of these effects with clinical response/toxicity. Clinical trial information: NCT01775631.

2043 Background: The chemokine receptors CXCR4 and CXCR7, and their shared ligand CXCL12/SDF-1, have been implicated in multiple aspects of tumorigenesis, including tumor cell proliferation, angiogenesis, vasculogenesis, and metastasis. Recently, a role for CXCR4 and CXCR7 has been postulated in the control of glioblastoma growth and vasculogenesis. We set out to define the expression patterns of these proteins on primary glioblastoma tumors and associated vasculature. Methods: First, a tumor microarray containing grades 1, 3, and 4 glioma samples were analyzed by immunohistochemical techniques for the expression of CXCR7. Second, two glioblastoma microarrays were analyzed by the same technique for CXCR7, CXCR4, and their shared chemokine ligand CXCL12. The same microarrays were also probed for the expression of the additional CXCR7 ligand, CXCL11/ITAC, as well as the chemokine receptor CXCR3, which is also a receptor for CXCL11. Tissues were scored in a blinded fashion by a certified neuropathologist for both the intensity of signal and location of signal for all proteins tested. Results: CXCR7 expression was largely dependent on tumor grade, as the receptor was usually absent on most grade 1 gliomas but was moderately-to-highly expressed in the majority of anaplastic astrocytomas and glioblastomas. CXCR7 expression on tumor-associated vasculature was seen in all samples and its expression level also increased with glioma grade. In contrast to CXCR7, CXCR4 expression in glioblastoma was usually limited to the glioma cells, with only infrequent expression on the vasculature. Conversely, CXCL12 expression in glioblastoma was usually limited to the vasculature. CXCR3 was detected in a subset of glioblastomas, and only on the glioma cells. The CXCR7 and CXCR3 ligand CXCL11 was, like CXCR7, expressed on both the glioma cells and vasculature. Conclusions: These results, in light of prior evidence for CXCR7 in tumor growth, suggest a positive role for CXCR7 in the development of glioblastoma. Because CXCR7 colocalizes with its ligands, CXCL12 and CXCL11, as well as their other receptors, CXCR4 and CXCR3, the function of CXCR7 in glioblastoma may lie in the regulation of both the CXCR4/CXCL12 and CXCR3/CXCL11 axes.

e21071 Background: Infiltration of specialized immune cells regulates the growth and survival of neoplasia. In a survey of public whole genome expression datasets we found that the gene for chemerin, a widely expressed endogenous chemoattractant protein, is downregulated in melanoma as well as other human cancers. Moreover, high chemerin mRNA expression predicted improved outcomes in human melanoma. Methods: Forced re-expression of chemerin by tumor cells was achieved by transfection. An alternate strategy involved direct intratumoral injection of recombinant chemerin into tumors. Tumor line expression of chemerin was confirmed by ELISA and functionality of expressed, secreted chemerin confirmed by chemotaxis of CMKLR1 (the main receptor for chemerin) positive cells. Tumors were evaluated by FACS and immunofluorescence for presence of recruited leukocytes. Results: In studies of the B16 transplantable mouse melanoma, tumor-expressed chemerin inhibited in vivo tumor growth without altering in vitro proliferation. Growth inhibition was associated with an altered profile of tumor infiltrating cells with an increase in natural killers (NK cells), and a relative reduction in myeloid derived suppressor cells and putative immune inhibitory plasmacytoid DC. Tumor inhibition required host expression of CMKLR1, the chemoattractant receptor for chemerin, and was abrogated by NK cell depletion. Intratumoral injection of chemerin also inhibited tumors, suggesting the potential for therapeutic application. Conclusions: We therefore conclude that chemerin recruits anti-tumor immune effector cells, and that it may act as an endogenous tumor suppressor, whose downregulation in melanoma and potentially other neoplasia contributes to immune evasion and tumor growth.

2514 Background: Antibody-dependent cell-mediated cytotoxicity (ADCC), mediated by natural killer (NK) cells, plays an important role in the efficacy of monoclonal antibodies (mAb)s. CD137 is a costimulatory molecule expressed on immune cells following activation, including NK cells. We hypothesize that as the antitumor efficacy of mAbs is due to ADCC, their activity can be enhanced by stimulation of NK cells with an anti-CD137 agonistic mAb. Methods: Upregulation of CD137 on NK cells was assessed using CD20+lymphoma, HER2+breast, and EGFR+head and neck cell lines and primary patient samples. NK cell degranulation, cytokine release and cytotoxicity were assessed by CD107a mobilization, IFN-γ secretion, and chromium release. Mechanism of synergy was explored by cell depletion in an immune competent mouse model. Xenotransplanted models were used to demonstrate anti-tumor activity and sufficiency of an innate immune response. Results: NK cells in human primary patient samples do not express CD137 at baseline, however CD137 is highly upregulated when encountering mAb-coated tumor cells. MAb-induced NK cell degranulation and cytotoxicity are enhanced by anti-CD137 agonistic mAb. In a murine lymphoma model, anti-CD137 mAb significantly enhances anti-tumor activity of anti-CD20 mAb leading to complete tumor resolution and prolonged survival. NK cell depletion completely abrogates the therapeutic effect. In seven xenotransplant models, sequential administration of rituximab, trastuzumab or cetuximab plus anti-CD137 mAb provided superior reduction in tumor burden and prolonged overall survival. In a phase 0 biomarker study, level of CD137 expression on circulating and intratumoral NK cells was influenced by disease burden, prior treatment, FcγRIII polymorphism, and time since mAb therapy. Conclusions: Our results demonstrate the synergy of anti-CD137 mAb and a tumor-targeting mAb by stimulation of mAb-activated NK cells with anti-CD137 mAb to enhance ADCC. These results support a novel, sequential antibody approach against CD20+B cell, HER2+breast, and EGFR+head and neck malignancies by targeting first the tumor and then the host immune system.

6619 Background: Arsenic trioxide (ATO) can induce remission in 80-90% of patients (pts) with relapsed APL. For pts achieving a 2nd remission autologous stem cell transplant (ASCT) improves 5-year ...

2509 Background: Mantle cell lymphoma (MCL) has a poor long-term prognosis. Though autologous transplant prolongs survival, novel therapies are needed to target the residual, myeloablation-resistan...

6505 Background: Most AML patients (pts) are elderly with poor outcomes, correlating with tumor suppressor gene (TSG) hypermethylation. Azacitidine (AZA) demethylates TSGs; lenalidomide (LEN) has anti-leukemia activity. We hypothesize this combination hypomethylates/activates TSGs and is a tolerated maintenance regimen for pts without curative options. Methods: We enrolled pts ≥ 60 with untreated AML. Cohort 1 received 75 mg/m2 AZA SC/IV (d 1-7), 21 days off, then a cycle of AZA (d 1-7) followed by LEN 5 mg PO (d 8-28), and 14 days off (d 29-42). Cohorts 2, 3 and 4 got the same dose/schedule of AZA with LEN 10, 25 and 50 mg, respectively. Pts received 12 cycles if a complete response (CR), CR with incomplete recovery (CRi) or partial response (PR) was achieved without toxicity. A genome wide assay of DNA methylation was performed. Results: Eighteen pts enrolled. Median age was 72 (64-86). Ten of 18 (56%) had AML with MDS, 7 had AML NOS (39%) and 1 had t-AML. Three of 18 (17%) had adverse cytogenetics; 15/...

TPS280 Background: Induction therapy results in suboptimal outcomes in elderly AML patients (pts). CpG hypermethylation of tumor suppressor gene (TSG) promoters can reduce expression and contribute to these poor outcomes. Azacitidine (aza) prevents DNA methyltransferase from methylating CpG cytosines, allowing transcription of previously silenced genes. Lenalidomide (len), an immunomodulatory agent, upregulates SPARC, a hypermethylated TSG with reduced expression in AML (Pellagatti A, et al. PNAS USA. 2007;104:11406). In addition, len was recently shown to activate demethylation of the promoter histone of p21, allowing expression of this TSG (Escoubet-Lozach L, et al. Cancer Res. 2009;69:7347). Therefore, we hypothesize that the low-intensity combination of aza and len will be a well-tolerated, mechanistically logical regimen that can synergistically upregulate TSG expression in elderly AML pts. Methods: Pts ≥60 with newly diagnosed untreated AML are eligible. In phase I, cohort 1 receives 75 mg/m2 aza SC...

8068 Background: Rituximab, a monoclonal antibody (mAb) directed against CD20, has significantly improved the outcome of patients with lymphoma. Antibody-dependant cell-mediated cytotoxicity (ADCC)...

8573 Background: Multiple translational efforts in HD are actively investigating augmentation of the anti-tumor immune response by stimulating cytotoxic T lymphocytes (CTL) against tumor-associated EBV antigens. It has previously been believed that this therapeutic strategy and presence of EBV-specific CTLs are limited to EBV-positive HD. Here, we challenge this belief by characterizing EBV-specific CTL responses in EBV-negative HD. Methods: Among 52 consecutive patients with EBV-negative HD, CTL responses to latent antigens (LMP2, LMP2a) and lytic antigens (BMLF, BRLF) were serially assessed at diagnosis, during chemotherapy, and throughout followup for 2 years by IFN-γ Elispot and flow cytometric tetramer analysis. Results: We detected weak EBV-specific responses to both lytic and latent antigens by IFN-γ Elispot among patients with EBV-negative HD. Response to lytic antigen, BMLF1, was more robust in function and size among healthy donors compared to patients as determined by IFN-γ Elispot and flow cytometry of BMLF1-tetramer positive, CD8 T cells. Chemoradiotherapy was associated temporally with an initial decrease in LMP2A- and BMLF1-specific responses during the first 5–15 weeks of treatment, which subsequently became more robust 20–50 weeks after diagnosis, 2 to 4-fold greater compared to response at diagnosis. At final follow-up (24 months), increases in both lytic (2.6-fold) and latent (2.5-fold) CTL responses were observed with robustness of lytic-specific response equivalent to healthy controls. No significant change in control peptide response was observed. Conclusions: We confirm evidence of EBV-specific CTLs in patients with EBV-negative HD and provide the first report of dynamic variance in this population during treatment, challenging prior belief that patients with HD remain immunodeficient following therapy and arguing that the clinical significance of EBV-specific immune responses in EBV-negative HD should be further investigated. [Table: see text] No significant financial relationships to disclose.

11059 Background: Clinical decisions in oncology are increasingly individualized and dependent upon accurate assessment of tumor biology, such as hormone receptor status. Imaging techniques are lim...

531 Background: Current convention is to perform a completion axillary lymph node dissection (ALND) for invasive breast cancer (BC) patients (pts) with positive sentinel lymph node(s) (+SLN), even though No significant financial relationships to disclose.