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BACKGROUND: In a pilot study involving patients with cutaneous squamous-cell carcinoma, a high percentage of patients had a pathological complete response with the use of two doses of neoadjuvant cemiplimab before surgery. Data from a phase 2 study are needed to confirm these findings. METHODS: We conducted a phase 2, confirmatory, multicenter, nonrandomized study to evaluate cemiplimab as neoadjuvant therapy in patients with resectable stage II, III, or IV (M0) cutaneous squamous-cell carcinoma. Patients received cemiplimab, administered at a dose of 350 mg every 3 weeks for up to four doses, before undergoing surgery with curative intent. The primary end point was a pathological complete response (the absence of viable tumor cells in the surgical specimen) on independent review at a central laboratory, with a null hypothesis that a pathological complete response would be observed in 25% of patients. Key secondary end points included a pathological major response (the presence of viable tumor cells that constitute ≤10% of the surgical specimen) on independent review, a pathological complete response and a pathological major response on investigator assessment at a local laboratory, an objective response on imaging, and adverse events. RESULTS: A total of 79 patients were enrolled and received neoadjuvant cemiplimab. On independent review, a pathological complete response was observed in 40 patients (51%; 95% confidence interval [CI], 39 to 62) and a pathological major response in 10 patients (13%; 95% CI, 6 to 22). These results were consistent with the pathological responses determined on investigator assessment. An objective response on imaging was observed in 54 patients (68%; 95% CI, 57 to 78). Adverse events of any grade that occurred during the study period, regardless of whether they were attributed to the study treatment, were observed in 69 patients (87%). Grade 3 or higher adverse events that occurred during the study period were observed in 14 patients (18%). CONCLUSIONS: Neoadjuvant therapy with cemiplimab was associated with a pathological complete response in a high percentage of patients with resectable cutaneous squamous-cell carcinoma. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov number, NCT04154943.)

Chemotherapy; Quality of life; Symptoms Quimioterapia; Calidad de vida; Síntomas Quimioteràpia; Qualitat de vida; Símptomes Background In a phase III, randomised, active-controlled study (EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9; R2810-ONC-1676; NCT03257267) and cemiplimab significantly improved survival versus investigator's choice of chemotherapy among patients with recurrent cervical cancer who had progressed on platinum-based therapy. Here we report patient-reported outcomes in this pivotal study. Methods Patients were randomised 1:1 to open-label cemiplimab (350 mg intravenously every 3 weeks) or investigator's choice of chemotherapy in 6-week cycles. Patients completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 during cycles 1–16. Least-squares mean changes from baseline in global health status (GHS)/quality of life (QoL) and physical functioning (PF) were secondary end-points in the statistical hierarchy. Results Of 608 patients (304/arm), 77.8% patients had squamous cell carcinoma and 22.2% patients had adenocarcinoma. Questionnaire completion rates were ∼90% throughout. In the squamous cell carcinoma population, overall between-group differences statistically significantly favoured cemiplimab in GHS/QoL (8.49; 95% confidence interval [CI]: 3.77–13.21; P = 0.0003) and PF (8.35; 95% CI: 4.08–12.62; P < 0.0001). Treatment differences favoured cemiplimab in both histologic populations by cycle 2. Overall changes from baseline in most functioning and symptom scales favoured cemiplimab, with clinically meaningful treatment differences in role functioning, appetite loss and pain in both populations. The sensitivity analyses, responder analyses and time to definitive deterioration favoured cemiplimab in both populations. Conclusions Cemiplimab conferred favourable differences in GHS/QoL and PF compared with chemotherapy among patients with recurrent cervical cancer, with benefits in PF by cycle 2, and clinically meaningful differences favouring cemiplimab in role functioning, appetite loss, and pain. This work was supported by Regeneron Pharmaceuticals, Inc., and Sanofi.

Background: Patients with recurrent cervical cancer have a poor prognosis. Cemiplimab, the fully human programmed cell death 1 (PD-1)-blocking antibody approved to treat lung and skin cancers, has been shown to have preliminary clinical activity in this population. Methods: In this phase 3 trial, we enrolled patients who had disease progression after first-line platinum-containing chemotherapy, regardless of their programmed cell death ligand 1 (PD-L1) status. Women were randomly assigned (1:1) to receive cemiplimab (350 mg every 3 weeks) or the investigator's choice of single-agent chemotherapy. The primary end point was overall survival. Progression-free survival and safety were also assessed. Results: A total of 608 women were enrolled (304 in each group). In the overall trial population, median overall survival was longer in the cemiplimab group than in the chemotherapy group (12.0 months vs. 8.5 months; hazard ratio for death, 0.69; 95% confidence interval [CI], 0.56 to 0.84; two-sided P

Cemiplimab; Càncer de coll uterí metastàtic; Càncer de coll uterí recurrent Cemiplimab; Cáncer de cuello uterino metastásico; Cáncer de cuello uterino recurrente Cemiplimab; Metastatic cervical cancer; Recurrent cervical cancer Objectives To characterize the safety, tolerability, and anti-tumor activity of cemiplimab as monotherapy or in combination with hypofractionated radiation therapy (hfRT) in patients with recurrent or metastatic cervical cancer. To determine the association between histology and programmed death-ligand 1 (PD-L1) expression. Methods In non-randomized phase I expansion cohorts, patients (squamous or non-squamous histology) received cemiplimab 3 mg/kg intravenously every 2 weeks for 48 weeks, either alone (monotherapy cohort) or with hfRT during week 2 (combination cohort). Due to insufficient tissue material, PD-L1 protein expression was evaluated in commercially purchased samples and mRNA expression levels were analyzed from The Cancer Genome Atlas (TCGA). Results Twenty patients enrolled in both cohorts in total; 10 had squamous histology. The most common adverse events of any grade were diarrhea, fatigue, and hypokalemia, occurring in 35%, 25%, and 25%, respectively. Objective response rate was 10% in each cohort; responders had squamous histology. Duration of response was 11.2 months and 6.4 months for the responder in the monotherapy and combination cohort, respectively. Irradiated lesions were not included in the response assessments. In separate archived specimens ( N = 155), PD-L1 protein expression in tumor and immune cells was negative (

BackgroundT-cell redirecting bispecific antibodies (bsAbs) are therapeutics that recognize two distinct antigens: a tumor-associated antigen on tumor cells to promote recruitment of T-cells to the tumor, and a receptor on T-cells to potentiate anti-tumor activity. REGN7075 is a human immunoglobulin G4-based costimulatory bsAb designed to bridge epidermal growth factor receptor (EGFR) positive tumor cells with CD28 positive T-cells and to provide amplified T-cell receptor-CD3 complex-mediated T-cell activation within the tumor, through the activation of CD28 co-stimulation. In genetically humanized immunocompetent mouse models, REGN7075 in combination with anti–PD-1 (antibody directed against programmed cell death-1 receptor) improved anti-tumor activity compared with either single agent alone.1MethodsThis is an open label, Phase I/II, first-in-human study evaluating the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of REGN7075 (EGFRxCD28) alone and in combination with cemiplimab in patients with advanced solid tumors (NCT04626635). Patients must have a protocol-defined advanced solid tumor, be ≥18 years of age (≥20 years in Japan), have an Eastern Cooperative Oncology Group performance status of 0 or 1, and be naïve to anti–PD-1/anti–PD-ligand(L)1.This study includes dose escalation (a 4+3 design modified from 3+3; Part 1) and expansion phases (Part 2). In Part 1, patients will receive a lead-in of REGN7075 monotherapy for 3 weeks followed by combination therapy with cemiplimab 350 mg every 3 weeks. Study therapies are administered until disease progression, intolerable adverse events, withdrawal of consent, or other stopping criterion is met. Once a recommended Phase 2 dose is determined in Part 1, four tumor-specific expansion cohorts will be opened: non-small cell lung cancer (PD-L1 ≥50%), triple-negative breast cancer, colorectal cancer (microsatellite stable), and cutaneous squamous cell carcinoma. Primary endpoints are safety and tolerability of REGN7075 alone or in combination with cemiplimab for Part 1, and objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 for Part 2. This study is currently open to enrollment.Trial RegistrationClinicalTrials.gov identifier NCT04626635.ReferencesWaite JC, Wang B, Haber L, et al. Tumor-targeted CD28 bispecific antibodies enhance the antitumor efficacy of PD-1 immunotherapy. Sci Transl Med 2020;12:2325.Ethics ApprovalThis study was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. The study protocol and all amendments were approved by the institutional review board/ethics committee at each participating study site.ConsentAll patients provided written informed consent.

Introduction/Background* There is no standard of care regimen in the second-line setting for women with recurrent/metastatic (R/M) cervical carcinoma. Cemiplimab was recently shown to significantly improve overall survival (OS) compared with investigator’s choice (IC) chemotherapy in patients with R/M cervical cancer after first-line platinum-based chemotherapy (NCT03257267; ESMO-VP-2021). We present a pre-planned exploratory subgroup analysis comparing cemiplimab to individual IC chemotherapy options. Methodology EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 is an open-label, randomised (1:1), multi-centre, Phase 3 clinical trial of anti-programmed cell death (PD)-1 cemiplimab vs IC single agent chemotherapy in R/M cervical cancer that has progressed after first-line platinum-based treatment. The selection of single-agent chemotherapy by the investigator (gemcitabine, pemetrexed, vinorelbine, topotecan or irinotecan) was not protocol-defined, but the regimen had to be chosen prior to randomisation. Adult females (age ≥18 years) were enrolled regardless of PD-ligand 1 expression and received cemiplimab 350 mg intravenously every 3 weeks or IC chemotherapy for up to 96 weeks; and were stratified by histology (squamous cell carcinoma/adenocarcinoma or adenosquamous), geographic region (North America/Asia/rest of world), prior bevacizumab, and ECOG performance status (0/1). Primary endpoint was OS. Additional endpoints included progression-free survival (PFS), objective response rate (ORR), duration of response, quality of life and safety. Data cutoff was 4 January 2021. Result(s)* A total of 608 patients were randomised: 304 to cemiplimab and 304 to IC chemotherapy (gemcitabine, n=121; premetrexed, n=111; vinorelbine, n=32; topotecan, n=21; irinotecan, n=19) across geographic regions and histologies. Median duration of study follow-up (range) was 4.8 months (0.0–25.9) for the overall population. At second interim analysis, the trial was stopped early for efficacy. OS, PFS and ORR (table 1) demonstrated improvements with cemiplimab vs each IC chemotherapy treatment similar to those observed with cemiplimab vs pooled IC chemotherapy. Conclusion* Improvements in OS, PFS and ORR with cemiplimab trended consistently with the results for the overall population regardless of IC chemotherapy drug.

Lessons Learned Background Refractory and metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) generally does not respond to PD-1 inhibitor monotherapy. Cemiplimab is a human anti–PD-1 monoclonal antibody. An expansion cohort enrolled patients with R/M HNSCC in a phase I study combining cemiplimab plus radiation therapy (RT), cyclophosphamide, and granulocyte macrophage colony-stimulating factor (GM-CSF). Methods Patients with R/M HNSCC refractory to at least first-line therapy and for whom palliative RT is clinically indicated received cemiplimab plus RT, cyclophosphamide, and GM-CSF. The co-primary objectives were the safety, tolerability, and efficacy of cemiplimab plus RT, cyclophosphamide, and GM-CSF in 15 patients with R/M HNSCC. Results Fifteen patients were enrolled. Patients discontinued treatment due to progression of disease. The most common treatment-emergent adverse events (TEAEs) of any grade were fatigue (40.0%), constipation (26.7%), and asthenia, dyspnea, maculo-papular rash, and pneumonia (each 20%). The only grade ≥3 TEAE that occurred in two patients was pneumonia (13.3%). By investigator assessment, there was one partial response (6.7%); disease control rate was 40.0% (95% confidence interval [CI], 16.3–67.7; five patients with stable disease); seven patients had progressive disease, and two were not evaluable. Median progression-free survival by investigator assessment was 1.8 months (95% CI, 1.7–4.7). Conclusion The regimen demonstrated tolerability but not efficacy above that which can be achieved with anti–PD-1 inhibitor monotherapy for R/M HNSCC.

ispartof: ANNALS OF ONCOLOGY vol:32 issue:7 pages:940-941 status: published

Monoclonal antibodies (mAbs) are potent cancer therapeutic agents, but exclusively recognize cell-surface targets whereas most cancer-associated proteins are found intracellularly. Hence, potential cancer therapy targets such as over expressed self-proteins, activated oncogenes, mutated tumor suppressors, and translocated gene products are not accessible to traditional mAb therapy. An emerging approach to target these epitopes is the use of TCR mimic mAbs (TCRm) that recognize epitopes similar to those of T cell receptors (TCR).TCRm antigens are composed of a linear peptide sequence derived from degraded proteins and presented in the context of cell-surface MHC molecules. We discuss how the nature of the TCRm epitopes provides both advantages (absolute tumor specificity and access to a new universe of important targets) and disadvantages (low density, MHC restriction, MHC down-regulation, and cross-reactive linear epitopes) to conventional mAb therapy. We will also discuss potential solutions to these obstacles.TCRm combine the specificity of TCR recognition with the potency, pharmacologic properties, and versatility of mAbs. The structure and presentation of a TCRm epitope has important consequences related to the choice of targets, mAb design, available peptides and MHC subtype restrictions, possible cross-reactivity, and therapeutic activity.

BackgroundCemiplimab, a high-affinity, potent human immunoglobulin G4 monoclonal antibody to programmed cell death-1 demonstrated antitumor activity in a Phase 1 advanced cutaneous squamous cell carcinoma (CSCC) expansion cohort (NCT02383212) and the pivotal Phase 2 study (NCT02760498). Here we report the primary analysis of fixed dose cemiplimab 350 mg intravenously every 3 weeks (Q3W) (Group 3) and provide a longer-term update after the primary analysis of weight-based cemiplimab 3 mg/kg intravenously every 2 weeks (Q2W) (Group 1) among metastatic CSCC (mCSCC) patients in the pivotal study (NCT02760498).MethodsThe primary objective for each group was objective response rate (ORR) per independent central review (ICR). Secondary endpoints included ORR by investigator review (INV), duration of response (DOR) per ICR and INV, and safety and tolerability.ResultsFor Group 3 (n=56) and Group 1 (n=59), median follow-up was 8.1 (range, 0.6 to 14.1) and 16.5 (range, 1.1 to 26.6) months, respectively. ORR per ICR was 41.1% (95% CI, 28.1% to 55.0%) in Group 3, 49.2% (95% CI, 35.9% to 62.5%) in Group 1, and 45.2% (95% CI, 35.9% to 54.8%) in both groups combined. Per ICR, Kaplan–Meier estimate for DOR at 8 months was 95.0% (95% CI, 69.5% to 99. 3%) in responding patients in Group 3, and at 12 months was 88.9% (95% CI, 69.3% to 96.3%) in responding patients in Group 1. Per INV, ORR was 51.8% (95% CI, 38.0% to 65.3%) in Group 3, 49.2% (95% CI, 35.9% to 62.5%) in Group 1, and 50.4% (95% CI, 41.0% to 59.9%) in both groups combined. Overall, the most common adverse events regardless of attribution were fatigue (27.0%) and diarrhea (23.5%).ConclusionIn patients with mCSCC, cemiplimab 350 mg intravenously Q3W produced substantial antitumor activity with durable response and an acceptable safety profile. Follow-up data of cemiplimab 3 mg/kg intravenously Q2W demonstrate ongoing durability of responses.Trial registration numberClinicaltrials.gov, NCT02760498. Registered May 3, 2016, https://clinicaltrials.gov/ct2/show/NCT02760498

Background No systemic therapies have been approved for the treatment of advanced cutaneous squamous-cell carcinoma. This cancer may be responsive to immune therapy, because the mutation burden of the tumor is high and the disease risk is strongly associated with immunosuppression. In the dose-escalation portion of the phase 1 study of cemiplimab, a deep and durable response was observed in a patient with metastatic cutaneous squamous-cell carcinoma. Methods We report the results of the phase 1 study of cemiplimab for expansion cohorts of patients with locally advanced or metastatic cutaneous squamous-cell carcinoma, as well as the results of the pivotal phase 2 study for a cohort of patients with metastatic disease (metastatic-disease cohort). In both studies, the patients received an intravenous dose of cemiplimab (3 mg per kilogram of body weight) every 2 weeks and were assessed for a response every 8 weeks. In the phase 2 study, the primary end point was the response rate, as assessed by independent central review. Results In the expansion cohorts of the phase 1 study, a response to cemiplimab was observed in 13 of 26 patients (50%; 95% confidence interval [CI], 30 to 70). In the metastatic-disease cohort of the phase 2 study, a response was observed in 28 of 59 patients (47%; 95% CI, 34 to 61). The median follow-up was 7.9 months in the metastatic-disease cohort of the phase 2 study. Among the 28 patients who had a response, the duration of response exceeded 6 months in 57%, and 82% continued to have a response and to receive cemiplimab at the time of data cutoff. Adverse events that occurred in at least 15% of the patients in the metastatic-disease cohort of the phase 2 study were diarrhea, fatigue, nausea, constipation, and rash; 7% of the patients discontinued treatment because of an adverse event. Conclusions Among patients with advanced cutaneous squamous-cell carcinoma, cemiplimab induced a response in approximately half the patients and was associated with adverse events that usually occur with immune checkpoint inhibitors. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT02383212 and NCT02760498 .).

BACKGROUND AND OBJECTIVE: Time to opioid administration (TTO) has been suggested as a quality of care measure for sickle cell disease patients with vaso-occlusive crisis (VOC). We sought to determine whether TTO was associated with outcomes of emergency department (ED) visits for VOC. METHODS: We conducted a single-center retrospective cohort study of ED visits for VOC. The primary outcome was hospital admission, with secondary outcomes of change between the first 2 pain scores, area under the curve (AUC) for pain scores at 4 hours (pain score AUC), total ED length of stay, and total intravenous opioids. In both univariate and multivariate analyses, mixed regression (logistic for admission, linear for secondary outcome variables) was used to evaluate association of TTO with outcome. RESULTS: In 177 subjects, 414 ED visits for VOC were identified. Inpatient admission occurred in 53% of visits. The median TTO for admitted patients was 86 minutes vs 87 minutes for those not admitted. TTO was not associated with inpatient admission in either univariate or multivariate analyses. In multivariate analyses with secondary outcomes, decreased TTO was associated with greater improvement between the first 2 pain scores, decreased pain score AUC, decreased total ED length of stay, and increased total opioids. CONCLUSIONS: Although TTO was not associated with admission, it was independently associated with 4 important secondary outcomes: change in initial pain scores, pain score AUC, total ED length of stay, and total intravenous opioids. The association of a process measure, TTO, with these outcomes encourages the institution of TTO reduction efforts in the ED.

Undifferentiated embryonal sarcoma of the liver (UESL) is a rare aggressive mesenchymal pediatric tumor. Previously, reported outcomes have been very poor. Here, we report a single-center experience of five patients with UESL treated with upfront gross total resection and adjuvant chemotherapy. We have a median follow-up of 8 years with a range from 5 to 19 years with 100% event-free survival.

Infection by human adenoviruses can lead to significant morbidity and mortality in immunocompromised hosts, such as allogeneic stem cell transplant (SCT) recipients, with limited effective treatment options. Specific cutaneous manifestations of disseminated adenovirus infection are not well described. We report a woman in her twenties who received an allogeneic T-cell-depleted peripheral blood SCT for the treatment of severe aplastic anaemia and, 5 months post-transplant, was hospitalized for severe systemic adenovirus infection with progressive involvement of the colon, liver and lungs. Despite therapy with intravenous cidofovir, oral brincidofovir and intravenous immunoglobulin, she had progression of adenoviraemia and dissemination of adenoviral disease. The patient developed a progressive rash characterized by keratotic papules that began on the palms and soles and spread to the entire body. Histopathological examination of skin biopsies of individual skin lesions from the palm and abdomen showed focal acantholytic dyskeratosis and keratinocytes with hyperchromatic nuclei. Several keratinocyte nuclei were immunoreactive for adenovirus. The patient was further treated with ribavirin and adenovirus-specific cytotoxic T lymphocytes but experienced multisystem progression of adenovirus infection culminating in death.

Poorly differentiated round cell sarcomas present diagnostic challenges due to their variable morphology and lack of specific immunophenotypic markers. We present a case of a 15-year-old female with a tibial tumor that exhibited features of Ewing-like sarcoma, including apparent rearrangement of the EWSR1 gene. Hybridization capture-based next-generation DNA sequencing showed evidence of complex genomic rearrangements, absence of known pathogenic Ewing-like chromosome translocations, and deletions RB1, PTCH1, and ATRX, supporting the diagnosis of osteosarcoma. This illustrates the potential of clinical genomic profiling to improve diagnosis and enable specifically targeted therapies for cancers with complex pathologies.

TPS5600Background: Patients with recurrent and metastatic cervical carcinoma experience modest survival benefit with first-line platinum-based chemotherapy with or without bevacizumab. Those with p...

Self-reactive B cells not controlled by receptor editing or clonal deletion may become anergic. We report that fully mature human B cells negative for surface IgM and retaining only IgD are autoreactive and functionally attenuated (referred to as naive IgD+IgM− B cells [BND]). These BND cells typically make up 2.5% of B cells in the peripheral blood, have antibody variable region genes in germline (unmutated) configuration, and, by all current measures, are fully mature. Analysis of 95 recombinant antibodies expressed from the variable genes of single BND cells demonstrated that they are predominantly autoreactive, binding to HEp-2 cell antigens and DNA. Upon B cell receptor cross-linkage, BND cells have a reduced capacity to mobilize intracellular calcium or phosphorylate tyrosines, demonstrating that they are anergic. However, intense stimulation causes BND cells to fully respond, suggesting that these cells could be the precursors of autoantibody secreting plasma cells in autoimmune diseases such as systemic lupus erythematosus or rheumatoid arthritis. This is the first identification of a distinct mature human B cell subset that is naturally autoreactive and controlled by the tolerizing mechanism of functional anergy.

Preferentially expressed antigen in melanoma (PRAME) is a cancer-testis antigen that is expressed in many cancers and leukemias. In healthy tissue, PRAME expression is limited to the testes and ovaries, making it a highly attractive cancer target. PRAME is an intracellular protein that cannot currently be drugged. After proteasomal processing, the PRAME300-309 peptide ALYVDSLFFL (ALY) is presented in the context of human leukocyte antigen HLA-A*02:01 molecules for recognition by the T cell receptor (TCR) of cytotoxic T cells. Here, we have described Pr20, a TCR mimic (TCRm) human IgG1 antibody that recognizes the cell-surface ALY peptide/HLA-A2 complex. Pr20 is an immunological tool and potential therapeutic agent. Pr20 bound to PRAME+HLA-A2+ cancers. An afucosylated Fc form (Pr20M) directed antibody-dependent cellular cytotoxicity against PRAME+HLA-A2+ leukemia cells and was therapeutically effective against mouse xenograft models of human leukemia. In some tumors, Pr20 binding markedly increased upon IFN-γ treatment, mediated by induction of the immunoproteasome catalytic subunit β5i. The immunoproteasome reduced internal destructive cleavages within the ALY epitope compared with the constitutive proteasome. The data provide rationale for developing TCRm antibodies as therapeutic agents for cancer, offer mechanistic insight on proteasomal regulation of tumor-associated peptide/HLA antigen complexes, and yield possible therapeutic solutions to target antigens with ultra-low surface presentation.

INTRODUCTION T Cell Receptor mimic (TCRm) antibodies to low-density peptide epitopes from undruggable intracellular proteins presented in the context of major histocompatibility (MHC) molecules are therapeutically effective in mouse models of human cancers. CD47 blockade by use of a high affinity SIRPα variant protein (CV1) has been shown to improve the effects of monoclonal antibodies to high-density antigens in tumor models by enhancement of antibody dependent cellular phagocytosis (ADCP). We asked if combination therapy with a TCRm antibody to Preferentially Expressed Antigen in Melanoma (PRAME) could enhance activity of both drugs in vitro and in vivo. Additionally, we explored the role of macrophage-secreted cytokines in the enhanced in vivo activity. METHODS We performed in vitro ADCP assays with human acute myeloid and acute lymphoid leukemia cell lines containing antigens of interest using the two agents alone and in combination. We performed therapy experiments in NSG mice using the same leukemia cell lines transformed with a luciferase vector and measured tumor burden through bioluminescent imaging. Survival was measured. We examined cell-surface expression of epitopes of interest and HLA on cell lines in vitro after incubation with IFNγ and TNFα using flow cytometry and performed in vitro ADCP assays with the leukemia cell lines after pretreatment with IFNγ. RESULTS CV1 and TCRm antibody showed additive effects in vitro with a statistically significant increase in phagocytosis in both antigen positive cell lines with combination therapy versus single agent therapy. CV1 and TCRm antibody showed greater than additive therapeutic effects in vivo with a 3-log reduction in leukemia burden relative to control untreated mice and a 5-10 fold reduction relative to single agent groups. After therapy was stopped, mice treated with the combination had statistically significant increases in survival (p CONCLUSIONS The elimination of anti-phagocytic signal produced by CD47 blockade with the high affinity SIRPα variant CV1, combined with the pro-phagocytic signal of Fc receptor engaging TCRm was effective even with an ultra-low density epitope (700-3000 sites per cell) in vitro and in vivo. A greater than additive effect was seen in two tumor models. These results support the potency of this drug combination. The large enhancement in activity in vivo vs. in vitro may be explained by macrophage-released cytokines leading to increased presentation of epitopes of interest and increased tumor kill. Disclosures Liu: Eureka Therapeutics: Employment, Equity Ownership, Patents & Royalties. Garcia:Alexo Therapeutics: Equity Ownership.

Immunosuppression by tumor-induced regulatory T (Treg) cells present major obstacles for successful immunotherapy. Treg expansion and its negative prognostic impact represent a general phenomenon seen in multiple types of cancer. Therefore, developing strategies for Treg depletion could enhance the reactivation of immune responses against the malignant tumor cells. However, the strategies of depleting Tregs have been hindered by the lack of specificity, which also leads to the depletion of anti-tumor effector cells. The transcription factor forkhead box p3 (FoxP3) is selectively expressed in and is essential to the suppressive function of Treg cells. FoxP3 thus would be an appealing target for eliminating Treg cells. However, Foxp3 is an undruggable intracellular protein. Here, we took a novel and unconventional approach to target Foxp3 by using a T cell receptor mimic (TCRm) mAb, which recognizes a human Foxp3-derived CD8 T cell epitope, presented by HLA-A*02:01 molecule. We show that the Foxp3 mAb specifically bound to CD4+CD25hiCD127lo Foxp3+ Treg cells from HLA-A0201 positive donors, and tumor cell lines co-expressing Foxp3 and HLA-A*02;01 molecule. Both afucosylated Fc enhanced human IgG1 and bispecific T cell engager formats of the Foxp3 mAb are able to kill in vitro-generated Treg clones from HLA-A0201+ donors and “Treg-like” cutaneous lymphoma cells (HLA-A*02:01+) that have a high level expression of CD4, CD25 and Fox3+. FoxP3-targeting antibodies could potentially be a novel approach in cancer immunotherapy by overcoming immunosuppression caused by Tregs and tumor cells expressing Foxp3. Citation Format: Tao Dao, Casey Jarvis, Andrew C. Scott, Tatyana Korontsvit, Victoria Zakhaleva, Dmitry Pankov, Manuel Direito de Morais Guerrerio, Melissa Mathias, Neal Cheng, Cheng Liu, David A. Scheinberg. Selective targeting of T regulatory cells by a TCR-mimic monoclonal antibody specific for foxp3-derived epitopes [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A058.

Successful antiretroviral pre-exposure prophylaxis (PrEP) for mucosal and intravenous HIV-1 transmission could reduce new infections among targeted high-risk populations including discordant couples, injection drug users, high-risk women and men who have sex with men. Targeted antiretroviral PrEP could be particularly effective at slowing the spread of HIV-1 if a single antiretroviral combination were found to be broadly protective across multiple routes of transmission. Therefore, we designed our in vivo preclinical study to systematically investigate whether rectal and intravenous HIV-1 transmission can be blocked by antiretrovirals administered systemically prior to HIV-1 exposure. We performed these studies using a highly relevant in vivo model of mucosal HIV-1 transmission, humanized Bone marrow/Liver/Thymus mice (BLT). BLT mice are susceptible to HIV-1 infection via three major physiological routes of viral transmission: vaginal, rectal and intravenous. Our results show that BLT mice given systemic antiretroviral PrEP are efficiently protected from HIV-1 infection regardless of the route of exposure. Specifically, systemic antiretroviral PrEP with emtricitabine and tenofovir disoproxil fumarate prevented both rectal (Chi square = 8.6, df = 1, p = 0.003) and intravenous (Chi square = 13, df = 1, p = 0.0003) HIV-1 transmission. Our results indicate that antiretroviral PrEP has the potential to be broadly effective at preventing new rectal or intravenous HIV transmissions in targeted high risk individuals. These in vivo preclinical findings provide strong experimental evidence supporting the potential clinical implementation of antiretroviral based pre-exposure prophylactic measures to prevent the spread of HIV/AIDS.

The discovery of lymphocytes bearing two light chains in mice carrying self-reactive antibody transgenes has challenged the “one lymphocyte–one antibody” rule. However, the extent and nature of allelically included cells in normal mice is unknown. We show that 10% of mature B cells coexpress both Igκ alleles. These cells are not the result of failure in allelic exclusion per se, but arise through receptor editing. We find that under physiological conditions, editing occurs both by deletion and by inclusion with equal probability. In addition, we demonstrate that B lymphocytes carrying two B-cell receptors are recruited to germinal center reactions, and thus fully participate in humoral immune responses. Our data measure the scope of allelic inclusion and provide a mechanism whereby autoreactive B cells might “escape” central tolerance.

Background: The natural history of sickle cell disease (SCD) includes premature death. Advancements in care, such as penicillin prophylaxis, have made death during childhood uncommon. Prior survival estimates for adults with SCD have been limited by survival bias (subjects enrolled as adults) or the limitations of administrative data. No prior study has estimated survival for adults with SCD from a newborn cohort. Herein, we report an continued observation of subjects in the Dallas Newborn Cohort (DNC)1. Methods: The DNC is an inception cohort of patients with SCD defined by: (1) diagnosis by Texas newborn screening after October 31, 1983; (2) evaluation in the pediatric sickle cell program at UT Southwestern (UTSW) / Children’s Medical Center Dallas (CMCD); and (3) confirmation of SS, SC, Sβ0 or Sβ+ genotype. Patients followed at CMCD are transitioned to adult care before the 19th birthday. To identify transitioned patients or those lost to follow-up (LTFU), we reviewed the medical records at Parkland Memorial Hospital (PMH) and UTSW University Hospital (UH), the public and private hospitals affiliated with CMCD and the most common care-sites for transitioned patients. In addition, for patients no longer actively followed at CMCD, we queried the National Death Index (NDI). The NDI is a centralized database of death records obtained from all state vital statistic bureaus in the US and is maintained by the National Center for Health Statistics. As of our query in April 2014, deaths occurring from 1/1/79 - 12/31/11 were available in the NDI. Probabilistic matching is performed by the NDI to identify subjects using identifiers such as name, social security number, birthdate, gender, state of birth, and race. Patients who were LTFU or transitioned to adult care were censored at 12/31/11 or the date of their last clinical encounter, whichever occurred latest. Patients actively followed at CMCD, PMH, or UH were censored at 12/31/13. In addition to descriptive statistics, we constructed survival curves using the Kaplan-Meier method to evaluate overall survival and survival by genotype. Also, Cox Proportional Hazard modeling was used to assess genotype, baseline hemoglobin, baseline reticulocyte count (%), and baseline oxygen saturation as potential predictors of early mortality. To test the sensitivity of the NDI to identify deceased individuals, we submitted 36 known deaths from the cohort. Results: The DNC is now comprised of 1214 patients with 16,636 years of follow-up. The cohort is 49.2% female with a mean age, and duration of follow-up, of 13.2 years (Range 0.1 – 30.0 years). SCD genotypes included 60.5% HbSS, 30.6% HbSC, 6.8% HbSβ+, and 2.1% HbSβ0. Of the 1214 patients in the cohort, 511 were active in the pediatric program, 195 were in the pediatric age range but had moved or were LTFU, 238 were adults with 1 or more visits at PMH or UH, 234 were adults with no subsequent identifiable clinical encounters, and 36 were deceased. Of 36 known deaths submitted to the NDI, 34 were identified by their databases (94.4% sensitivity). Of the 606 patients who were LTFU or aged out of the pediatric program, only 10 were reported to have died by the NDI. One of them was confirmed to be erroneous because the patient had clinical encounters after the NDI-reported date of death. In addition to these 9 deaths in the NDI, 8 additional patients were known to have died as of 12/31/13, bringing the total number of deaths to 53 (4.3%). Of these, 21 (39.6%) have been identified since the last cohort update in 2007. Overall survival in the DNC to age 25 years was 91.4% (95% CI: 88.4%, 93.7%) for all members (Figure), 87.7% (95% CI: 83.3%, 91%) for those with HbSS or HbSβ0, and 98.6% (95% CI: 96.7%, 99.4%) for those with HbSC or HbSβ+. In univariate analysis, early mortality was associated with SS or Sβ0 genotypes (compared to HbSC or HbSβ+), lower baseline hemoglobin, and low baseline SpO2 but not gender or reticulocytes. In multivariate analysis, early mortality was associated with only lower baseline hemoglobin (Hazard Ratio 0.76 [95% CI 0.59, 0.98], P=0.037). Conclusions: These are the first modern estimates of survival into adulthood with an unbiased newborn cohort of SCD patients. Early mortality is associated with low baseline hemoglobin. Survival to age 20 remains excellent at 95% but the mortality rate appears to accelerate in early adulthood. Reference: 1. Quinn et al. Blood. 115(17):3447-52, 2010. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.