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We evaluated the safety and activity of autologous T cells expressing NY-ESO-1c259, an affinity-enhanced T-cell receptor (TCR) recognizing an HLA-A2–restricted NY-ESO-1/LAGE1a–derived peptide, in patients with metastatic synovial sarcoma (NY-ESO-1c259T cells). Confirmed antitumor responses occurred in 50% of patients (6/12) and were characterized by tumor shrinkage over several months. Circulating NY-ESO-1c259T cells were present postinfusion in all patients and persisted for at least 6 months in all responders. Most of the infused NY-ESO-1c259T cells exhibited an effector memory phenotype following ex vivo expansion, but the persisting pools comprised largely central memory and stem-cell memory subsets, which remained polyfunctional and showed no evidence of T-cell exhaustion despite persistent tumor burdens. Next-generation sequencing of endogenous TCRs in CD8+ NY-ESO-1c259T cells revealed clonal diversity without contraction over time. These data suggest that regenerative pools of NY-ESO-1c259T cells produced a continuing supply of effector cells to mediate sustained, clinically meaningful antitumor effects.Significance: Metastatic synovial sarcoma is incurable with standard therapy. We employed engineered T cells targeting NY-ESO-1, and the data suggest that robust, self-regenerating pools of CD8+ NY-ESO-1c259T cells produce a continuing supply of effector cells over several months that mediate clinically meaningful antitumor effects despite prolonged exposure to antigen. Cancer Discov; 8(8); 944–57. ©2018 AACR.See related commentary by Keung and Tawbi, p. 914.This article is highlighted in the In This Issue feature, p. 899

Figure S1. Consort diagram. Figure S2. Longitudinal analyses of persistence, memory cells and exhaustion marker expression. Figure S3. NY-ESO-1c259T cells exhibit and maintain polyfunctionality prior to and postinfusion. Figure S4. NY-ESO-1c259TCR+CD3+ T cells from the manufactured product and post-infusion PBMCs from a representative patient. Figure S5. Tumor analyses following NY-ESO-1c259T cell therapy in patient 202. Figure S6. NY-ESO-1 Expression at Screening and Relapse. Figure S7. Analysis of TCRBV sequences within sorted cell subsets.

BackgroundADP-A2M10 specific peptide enhanced affinity receptor (SPEAR) T cells (ADP-A2M10) are genetically engineered autologous T cells that express a high-affinity melanoma-associated antigen A10 (MAGE-A10)-specific T-cell receptor (TCR) targeting MAGE-A10+ tumors in the context of human leukocyte antigen (HLA)-A*02. ADP-0022-003 was a phase I dose-escalation trial that aimed to evaluate the safety and antitumor activity of ADP-A2M10 in non-small cell lung cancer (NSCLC) (NCT02592577).MethodsEligible patients were HLA-A*02 positive with advanced NSCLC expressing MAGE-A10. Patients underwent apheresis; T cells were isolated, transduced with a lentiviral vector containing the TCR targeting MAGE-A10, and expanded. Patients underwent lymphodepletion with varying doses/schedules of fludarabine and cyclophosphamide prior to receiving ADP-A2M10. ADP-A2M10 were administered at 0.08–0.12×109 (dose group 1), 0.5–1.2×109 (dose group 2), and 1.2–15×109 (dose group 3/expansion) transduced cells.ResultsEleven patients (male, n=6; female, n=5) with NSCLC (adenocarcinoma, n=8; squamous cell carcinoma, n=3) were treated. Five, three, and three patients received cells in dose group 1, dose group 2, and dose group 3/expansion, respectively. The most frequently reported grade ≥3 adverse events were lymphopenia (n=11), leukopenia (n=10), neutropenia (n=8), anemia (n=6), thrombocytopenia (n=5), and hyponatremia (n=5). Three patients presented with cytokine release syndrome (grades 1, 2, and 4, respectively). One patient received the highest dose of lymphodepletion (fludarabine 30 mg/m2 on days –5 to –2 and cyclophosphamide 1800 mg/m2 on days −5 to −4) prior to a second infusion of ADP-A2M10 and had a partial response, subsequently complicated by aplastic anemia and death. Responses included: partial response (after second infusion; one patient), stable disease (four patients), clinical or radiographic progressive disease (five patients), and not evaluable (one patient). ADP-A2M10 were detectable in peripheral blood and in tumor tissue. Peak persistence was higher in patients who received higher doses of ADP-A2M10.ConclusionsADP-A2M10 demonstrated an acceptable safety profile and no evidence of toxicity related to off-target binding or alloreactivity. There was persistence of ADP-A2M10 in peripheral blood as well as ADP-A2M10 trafficking into the tumor. Given the discovery that MAGE-A10 and MAGE-A4 expression frequently overlap, this clinical program closed as trials with SPEAR T cells targeting MAGE-A4 are ongoing.

We evaluated the safety and activity of autologous T cells expressing NY-ESO-1c259, an affinity-enhanced T-cell receptor (TCR) recognizing an HLA-A2–restricted NY-ESO-1/LAGE1a–derived peptide, in patients with metastatic synovial sarcoma (NY-ESO-1c259T cells). Confirmed antitumor responses occurred in 50% of patients (6/12) and were characterized by tumor shrinkage over several months. Circulating NY-ESO-1c259T cells were present postinfusion in all patients and persisted for at least 6 months in all responders. Most of the infused NY-ESO-1c259T cells exhibited an effector memory phenotype following ex vivo expansion, but the persisting pools comprised largely central memory and stem-cell memory subsets, which remained polyfunctional and showed no evidence of T-cell exhaustion despite persistent tumor burdens. Next-generation sequencing of endogenous TCRs in CD8+ NY-ESO-1c259T cells revealed clonal diversity without contraction over time. These data suggest that regenerative pools of NY-ESO-1c259T cells produced a continuing supply of effector cells to mediate sustained, clinically meaningful antitumor effects. Significance: Metastatic synovial sarcoma is incurable with standard therapy. We employed engineered T cells targeting NY-ESO-1, and the data suggest that robust, self-regenerating pools of CD8+ NY-ESO-1c259T cells produce a continuing supply of effector cells over several months that mediate clinically meaningful antitumor effects despite prolonged exposure to antigen. Cancer Discov; 8(8); 944–57. ©2018 AACR. See related commentary by Keung and Tawbi, p. 914. This article is highlighted in the In This Issue feature, p. 899

Background This study (NCT03132922) evaluates safety, tolerability, and antitumor activity of ADP-A2M4, genetically engineered autologous specific peptide enhanced affinity receptor (SPEAR) T-cells directed towards a MAGE-A4 peptide expressed in the context of HLA-A*02. Here, we report on a subset of patients (pts) with synovial sarcoma (SS). Methods In this first-in-human T-cell dose-escalation study, pts who are HLA-A*02+ (excluding *02:05, *02:07), have inoperable or metastatic MAGE-A4+ disease, and meet entry criteria are eligible for treatment. Following apheresis, T-cells are isolated, transduced with MAGE-A4c1032TCR, and expanded. The lymphodepletion chemotherapy increased in intensity as the study progressed, with max dose of 30mg/m2/d fludarabine x 4 d and 1800mg/m2/d cyclophosphamide x 2 d. During dose escalation, 3 pts with various tumor types received 0.1x109 (±20%), 1x109 (range: 0.5 – 1.2 × 109), or 5x109 (range: 1.2 – 6 × 109) transduced cells and were monitored for dose-limiting toxicities (DLTs). During expansion, 30 pts (not only SS) will be treated with 1.2 – 10x109 transduced cells. Disease is assessed per RECIST by CT/MRI at wk 6, 12, 18, and 24, and every 3mo for 2yr, then every 6mo or until progression. Correlative studies will investigate transduced cell persistence, phenotype, and function, and serum and tumor microenvironment factors. Results No DLTs were reported. ADP-A2M4 was well tolerated, with adverse events consistent with chemotherapy or other immunotherapies. 10 pts with SS have been treated in cohort 3 and the expansion phase (30Apr19). Median T-cell dose was 9.7x109 (4.49 - 9.98x109). 8 pts have post-baseline tumor assessments. There are 3 confirmed partial responses (PR) (-86%, -44%, -54), and 1 unconfirmed PR (-31%) at wk 6. Best response was stable disease in 3 pts (-27% and -15%, ongoing, and +12%, progressed) and progressive disease in 1. 2 pts have yet to be assessed. Ex vivo analysis of transduced cells from peripheral blood and tumor showed cells were cytolytic and activated in an antigen-specific manner. Conclusions ADP-A2M4 induced clinical responses in pts with SS. Transduced T-cells expand upon exposure to antigen and are functional. Updated data from this ongoing study will be presented. Clinical trial identification NCT03132922, First posted on April 28, 2017. Editorial acknowledgement Debra Brocksmith, MB ChB, PhD, of Envision Pharma Group; contracted by Adaptimmune. Legal entity responsible for the study Adaptimmune. Funding Adaptimmune. Disclosure B.A. Van Tine: Research grant / Funding (self): Pfizer; Research grant / Funding (self): Tracon; Research grant / Funding (self): Merck; Advisory / Consultancy: Epizyme; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy: CytRX; Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen; Advisory / Consultancy: Immune Design; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Plexxicon; Advisory / Consultancy: Adaptimmune; Speaker Bureau / Expert testimony: Caris. M.O. Butler: Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Merck; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self): Roche; Advisory / Consultancy: Adaptimmune; Advisory / Consultancy: EMD Serono; Advisory / Consultancy: GSK; Advisory / Consultancy: Immunocore; Advisory / Consultancy: Immunovaccine; Research grant / Funding (institution): Takara Bio. M.L. Johnson: Research grant / Funding (institution): BerGenBio; Research grant / Funding (institution): Lilly; Research grant / Funding (institution), Travel / Accommodation / Expenses: EMD Serono; Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Mirati Therapeutics; Research grant / Funding (institution): Genmab; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Additional travel from: Astellas, AstraZeneca, Boehringer Ingelheim, Clovis, Daiichi Sankyo, Bristol-Myers Squibb, Exelixis, Incyte, Merck, Sysmex Inostics, Vapotherm: Genentech; Research grant / Funding (institution): Stemcentrix; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Checkpoint Therapeutics; Research grant / Funding (institution): Array Biopharma; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Apexigen; Research grant / Funding (institution), Travel / Accommodation / Expenses: AbbVie; Research grant / Funding (institution): Tarveda; Research grant / Funding (institution): Adaptimmune; Research grant / Funding (institution), Additional advisory for: Gelgene, Boehringer Ingelheim, Sanofi, LOXO, Calithera, Merck, Araxes Pharma, Mersana Therapeutics, BeiGene, Incyte, Guardant Health, Bristol-Myers Squibb, Ribon Therapeutics: Syndax; Research grant / Funding (institution), Additional grant funding from: Boehringer Ingelheim, Sanofi, Hengrui Therapuetics INC, Merck, Daiichi-Sankyo, Lycera, G1 Therapeutics, Dynavax, LOXO, Cytomx, BeiGene, Birdie, Corvus, Incyte, Genocea, Gritstone, Amgen, Bristol-Myers Squibb, Kadmon, Clovis, Acerta, OncoMed, Guardant Health, Takeda, Shattuck Labs, GSK: Neovia. J. Clarke: Research grant / Funding (self): MedPacto; Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self): Eli Lilly; Research grant / Funding (self): Genentech; Research grant / Funding (self): Spectrum; Research grant / Funding (self): Adaptimmune; Research grant / Funding (self): Bayer; Research grant / Funding (self): AbbVie; Research grant / Funding (self): Moderna; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony: Guardant; Advisory / Consultancy: AstraZeneca. D. Liebner: Advisory / Consultancy: Foundation Medicine; Advisory / Consultancy: Blueprint Medicines. K. Odunsi: Research grant / Funding (self): ITeos Therapeutics. A.J. Olszanski: Advisory / Consultancy, Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy: Merck; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Array; Advisory / Consultancy, Research grant / Funding (self): EMD Serono; Advisory / Consultancy: Iovance; Advisory / Consultancy: Novartis; Advisory / Consultancy, Research grant / Funding (self): Alkermes; Research grant / Funding (self): Adaptimmune; Research grant / Funding (self): Astellas; Research grant / Funding (self): Boston Biomedical; Research grant / Funding (self): Checkmate Pharmaceutics; Research grant / Funding (self): GSK; Research grant / Funding (self): Immunocore; Research grant / Funding (self): Intensity Therapeutics; Research grant / Funding (self): Kartos; Research grant / Funding (self): Kura; Research grant / Funding (self): Oncoceutics; Research grant / Funding (self): Targovax. S. Basu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Adaptimmune. F. Brophy: Shareholder / Stockholder / Stock options, Full / Part-time employment: Adaptimmune. T. Holdich: Shareholder / Stockholder / Stock options, Full / Part-time employment: Adaptimmune. T. Trivedi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Adaptimmune. R.G. Amado: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Adaptimmune. D.S. Hong: Research grant / Funding (self): AbbVie; Advisory / Consultancy, Research grant / Funding (self): Adaptimmune; Research grant / Funding (self): Amgen; Research grant / Funding (self): AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): Bayer; Research grant / Funding (self): Bristol-Myers Squibb; Research grant / Funding (self): Daiichi-Sankyo; Research grant / Funding (self): Eisai; Research grant / Funding (self): Fate Therapeutics; Advisory / Consultancy, Research grant / Funding (self): Genentech; Research grant / Funding (self), Travel / Accommodation / Expenses: Genmab; Research grant / Funding (self): Ignyta; Advisory / Consultancy, Research grant / Funding (self): Infinity; Research grant / Funding (self): Kite; Research grant / Funding (self): Kyowa; Research grant / Funding (self): Lilly; Research grant / Funding (self), Travel / Accommodation / Expenses: LOXO; Research grant / Funding (self): MedImmune; Research grant / Funding (self): Merck; Research grant / Funding (self), Additional grant funding from: miRNA, Molecular Templates, Mologen, NCI-CTEP, Novartics, Pfizer, Seattle Genetics, Takeda. Additional advisory consulting for: Alpha Insights, Axiom, Baxter, GLG, Group H, Guidepoint Global, Merrimack, Medscape, Numab, Pfizer, Seattle Genetics, Takeda, Trieza Therapeutics, WebMD; Travel support from MiRNA, AACR, ASCO, SITC; ownership interests in Molecular Match, OncoResponse, Presagia Inc: Mirati. All other authors have declared no conflicts of interest.

We evaluated the safety and activity of autologous T cells expressing NY-ESO-1

Specific immunotherapy is a well-established treatment for allergic rhinoconjunctivitis; conventional regimens are lengthy, however, reducing convenience and cost-effectiveness. This study evaluated the efficacy and safety of an ultrashort course (four doses) of the immunotherapy Grass Modified Allergen Tyrosine Adsorbate (Allergy Therapeutics, Worthing, U.K.) monophosphoryl lipid A (MATA MPL). Subjects were randomized to receive four injections of either Grass MATA MPL (n 514; 300-2000 standardized units/injection) or placebo (n 514) before the grass pollen season. They used electronic diaries to record allergy symptoms and medication use during the pollen season. The primary end point was the difference between the mean combined symptom and medication scores in the Grass MATA MPL and placebo groups during the 4 local peak pollen weeks. The injection course was completed by 95.3 and 97.7% of the Grass MATA MPL and placebo groups, respectively, and was well tolerated. Grass MATA MPL treatment afforded a 13.6% benefit over placebo in the 4 peak pollen weeks (p 0.0038). The benefit in subjects with 28 complete diary entries during the 4 peak pollen weeks was 24.3% (p 0.0031). Significant benefits over placebo were observed in subjects with severe symptoms (16.6%; p 0.0023), in those who had a history of allergic rhinoconjunctivitis for up to 35 years (up to 31%; p 0.0059) and at sites with a higher burden of disease (31%; p 0.0001). The ultrashort course of Grass MATA MPL was well tolerated and provided a significant benefit over placebo in relieving allergy symptoms. (Allergy Asthma Proc 32:239–247, 2011; doi: 10.2500/aap.2011.32.3453)

Circulating T-cells, bearing T-cell receptors (TCRs) that have passed thymic selection, generally have low affinity for self-protein-derived cancer antigens and therefore have a limited ability to detect and eliminate tumor cells. Engineering TCRs to enhance and optimize their affinity, and therefore potency, for cancer targets is a promising strategy for adoptive immunotherapy in cancer patients. Modification of TCRs can potentially generate cross-reactivity to antigens expressed by normal tissue. Such cross reactivity might not be detected by in vivo animal studies, due to species differences in the antigenic repertoire. To mitigate the risk of such toxicities in clinical trials, we developed a comprehensive in vitro testing strategy. This strategy involves systematic substitution at each position of the antigenic peptide sequence using all natural amino acids to generate a profile of peptide specificity (“X-scan”). The likelihood of off-target reactivity was investigated by searching the human proteome for sequences matching this profile and testing against a panel of cell lines. Starting from a panel of parental TCRs with diverse sequences, we engineered several affinity-enhanced TCRs specific for the cancer-testis antigen MAGE-A10. The properties of two of these TCRs, which had the optimal balance of potency and specificity, could not be distinguished effectively with conventional biochemical and cellular assays. The X-scan method permitted us to select the most specific and potent candidate for further pre-clinical testing. This MAGE-A10c796 TCR is now being studied in clinical trials to treat HLA-A2+ patients with non-small cell lung cancer (NCT02592577), urothelial cancers, melanoma, or head and neck cancers (NCT02989064). Citation Format: Ellen Border, Joseph P. Sanderson, Thomas Weissensteiner, Natalie Hyland, Tom Holdich, Francine Brophy, Rafael Amado, Andrew Gerry, Nicholas Pumphrey. Selection of affinity-enhanced T-cell receptors for adoptive T-cell therapy targeting MAGE-A10 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2564.

3056Background: MAGE-A10 is expressed in 10-50% of urothelial, melanoma, head and neck (HNC), and non-small cell lung cancers (NSCLC). Affinity-enhanced autologous MAGE-A10c796T cells directed towa...

Background: NY-ESO-1 and LAGE-1a are cancer-testis antigens that are overexpressed in patients with multiple myeloma (MM), and the incidence of these antigens correlates with tumor proliferation and other high-risk features. Genetically engineered NY-ESO-1 SPEAR (specific peptide enhanced affinity receptor) T-cells (NY-ESO-1c259T cells) recognize the peptide sequence SLLMWITQC expressed by NY-ESO-1 or LAGE-1a in the context of HLA-A*02 presentation. This study evaluated treatment with NY-ESO-1SPEAR T-cells post-autologous stem cell transplant (ASCT) in patients with advanced MM. Methods: Eligible patients were HLA-A*02:01, 02:05 or 02:06 positive, with refractory, relapsed or high risk MM associated with one or more adverse cytogenetic abnormalities. Eligible patients' tumors also expressed NY-ESO-1 and/or LAGE-1a by qPCR. The primary study endpoint was safety. Secondary objectives included overall response rate (ORR) (sCR+CR+VGPR+PR) evaluated with the International Myeloma Working Group Criteria (Rajkumar S.V. et al., Blood 2011), progression-free survival (PFS), overall survival (OS), best overall response (BOR), duration of response (DOR), as well as gene-marked cell persistence. Lymphocytes were obtained by leukapheresis, isolated, activated, transduced to express NY-ESO-1c259T cell receptor, and expanded using anti-CD3/anti-CD28 immunomagnetic beads. While the SPEAR T-cells were being manufactured, stem cell mobilization was conducted using 1.5 g/m2 of cyclophosphamide plus G-CSF, and stem cells were collected (minimum: 2 × 106 CD34+ progenitors/kg). Once the manufactured product was ready, high-dose melphalan (140-200 mg/m2) was given 2 days before stem cell infusion. Two days after the stem cell infusion, the SPEAR T-cells were infused (median dose 3.1 × 109 of transduced T-cells, range 0.5-5.1 × 109). Disease was assessed at days 42, 100, 180, 270 and 360 post-T-cell infusion, and then every 3 months. Patients meeting the criteria for lenalidomide maintenance therapy received 10 mg/day starting around day 100 post-ASCT. Results: Twenty-five patients were enrolled, and all have been treated. Median age at enrollment was 61 yr (range 45 - 72); 60% were male. Based on analyses through July 2017, ORR at day 100 was 76% (1 sCR; 12 VGPR; 6PR), and at year 1, 13 patients were progression free (52%) of which 11 were responders (1 sCR; 1 CR; 8 VGPR; 1 PR). Three patients remain disease progression-free at 39, 56 and 61 months post T-cell infusion. Median PFS was ~13 months (range 3-61 months). Eleven of 25 patients (44%) are alive, and median survival was ~35 months (range 6-68 months). The most common adverse events (experienced by >70%) were diarrhea (100%), nausea (100%), anemia (96%), decreased appetite (92%), thrombocytopenia (92%), fatigue (88%), pyrexia (84%), rash (84%), hypokalemia (76%), febrile neutropenia (72%) and vomiting (72%). Autologous GVHD (24%) was reported in 6 patients (3 G3, 3 ≤G2); all resolved with corticosteroids and supportive therapy. No fatal adverse events have been reported. Conclusions: NY-ESO-1 SPEAR T-cell therapy in the setting of autologous stem cell transplant has promising efficacy and acceptable safety. GVHD, which manifests in a similar way as reported in prior transplant studies and is more frequent with adoptive T cell transfer (engineered or not engineered), appears manageable with appropriate supportive care. Analyses of transduced cell persistence, T-cell clonality, and minimal residual disease (MRD) genetic studies are ongoing and will be presented along with the efficacy and safety data for all 25 patients. Disclosures Chagin: Adaptimmune: Employment. Faitg: Adaptimmune: Employment. Iyengar: Adaptimmune: Employment. Trivedi: Adaptimmune: Employment. Norry: Adaptimmune: Employment. Holdich: Adaptimmune: Employment. Binder-Scholl: Adaptimmune: Employment. Amado: Adaptimmune: Employment. Fang: Adaptimmune: Employment.

Apricitabine is a novel deoxycytidine analogue reverse transcriptase inhibitor with clinical efficacy against both wild-type and drug-resistant HIV. The objective of this study was to evaluate the influence of feeding on apricitabine absorption and plasma pharmacokinetics.Twenty healthy, male, HIV-negative volunteers were recruited for this randomised, open-label, crossover study and administered 1200 mg apricitabine orally either following fasting or a high-fat meal. Multiple blood samples were collected over a time course between 0 and 36 h following dosing, and plasma apricitabine concentration was measured using liquid chromatography-tandem mass spectrometry.Pharmacokinetic parameters were calculated from the drug concentration-time data for apricitabine using noncompartmental methods. Geometric means for maximum concentration (C(max)) and area under the apricitabine concentration versus time curve (AUC) for both the fasted and fed states were calculated and tested for bioequivalence at the 0.05 level by constructing the 90% confidence interval for the ratio of geometric means.Apricitabine was well tolerated by all study participants. Plasma concentrations increased rapidly following oral administration, with C(max) being attained within 2 - 4 h. The pharmacokinetics of apricitabine was similar between the two states: the geometric means of both C(max) and AUC increased slightly between fasting and the administration of a high-fat meal, however the 90% confidence intervals around the ratio of the geometric means were within the standard bioequivalence criteria.Bioequivalence between the fed and fasting states was identified, indicating that a high-fat meal had no significant impact on the pharmacokinetics of single 1200 mg doses of apricitabine in healthy volunteers.

Despite recent therapeutic advances, multiple myeloma (MM) remains largely incurable. Herein we report results of a phase I/II trial to evaluate the safety and activity of autologous T-cells engineered to express an affinity-enhanced T-cell receptor (TCR) recognizing a naturally processed peptide shared by the cancer-testis antigens NY-ESO-1 and LAGE-1. Twenty patients with antigen-positive MM received an average 2.4×109 engineered T cells two days after autologous stem cell transplant (ASCT). Infusions were well-tolerated without clinically apparent cytokine release syndrome, despite high IL-6 levels. Engineered T-cells expanded, persisted, trafficked to marrow and exhibited a cytotoxic phenotype. Persistence of engineered T cells in blood was inversely associated with NY-ESO-1 levels in the marrow. Disease progression was associated with loss of T cell persistence or antigen escape, consistent with the expected mechanism of action of the transferred T cells. Encouraging clinical responses were observed in 16 of 20 patients (80%) with advanced disease, with a median progression free survival of 19.1 months. NY-ESO-1/LAGE-1 TCR-engineered T-cells were safe, trafficked to marrow and showed extended persistence that correlated with clinical activity against antigen-positive myeloma.

3000 Background: NY-ESO-1 is expressed in ~70% of synovial sarcomas (SS). NY-ESO-1c259T cells recognizing an NY-ESO-1 derived peptide complexed with HLA-A*02 are being studied in SS. Methods: Eligible patients (pt) are HLA-A*02:01, 02:05 or 02:06, with unresectable, metastatic or recurrent SS expressing NY-ESO-1. Primary endpoint of ORR (CR+PR) is evaluated in high (≥ 50% tumor cells express 2+/3+) and low (≥ 1+ in ≥ 1% cells, not exceeding 2+/3+ in ≥ 50% cells) NY-ESO-1 expressers with different lymphodepleting regimens. Secondary endpoints are safety, DOR, PFS, OS, and gene-marked cell persistence. Lymphocytes are obtained by leukapheresis, isolated, activated, transduced to express NY-ESO-1c259T, and expanded. Target dose is 1–6 × 109cells. Disease is assessed at wk 4, 8 and 12 post-T-cell infusion, and then every 3 months. Results: 34 pt have been enrolled with 24 treated. 50% are male; median age is 30 yr (range 15 – 73). 12/15 pt in cohort 1 were treated. ORR was 50% (1 CR; 5 PR). Time to response was 6 wk (range 4-9) and median DOR 31 wk (range 13-72). Cohort 3 was closed due to only 1 PR out of 5 pt. Evaluation is ongoing in cohorts 2 (6 enrolled; 5 treated) and 4 (8 enrolled; 2 treated) as of 1/9/17. The most common AE are leukopenia (96%), nausea and pyrexia (88%), neutropenia (88%), lymphopenia (83%), anemia (79%), and thrombocytopenia (79%). 11 events of CRS were reported (3 G3; 1 G4), with no events of seizure, cerebral edema or fatal neurotoxicity; all resolved with supportive therapy. One fatal SAE (bone marrow failure) occurred in cohort 2; investigations have not identified a mechanism by which NY-ESO-1c259T may have caused this event. Conclusions: NY-ESO-1c259T has promising efficacy and acceptable safety. CRS is not associated with severe neurotoxicity and appears manageable with appropriate supportive care. Cohort 3 data indicate that Flu may be important for efficacy. Efficacy and safety data will be further evaluated and presented. Clinical trial information: NCT01343043. [Table: see text]

TPS3096 Background: Non-small cell lung cancer (NSCLC) accounts for 84% of lung cancer. Survival has recently been impacted by molecularly targeted therapies and checkpoint inhibitors (CPI), and the promising CPI results implicate a role for the immune system in NSCLC. 10-40% of NSCLC express NY-ESO-1 or MAGE-A10 cancer/testis antigens. These studies will evaluate the safety and antitumor activity of genetically engineered affinity enhanced TCRs (NY-ESO-1c259T or MAGE-A10c796T) directed towards a NYESO-1 or MAGE-A10 derived peptides complexed with HLA-A*02. In addition, correlative studies to evaluate persistence, phenotype, functionality of engineered T cells, mechanisms of resistance and antigen spreading will be performed. Methods: Patients (pt) are screened (NCT02636855) to identify those who have the relevant HLA-A*02 alleles and NY-ESO-1 or MAGE-A10 tumor expression. For entry into either treatment protocol, pt must have Stage IIIb or IV NSCLC, have failed at least one platinum-containing regimen (may have received CPIs), have measurable disease, ECOG 0-1, adequate organ function, and be without brain metastases, history of severe autoimmune disease or current uncontrolled illness. Following apheresis, T cells are isolated and expanded with CD3/CD28 beads, transduced with a lentiviral vector containing the NY-ESO-1c259T or MAGE-A10c795 TCR, and infused into the pt following lymphodepleting chemotherapy with fludarabine and cyclophosphamide. The NY-ESO-1c259T study is a 10 pt study utilizing a dose of 1-6 x 109 transduced T cells. The MAGE-A10c796T first-in-human study is a modified 3+3 design in up to 28 pt with escalating doses of 0.1, 1.0 and 1-6 x 109 transduced T cells, with staggered treatments to allow for safety review; dose escalation will be guided by the DLT observed and by safety review committee guidance. Response to treatment will be assessed by RECIST v1.1 at weeks 4, 8, 16, 24, every 3 months (for 2 yr) and every 6 months until disease progression. Clinical trial information: NCT02588612/NCT02592577.

3040Background: Cytokine release syndrome (CRS) is observed with adoptive T-cell therapies (ACT) with varying frequency. CRS can be life threatening and may require steroids, which hinder the effectiveness of ACT. CRS prevalence and severity within the context NY-ESO-1C259T across 5 studies in 4 tumor types were examined: synovial sarcoma (SS), ovarian cancer (OC), myeloma and melanoma. Methods: A review of CRS including evaluation of concurrent AEs and reported symptoms, cytokine levels and CRP was performed in pts treated with NY-ESO-1C259T. AEs that are known manifestations of CRS were summarized for each pt. diagnosed with CRS. CRP was measured by the hospital laboratory. Serum cytokines were measured by Luminex. Results: Of 53 pts treated with NY-ESO-1C259T, 7 were diagnosed with CRS (Table). 2/7 pts received immunomodulatory treatment for mitigation of CRS: methylprednisolone 2 mg/kg x 2 doses with prednisone taper (n=1, G3) and Tocilizumab 4 mg/kg x 1 dose (n=1 G4). Diagnosis of CRS was made within...

TPS3101Background: The immunogenic cancer testis antigen NY-ESO-1 is expressed in several cancers. While NY-ESO-1 is not expressed in vital tissues, it is expressed in approximately 60% in advance ...

Sequential design can provide efficient use of data from patients entered into the study. Dependent on the selected end-point, patients may contribute to the outcome throughout the duration of the study. This use of data as available may reduce sample size, particularly if drugs are very similar or notably different. In this latter circumstance the study is likely to conclude sooner than with a fixed sample size, thereby reducing the exposure of patients to an inferior treatment. If small differences in treatment exist, then the sample size may increase; however, on final completion of the study a statistically robust outcome will have been achieved. In establishing the parameters of the sequential analysis a treatment difference considered to be clinically significantly will have been specified. Hence completion of the study allows a firm conclusion to be made as to whether treatments are both clinically and statistically similar or different.

Background and objective: This study aimed to investigate the multiple-dose pharmacokinetics of apricitabine, a novel deoxycytidine analogue reverse transcriptase inhibitor, in antiretroviral-naive patients with HIV-1 infection. Methods: This was an international, randomized, double-blind, placebo-controlled, multicentre, dose-ranging study. Patients received 10 days’ oral placebo or apricitabine 200, 400, 600 or 800 mg twice daily or 800 or 1200 mg once daily. On days 1 and 8, blood and urine samples were collected over 24 hours for pharmacokinetic analysis. Apricitabine triphosphate pharmacokinetics were investigated in peripheral blood mononuclear cells (PBMCs) on day 8. Results: Overall, 63 patients (mean age 33.9 ± 8.7 years; mean weight 71.6 ± 15.4 kg) were randomized, and 62 patients completed the study. Apricitabine was rapidly absorbed, with peak plasma concentrations attained within approximately 1.5–2.5 hours. Pharmacokinetics were linear over the range 200–800 mg twice daily. Apricitabine was predominantly excreted via the kidneys, with no significant accumulation during repeated administration. Steady-state conditions were attained by day 8. Apricitabine triphosphate exposure in PBMCs was roughly proportional to the dose of apricitabine across the dose range 200–800 mg twice daily, with adequate correlations between plasma exposure to apricitabine (9910 ng/mL per 65 kg for 800-mg twice-daily administration) and PBMC exposure to apricitabine triphosphate (maximum concentration [Cmax] = 5.55 ± 1.94 pmol/million cells for 800-mg twice-daily administration). Apricitabine was well tolerated. Conclusion: Apricitabine shows essentially linear pharmacokinetics during repeated administration in patients with HIV-1 infection.

Meeting abstracts Preclinical safety testing for adoptive immunotherapies utilising T cell receptor-(TCR) engineered T cells relies on stringent target validation and a robust pre-clinical specificity testing strategy. Specific safety concerns include on-target off-tumour toxicity and off-target

NY-ESO-1 is expressed in ∼70% of synovial sarcomas and not expressed in vital tissues. We report interim results of NCT01343043 evaluating safety and activity of autologous T cells engineered to express an HLA-A2+ restricted, affinity-enhanced T cell receptor (TCR) targeting NY-ESO-1. HLA-A2+ patients with unresectable, metastatic, or recurrent synovial sarcoma were eligible if tumors expressed NY-ESO-1 by IHC. Lymphocytes were activated using anti-CD3/28 microbeads, genetically modified with a lentivector, then cryopreserved. Subjects received fludarabine 30mg/m2/d (D-6 to -2) and cyclophosphamide 1800mg/m2/d (D-3,-2), and infusion of engineered T cells. Systemic IL-2 was not administered. Nine subjects have received NY-ESO-1 cell infusions. Median transduced T cell dose was 3.4 × 109 cells (range 0.4-14.4), 60×106 cells/kg (range 5.7-165.5), and median transduction efficiency was 45.8%. Toxicity likely attributable to the T cells included fever, and grade 1-2 cytokine release syndrome. No autoimmune toxicity has been observed. Circulating engineered NY-ESO-1 cells were detected in all patients, peaking 3-21 days post-infusion. Persistence has been evaluated beyond 3 months in 4 subjects, all of whom had detectable NY-ESO-1 cells at 4 mos, 6 mos+, 12 mos+ and 12 mos+. We identified persisting NY-ESO-1 T cells using dextamer and/or anti-vβ13.1 mAbs, and observed that a high fraction of CD4+ and CD8+ NY-ESO-1 TCR expressing T cells were CD45RA+CCR7+CD95+, consistent with a stem cell memory phenotype. Persisting cells also demonstrate a polyfunctional (IFN-γ and TNF-α) and cytotoxic (CD107a and granzyme B) signature without overexpression of exhaustion markers (PD-1, LAG-3, and TIM-3). Of 8 patients whose follow-up is sufficient to assess response, 4 experienced objective responses (1CR x 9 mos, 1PR x 9 mos, 2PR x 6 mos). Tumor shrinkage could not be attributed to chemotherapy alone as progressive decreases in tumor size were observed over several months following completion of the lymphodepleting regimen. All PR patients (2 upon signs of progression and 1 still responding to therapy) ultimately underwent resection for residual disease and two remain without evidence of disease. Adoptive immunotherapy with NY-ESO-1 engineered T cells shows promising results in synovial sarcoma with acceptable toxicity. High dose IL-2 is not required for therapeutic benefit with this regimen. Citation Format: Melinda S. Merchant, Sandra P. D'Angelo, Hua Zhang, Donna Bernstein, Gwen Binder-Scholl, Tom Holdich, Luca Melchiori, Dan Williams, Marylene Fortin, Yoav Peretz, Jason Howe, Michael Mehler, Bruce A. Hug, Matthew Wright, Stephen Grupp, Paul A. Meyers, William Tap, Bent Jakobsen, Crystal L. Mackall. Genetically engineered NY-ESO-1-specific T cells in HLA-A2+ patients with synovial sarcoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4707. doi:10.1158/1538-7445.AM2015-4707

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Adoptive immunotherapy for cancer has been limited by a lack of antigen specificity, low levels of target expression, and failure to break self-tolerance. We hypothesized that infusion of genetically modified tumor-specific T cells following autologous stem cell transplant (ASCT) may overcome these barriers for multiple myeloma (MM). To test this, we conducted a phase I/II clinical trial ([NCT01352286][1]) in which T cells engineered with an HLA-A*0201 restricted, affinity-enhanced TCR recognizing NY-ESO-1 / LAGE-1 peptides (NY-ESOc259-T), were infused in the setting of profound lymphodepletion that accompanies high-dose chemotherapy given with ASCT. HLA-A*0201 MM patients eligible for ASCT, with antigen positive tumor were enrolled. NY-ESOc259-T was manufactured in a 10 day process using anti-CD3/CD28 microbeads and lentiviral vector, and was administered two days following ASCT. IMWG criteria were used to assess response at day 100 with the addition of a near complete response category (nCR) due to the common occurrence of oligoclonal banding observed following rapid post-ASCT immune reconstitution. Blood and marrow samples were taken at multiple timepoints for serum cytokine analysis, NY-ESOc259-T persistence and trafficking, multiparameter flow analysis to examine the phenotype and function of NY-ESOc259-T, and tumor biomarker analysis. 25 of 29 enrolled patients were infused. A mean of 2.8 × 109 engineered cells were administered (range 8.3 × 108-4.2 × 109), and the average transduction efficiency was 33% (range 30%-45%). Patients tended to have advanced disease (64% chromosomal abnormalities, and 24% prior ASCT). At 3 months, 67% (16/24) and 58% (14/24) of patients were in VGPR and nCR or better, respectively. Infusions were well-tolerated and no cytokine release syndrome was reported. NY-ESOc259-T persisted at 6 months in all but one patient, and in a subset of patients at 2 years; marrow infiltration was consistently observed from day 7 through day 180. NY-ESOc259-T initially displayed a dominant activated effector phenotype which converted towards a dominant effector memory phenotype by 1 year post infusion, in a pattern that mirrored clinical responses. Persisting cells demonstrated a polyfunctional response (IFN-γ and TNF-α) with a cytotoxic (CD107a and granzyme B) signature without overexpression of exhaustion markers (PD-1, LAG-3, and TIM-3). Tumor biomarker analysis is ongoing. MM relapse occurred in 13/25 patients. This data show that NY-ESOc259-T cells exhibit robust trafficking and expansion, durable persistence without exhaustion, and follow a natural immune expansion and contraction pattern consistent with an antigen-driven mechanism of action. Relapse correlated with a loss of persistence or tumor antigen escape, suggesting that targeting multiple antigens and maintenance infusions may increase durable remissions. Citation Format: Aaron Rapoport, Edward Stadtmauer, Luca Melchiori, Ryan Wong, Eduardo Davila, Gwendolyn Binder-Scholl, Tom Holdich, Dan Vogl, Brendan Weiss, Jeffrey Finkelstein, Simon Lacey, Sarah Bond, Marylene Fortin, Yoav Peretz, Joanna Brewer, Alan Bennett, Andrew Gerry, Nick Pumphrey, Helen Tayton-Martin, Lilliam Ribeiro, Ashraf Badros, Saul Yanovich, Nancy Hardy, Jean Yared, Naseem Kerr, Sunita Philip, Sandra Wesphal, Bruce L. Levine, Carl June, Michael Kalos, Bent Jakobsen. NY-ESO T cells administered post ASCT for MM exhibit extended functionality without exhaustion in a natural pattern of effector and memory programming. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4701. doi:10.1158/1538-7445.AM2015-4701 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01352286&atom=%2Fcanres%2F75%2F15_Supplement%2F4701.atom

TPS3102 Background: NY-ESO-1 (CTAG-1B) is a cancer testis antigen associated with spontaneous and vaccine-induced immunity that can lead to improved clinical outcomes. NY-ESO-1 is not expressed in vital tissues, and is expressed in approximately 40% of ovarian, 60% of advanced myeloma, and 70% of synovial sarcoma tumors. Expression is correlated with tumor proliferation and high risk features. A human-derived affinity-optimized TCR that recognizes the NY-ESO-1 derived SLLMWITQC peptide in complex with HLA‐A*0201 (NY-ESOc259) has been generated, and clinically tested as previously described using adoptive T cell transfer with supportive IL-21 Methods: Multiple clinical studies were initiated in HLA-A201+ patients with NY-ESO-1 expressing tumors. NY-ESO-1c259-engineered autologous T-cells are manufactured centrally, using a 12 day commercial-grade closed system, and are administered without supportive IL-2. 40 patients have been infused: 25/26 on a phase I/II study in adults with systemic or multifocal myel...

Background: Apricitabine is a novel deoxycytidine analogue reverse transcriptase inhibitor that is undergoing clinical development for the treatment of HIV-1 infection. This study was performed to investigate the pharmacokinetics of single oral doses of apricitabine in healthy volunteers. Methods: A total of 26 healthy volunteers (14 males, 12 females) took part in this study. Participants received single oral doses of apricitabine 400mg, 800mg and 1600mg in ascending order at intervals of at least 1 week. Concentrations of apricitabine in plasma and urine were monitored over 24 hours after dosing. Results: Apricitabine was rapidly absorbed after oral administration, with peak plasma concentrations (Cmax) being attained approximately 1.5–2 hours after dosing. Plasma concentrations declined in a log-linear manner over at least 12 hours, with an elimination half-life of approximately 3 hours. The majority of the dose (65–80%) was excreted in the urine as unchanged drug within 24 hours. The pharmacokinetics of apricitabine were largely linear with respect to dose. In the overall study population, the area under the concentration-time curve (AUC) decreased by 4% with a dose of 800mg and by 14% with the 1600mg dose compared with the value predicted from the 400mg dose. In females, however, there was a slightly greater departure from linearity: AUC decreased by 8% with a dose of 800mg, and by 21% with a dose of 1600mg. When pharmacokinetic parameters were normalised for bodyweight, there were no significant differences between values in males and females. There was no evidence of enantiomeric interconversion of apricitabine. All doses of apricitabine were well tolerated. Conclusion:Apricitabine is rapidly absorbed and shows predictable pharmacokinetics after oral administration. Clearance is predominantly by renal excretion of the unchanged drug, which suggests a low potential for interactions with drugs that are subject to hepatic metabolism.

Specific immunotherapy acts to modify the underlying cause of allergic rhinoconjunctivitis. Addition of adjuvants, such as monophosphoryl lipid A (MPL), might allow for efficacious and safe treatment with only 4 injections administered preseasonally, which is in contrast to most available schedules requiring long injection courses.The primary objective was to assess the clinical efficacy of Ragweed MATA MPL (short ragweed pollen allergoid adsorbed to L-Tyrosine + MPL) versus placebo in reducing allergic rhinoconjunctivitis symptoms caused by ragweed pollen in an environmental exposure chamber (EEC) 3 weeks after treatment.This was a randomized, double-blind, placebo-controlled phase IIb study to evaluate the clinical efficacy and safety of Ragweed MATA MPL compared with placebo by using controlled ragweed pollen exposure in an EEC. Two hundred twenty-eight patients with a history of ragweed allergy and positive skin prick test responses to ragweed were randomized and received 4 weekly injections of active treatment or placebo. Total nasal and nonnasal symptom scores were obtained in the EEC before and after treatment.Mean improvement in total symptom scores in the Ragweed MATA MPL group was statistically significantly greater than in the placebo group (relative mean improvement of active vs placebo, 48%; P.05; median improvement, 82%). The majority of adverse events (AEs) experienced by subjects were mild injection-site reactions. No severe systemic AEs or serious AEs occurred during the study.This study demonstrated that an ultrashort course of Ragweed MATA MPL is efficacious in reducing allergy symptoms in patients with seasonal allergic rhinitis and that it is well tolerated.

Meeting abstracts Relapsed or metastatic synovial sarcoma remains a significant unmet medical need. NY-ESO-1 is an attractive target for sarcoma, since it is expressed in approximately 70% of synovial sarcomas but not on vital tissues. We generated NY-ESOc259, a human-derived affinity-enhanced T