bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biomarkers and associations with the clinical activity of PD-L1 blockade in a MPDL3280A study.
Authors: Powderly John D. , Koeppen Hartmut , Hodi F. Stephen , Sosman Jeffrey Alan , Gettinger Scott N. , Desai Rupal , Tabernero Josep , Soria Jean-Charles , Hamid Omid , Fine Gregg Daniel , Xiao Yuanyuan , Mokatrin Ahmad , Wu Jenny , Anderson Maria , Irving Bryan A. , Chen Daniel S. , Kowanetz Marcin 
Published: March 2020

3001 Background: PD-L1, which is highly expressed on tumors, is a ligand of PD-1, an inhibitory receptor present on activated T cells. PD-L1 expression is regulated by intrinsic (mutations) and adaptive (tumor infiltrating T cells) mechanisms. 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. Methods: A Ph I study was conducted with MPDL3280A administered IV q3w in pts with locally advanced or metastatic solid tumors. The expansion cohort required available tumor tissue. In addition, the study included a serial biopsy cohort with tumor sampling prior to and during treatment. Tumor samples were analyzed by IHC and a Genentech immunochip measuring ≈90 immune-related genes to characterize the tumor immune microenvironment at baseline (BL) and/or during MPDL3280A treatment. Further, blood-based biomarkers and circulating immune cell subsets were serially measured. Results: Pretreatment tumor samples were available for IHC from 112 pts and for immunochip from 96 pts.In addition, 23 pts had paired BL and on-treatment samples. Blood-based biomarkers were evaluated in 76 pts. Elevated BL PD-L1 expression by IHC was associated with response to MPDL3280A, and coordinated expression of PD-L1 and CD8+ T-cells was observed. Furthermore, a T-cell gene signature (including CD8, IFNg and Granzyme-A) was associated with treatment response. On treatment, responding tumors showed increasing PD-L1 expression and a Th1-dominant immune infiltrate, providing evidence for adaptive PD-L1 upregulation. Nonresponders showed minimal tumor CD8+ T-cell infiltration and an absence of T-cell activation (measured by Granzyme-A and Perforin expression). Additionally, a subpopulation of pts exhibited changes in circulating cytokines (IFNg) and activated T-cell subsets (HLADR+Ki67+). Conclusions: PD-L1 tumor expression and T-cell gene signature correlate with response to MPDL3280A. MPDL3280A therapy led to T-cell reactivation and restored antitumor immunity. These data provide mechanistic insights into immunotherapy and support pt selection for treatment with MPDL3280A monotherapy. Clinical trial information: NCT01375842.
Randomized phase II clinical trial of the anti-HER2 (GP2) vaccine to prevent recurrence in high-risk breast cancer patients: A planned interim analysis.
Authors: Trappey Francois , Berry John S. , Vreeland Timothy J , Hale Diane F. , Sears Alan K. , Ponniah Sathibalan , Perez Sonia A. , Clifton Guy T. , Papamichail Michael , Peoples George Earl , Mittendorf Elizabeth Ann 
Published: March 2020

3005 Background: A prospective, randomized, multi-center, placebo-controlled, single-blinded, phase II trial was designed to evaluate the safety and clinical efficacy of GP2, a HER2-derived peptide vaccine, in breast cancer patients. Methods: Clinically disease-free, node-positive or high-risk node-negative patients (pts) with any level of HER2 expression were enrolled after standard of care therapy. HLA-A2+ pts were randomized to receive GP2 + GM-CSF (VG) or GM-CSF alone (CG). HLA A2- controls from a parallel arm of the study were also eligible for evaluation, the extended CG (ECG). Pts receive 6 monthly intradermal inoculations (R0-R6) during the primary vaccine series followed by four boosters every 6 mos. Immune responses (IR) were measured by delayed type hypersensitivity (DTH) at R0 and R6. This planned interim analysis was performed at 24 months median follow-up. Results: We have currently enrolled 172 pts (46, VG; 43, CG; 83 extended CG). There are no differences between groups with respect to age, rate of node positivity, tumor grade, tumor size, ER/PR status, and HER2 over-expression (all p > 0.05). Maximum local toxicity (tox) was similar between the two groups (grade (Gr) 1 and 2: VG 93%, CG 98%; Gr 3: VG 2%, CG 1%). Maximum systemic tox was also similar between the groups (Gr 1 and 2: VG 91%, CG 85%). No Gr 3 systemic tox has been reported. The most frequent systemic reactions are fatigue, headache, and myalgias. IR to GP2 has been robust. DTH is increased from R0 to R6 in the VG (3.0±0.98 to 21.5±4.04 mm, p < 0.01) vs. the smaller increase in CG (2.6±0.89 to 6.0±1.6 mm, p = 0.01). VG DTH at R6 is significantly higher than the CG (21.5 vs 6.0 mm, p < 0.01). The recurrence rate (RR) is decreased in the VG vs CG (4.3% vs. 11.6%, p = 0.41) and VG vs ECG (4.3% vs 9.5%, p = 0.41). In pts with HER2-overexpressing (IHC3+ or FISH+) tumors, the RR is decreased in the VG (0% vs 5% CG, p = 0.28). For TNBC (HER2 low, ER/PR-) pts, the RR is reduced in the VG vs ECG (0% vs 10.6%, p = 0.251). Conclusions: The GP2 vaccine is safe and the minimal toxicity is comparable between the VG and CG, suggesting that it is due to GM-CSF. Robust in vivo immune response has correlated with a >50% reduction in breast cancer recurrences in the VG. Clinical trial information: NCT00524277.
Nonclinical evaluation of the combination of mouse IL-21 and anti- mouse CTLA-4 or PD-1 blocking antibodies in mouse tumor models.
Authors: Jure-Kunkel Maria , Selby Mark , Lewis Katherine , Masters Gregg , Valle Jose , Grosso Joseph , Dito Gennaro , Curtis Wendy , Garcia Richard , Holdren Matthew , Korman Alan J. , Dillon Stacey 
Published: March 2020

3019 Background: Interleukin 21 (IL-21), a γc chain family cytokine, is produced primarily by CD4+ T cells and has many effects on immune cells, including enhancing CD8+ T cell and NK cell proliferation and cytotoxicity. Recombinant IL-21 (rIL-21) therapy resulted in objective responses in ~20% of melanoma and renal cell carcinoma patients. In mouse models, monoclonal antibody (mAb) blockade of CTLA-4 prolongs antigen-specific T cell responses, while blockade of programmed death 1 (PD-1) reverses tumor induced T cell suppression. Ipilimumab, a CTLA-4 blocking mAb, significantly improved overall survival in patients with metastatic melanoma in 2 phase III trials, and in phase I studies a PD-1 blocking mAb (nivolumab) has antitumor activity in various cancers. Side effect profiles for each mAb have been related to their mechanism and are generally manageable. It was hypothesized that combination of IL-21 plus CTLA-4 or PD-1 blockade may enhance antitumor responses, potentially leading to improved clinical activity. Methods: Preclinical studies were conducted to test the antitumor activity of mouse IL-21 (mIL-21) in combination with an anti-mouse PD-1 (mPD-1) mAb (4H2-IgG1) or with an anti-mCTLA-4 blocking mAb (9D9-IgG2b) in syngeneic mouse tumor models, including MC38, CT-26, EMT-6, and B16F10. mIL-21 was tested at doses ranging from 50-200 μg/dose, administered up to 3d/wk. mCTLA-4 mAb or mPD-1 mAb were administered 3-4x total at 200-300 μg/dose. Results: Combination treatments produced enhanced antitumor activity vs. monotherapy. In the MC38 model, mIL-21 treatment led to 30% median tumor growth inhibition (TGI) by d29, while mPD-1 mAb produced 60% median TGI and 1/10 tumor-free mice. Combination of both agents led to synergistic antitumor activity, with complete regressions (CR) in 7/10 mice and 99.9% median TGI (p=0.046). CTLA-4 mAb + mIL-21 also produced synergistic activity in the MC38 model. By d21, mIL-21 monotherapy induced 34% TGI while CTLA-4 mAb resulted in 28% TGI, with no CR in either group. Combination resulted in 6/8 mice with CR and 86% TGI (p<0.05). Conclusions: These results support the use of rIL-21+nivolumab and rIL-21+ipilimumab in recently initiated clinical trials.
Anti-CD20-interferon-alpha fusion protein has superior in vivo activity against human B-cell lymphomas compared to rituximab and enhanced complement-dependent cytotoxicity in vitro.
Authors: Yamada Reiko E , Steward Kristopher K , Ngarmchamnanrith Gataree , Trinh Ryan K , Khare Sanjay , Sachdev Raj , Grewal Iqbal S , Morrison Sherie L , Timmerman John 
Published: March 2020

3024 Background: We previously reported an anti-CD20-interferon (IFN)-alpha fusion protein able to induce apoptosis and promote in vivo eradication of a human CD20-expressing mouse B cell lymphoma (Xuan et al, Blood 2010). We now report the activity of a recombinant anti-CD20-human IFNα fusion protein against human non-Hodgkin B cell lymphomas (NHL). Methods: Anti-CD20-hIFNα was evaluated against a panel of human Burkitt, diffuse large B cell (DLBCL), and mantle cell lymphoma cell lines. Proliferation was measured by [3H]-thymidine, complement-dependent cytotoxicity (CDC) by PI flow cytometry, and antibody-dependent cellular cytotoxicity (ADCC) by LDH release using PBMC effectors. NHL xenografts were grown in SCID mice. Results: Anti-CD20-hIFNα induced stronger growth inhibition than rituximab, particularly against Burkitt and germinal center-type DLBCL NHLs. Tumor growth inhibition by anti-CD20-hIFNα was associated with substantial apoptosis in some cell lines. Anti-CD20-hIFNα exhibited potent ADCC activity against Daudi, Ramos, and Raji cells, identical to rituximab. Surprisingly, anti-CD20-hIFNα exhibited superior CDC compared to rituximab against Daudi, Ramos, and Raji cells, that was dependent upon linkage of IFNα to the anti-CD20 antibody, and correlated with improved complement fixation. Importantly, anti-CD20-hIFNα achieved superior efficacy compared to rituximab and control fusion protein against multiple NHL xenografts in SCID mice (Raji: p=0.002 and OCI-Ly19: p<0.0001). At antibody doses at which Raji xenografts progressed through rituximab, anti-CD20-hIFNα eradicated 50-88% of established tumors. Non-targeted control fusion protein had only minor effects on tumor growth. Conclusions: Anti-CD20-hIFNα has stronger direct anti-proliferative and CDC activities than rituximab against human NHL while retaining potent ADCC activity, and also has the ability to eradicate established NHL xenografts in vivo. These results support the further development of anti-CD20-hIFNα for the treatment of B cell NHL, and a phase I first-in-human clinical trial is currently being planned.
A phase I study of indoximod in combination with docetaxel in metastatic solid tumors.
Authors: Jackson Erica , Dees Elizabeth Claire , Kauh John S. , Harvey R Donald , Neuger Anthony , Lush Richard , Antonia Scott J. , Minton Susan E. , Ismail-Khan Roohi , Han Hyo S. , Vahanian Nicholas N. , Ramsey William Jay , Link Charles J. , Streicher Howard , Sullivan Daniel , Soliman Hatem Hussein 
Published: March 2020

3026 Background: The indoleamine-2, 3-dioxygenase (IDO) pathway catabolizes tryptophan to create a state of immunosuppression. Indoximod (1-methyl-(D)-tryptophan, D-1MT) is an IDO pathway modulator. Preclinical studies in MMTV-neu mouse models have shown indoximod combined with chemotherapy was more effective in causing tumor regression than either agent alone. Based on this data, a phase IB trial was designed to study the safety of the combination of docetaxel (Doc) and indoximod. The primary goal of this trial was to determine the MTD for the combination of Doc and oral indoximod. Secondary endpoints were PK data and efficacy for indoximod/Doc. Methods: This phase IB study consisted of 5 dose levels (DL). Doc was dosed IV q 3 wks at 60 mg/m2 in DL 1-4 and 75 mg/m2 at DL 5. Indoximod was dosed at 300, 600, 1,000, 2,000, and 1,200 mg PO BID continuously in DL 1-5 respectively. MTD was determined using a 3+3 design. The DLT rule was 1st cycle ≥G3 non-heme AEs or ≥G4 heme AEs despite supportive care or that delay therapy >14d. The PK of indoximod and Doc was analyzed using a HPLC assay. PK was measured on C1D1 and 8. Standard eligibility/exclusion criteria applied along with exclusion of patients previously treated with ipilumimab. Treatment was continued until disease progression, intolerance, or unacceptable side effects. Results: Total # of patients treated at DL1-5 were 7, 6, 6, 2, and 6 respectively, with 22 total patients evaluable for response. DLTs included: G3 dehydration (at 300 mg), G5 neutropenic colitis (at 600 mg), G3 hypotension (at 2,000 mg) and G3 mucositis (at 2,000 mg). DL 5 was well tolerated and is the recommended phase II dose. The most frequent adverse events were fatigue (58.6%), anemia (51.7%), hyperglycemia (48.3%), infection (44.8%), and nausea (41.4%). There were 4 PRs (2 breast, 1 NSCLC, 1 thymic), 9 SD, and 9 PD. There were no drug-drug interactions, and PK was similar to Doc and indoximod single-agent studies. Conclusions: The Doc+ indoximod combination was well tolerated with no increase in expected toxicities or unexpected PK interactions. It was active in a pretreated population of patients with metastatic solid tumors. The RP2D is 75 mg/m2 of Doc with 1,200 mg of indoximod BID for the current phase II metastatic breast cancer trial. NCT01191216 Clinical trial information: NCT01191216.
A novel method to identify and monitor endogenous tumor-reactive T cells by high expression of CD11a (LFA-1) and PD-1 (CD279) as immunologic readout for evaluating the efficacy of PD-1 blockade.
Authors: Dong Haidong , Markovic Svetomir , Krco Christopher J , Kwon Eugene D. 
Published: March 2020

3037 Background: Tumor immunotherapies directed towards enhancing natural or endogenous anti-tumor T-cell immunity in patients with advanced malignancies are currently being implemented in clinic with promising results. In order to optimize therapeutic protocols and monitor the effectiveness of such therapies, a reliable T-cell marker is needed. Methods: We utilized CD11a (LFA-1, lymphocyte functional-associated antigen 1), an integrin up-regulated on effector and memory CD8 T-cells, and PD-1 (programmed death-1), an immunoregulatory receptor expressed by activated T cells, as biomarkers to identify, quantitate and monitor endogenous tumor-reactive cytotoxic lymphocytes (CTLs) in two mouse tumor models and the peripheral blood (PB) of 12 patients with stage IV melanoma. Results: High expression of CD11a and PD-1 was identified among CD8 T-cells residing within primary and metastatic murine tumor sites, as well as in spontaneous murine breast cancer tissues. In the PB of melanoma patients, tumor antigen-specific CD8 T cells were associated with a population of CD11a high CD8 T-cells which co-expressed high levels of PD-1, as opposed to eleven healthy donors who had a much lower frequency of PD-1+ CD11a high CD8 T-cells (p <0.0001). Phenotypic analysis showed that CD11a high CD8 T-cells are proliferating (Ki67 positive) activated (CD62L low, CD69 high) T-cells. Increased CD11a high CD8 T-cells and delayed tumor growth were observed in PD-1 deficient mice, suggesting that the antitumor effector function of CD8 T cells is compromised by co-expression of elevated levels of PD-1. Conclusions: CD11a high CD8 T-cell population expresses high levels of PD-1 and is likely the cellular target of PD-1 blockade therapy. High expression of CD11a (LFA-1) and PD-1 (CD279) by CD8 T-cells may represent a novel biomarker to identify and monitor endogenous tumor-reactive CTLs. This may not only provide an immunological readout for evaluating the efficacy of therapy, but also contribute to the selection of patients with solid malignancies likely to benefit from anti-PD-1 therapy.
Phase I study of weekly treatment with paclitaxel injection concentrate for nanodispersion (PICN), a novel solvent and protein-free formulation of paclitaxel.
Authors: Jain Minish Mahendra , Deshmukh Chetan Dilip , Bondarde Shailesh Arjun , Bhatt Niraj , Shinde Vijay , Bhowmik Shravanti , Divekar Ganesh 
Published: March 2020

3039 Background: PICN is a novel solvent and protein-free 100-110 nm particle formulation of paclitaxel stabilized with polymer and lipid using Nanotecton Technology. Paclitaxel has shown superior safety and efficacy profile when administered on a weekly schedule. We studied safety, tolerability, and pharmacokinetics (PK) of PICN using a weekly schedule in patients with advanced solid malignancies. Methods: Patients aged18-65 years with advanced solid malignancies, ECOG performance status ≤ 2, estimated survival ≥ 12 weeks, and adequate organ function were enrolled. A standard phase I, 3+3 dose escalation design to determine the maximum tolerated dose (MTD) of PICN administered on a weekly schedule (three consecutive weeks, one week recovery) was employed. PICN dose was escalated at pre-determined fixed dose levels of 80, 100, 125, 150, 175, and 200 mg/m2. PICN was administered as a 30 min infusion without any premedication for hypersensitivity. Results: Twenty-one patients treated with PICN had a mean age of 52.1 yrs (range 35-67); 20 were female and entered with metastatic breast cancer (MBC; n=15), cervical cancer (n=3), skin cancer (n=2). One male had oral cancer. Doses studied were 80 (n=3), 100 (n=3), 125 (n=3), 150 (n=3), 175 (n=6), and 200 (n=3) mg/m2. Despite the lack of dexamethasone premedication, no patient receiving PICN reported hypersensitivity reaction. Two DLTs (neutropenia and febrile neutropenia; both grade 3) were reported at PICN 200 mg/m2. PICN PK (AUC0-24, AUC0-∞, and Cmax) increased in a dose proportionate manner from 80 to 200 mg/m2. Grade 3 or worse related AEs were: neutropenia, leucopenia, peripheral neuropathy, febrile neutropenia, anemia, thrombocytopenia, fatigue, syncope, hypotension and maculopapular rash. Partial responses were observed in MBC (100, 125, 150, 175, and 200 mg/m2) and cervical cancer (80 mg/m2). Conclusions: PICN on thrice monthly schedule was tolerable in the dose range evaluated. Two DTLs were reported: neutropenia and febrile neutropenia (both grade 3). Anti-tumor activity was observed in MBC and cervical cancer. Final trial data for PICN PK, safety, and efficacy will be presented at the conference. Clinical trial information: CTRI/2011/11/002124.
Circulating endothelial microparticles (EMP) modifications as predictive biomarkers of resistance to chemotherapy for breast cancer (BC).
Authors: Garcia-Garre Elisa , Luengo-Gil Gines , Montoro-Garcia Silvia , Zafra Marta , Gonzalez-Billalabeitia Enrique , de la Morena Pilar , Garcia-Martinez Elena , Lip Gregory Y , Vicente Vicente , Ayala Francisco 
Published: March 2020

3042 Background: Growing evidence indicates that EMP may both modulate angiogenesis and endothelial injury in cancer and cardiovascular disease. However, it has not been shown whether in vivo release of EMP might reflect the tumor response or the antiangiogenic effects of chemotherapy (CT). The aim of this work was to evaluate the relationship between the levels of small-size EMP (sEMP) and resistance to CT in locally advanced and metastatic BC. Methods: Citrated platelet-free plasma was obtained from BC patients before and after 3-4 cycles of chemotherapy. Small-size CD144+ sEMP (0.1-0.5 μm diameter) were prospectively quantified using a high resolution Apogee A50 flow cytometer. Association of EMP with clinical variables, response to CT and survival was analyzed. Response (partial or complete) was defined by RECIST criteria. Results: 45 BC patients were included (20, metastatic; 25, locally advanced). Treatment included anthracyclines in 66.7% of patients and taxanes in 15.5%. Small-size EMP baseline counts were higher in premenopausal women (p=0.008), but no association with other clinical or pathological characteristic was found. A significant decrease of circulating sEMP was observed after treatment with CT in the whole group of patients with paired samples available (n=33): pre-CT: 416.2 ± 365 vs. post-CT: 340.7 ± 458 (p=0.005). Lower chemotherapy-induced sEMP decrease was associated to treatment resistance: ROC analysis demonstrated a 66.7% sensitivity and 72.2% specificity of lower sEMP decrease for lack of response to CT using a decline cut-point of -40 sEMP (close to median decrease: -47). With the same cut-point of low sEMP decrease, odds ratio for treatment resistance was 5.2 (95% confidence interval, 1.17-23.04; p=0.03). No clear association of the degree of sEMP decrease was found for disease or progression free survival in the neoadjuvant or in the metastatic setting. Conclusions: This study suggests that circulating sEMP decrease after CT and are tightly associated with treatment resistance in BC patients. These findings indicate pathophysiological roles for sEMP in BC and support their potential role as treatment resistance biomarkers.
Clinical and pharmacodynamic (PD) results of a phase I trial with AMP-224 (B7-DC Fc) that binds to the PD-1 receptor.
Authors: Infante Jeffrey R. , Powderly John D. , Burris Howard A. , Kittaneh Muaiad , Grice Jessica Houston , Smothers James F , Brett Sara , Fleming Margaret E. , May Rena , Marshall Shannon , Devenport Martin , Pillemer Stanley , Pardoll Drew M. , Chen Lieping , Langermann Solomon , LoRusso Patricia 
Published: March 2020

3044 Background: PD-1/B7-H1 (PD-L1) axis blockade can reinvigorate T cells, and overcome tumor immune evasion of multiple tumor types. AMP-224 is the first recombinant B7-DC-Fc fusion protein tested in patients that binds to and modulates the PD-1 axis through a unique MOA. The MoA hypothesis for AMP-224 is depletion of PD-1high expressing T-cells representing exhausted effector cells. Subsequent replenishment of the T-cell pool with functional T-cells may restore immune function. Methods: Patients with advanced solid tumors received low dose CTX on Day 0, followed by AMP-224 (IV infusion) on Days 1 and 15 of each 28-day cycle in doses ranging from 0.3 to 30 mg/kg. Blood samples were assessed serially for changes in lymphocyte subsets, PD-1HIT cells and T cell effector function. IHC staining of paired biopsies for B7-H1, CD8, PD-1, CD4 and FoxP3 was performed to assess immunological status of the tumor at baseline and following treatment and then relative to peripheral readouts. Results: 42 patients (83% melanoma) were treated with varying doses of AMP-224 [0.3 mg/kg (n = 6); 1 mg/kg (n=4); 3 mg/kg (n = 4); 10 mg/kg (n = 22); 30 mg/kg (n = 6)]. Infusion reactions were common (69% across dose cohorts) and occurred mostly at higher doses (86% at the 10 mg/kg dose). No drug-related inflammatory adverse events were identified contrary to PD-1 blocking antibodies. Fresh pre-treatment biopsies were collected from 33/42 (78.5%) patients and paired biopsies have been collected thus far from 19/36 (52.7%) patients on study. 31% of baseline tumors were B7-H1+. Several PD readouts in the periphery showed reductions in PD-1HIcells and emergence of a functional T cell response (increases in IFNg+, TNFa+, IL-2+ CD4 and CD8 T cells) in individual patients where partial response, stable disease, and mixed responses were seen. Conclusions: Data from peripheral readouts is consistent with hypothesized AMP-224 MoA. B7-H1+ was not always predictive of functional response to AMP-224 immunotherapy. Comprehensive PD readouts and evaluation of PK/PD relationships will be presented and may ultimately predict restoration of immune competence even in the presence of initial disease progression. Clinical trial information: NCT01352884.