bluuebunny/crossref_metadata_2025 huggingface dataset:
Results from phase Ib studies of PX-12, a thioredoxin inhibitor in patients with advanced solid malignancies
Authors: Ramanathan R. K. , Dragovich T. , Richards D. , Stephenson J. , Pestano L. , Hiscox A. , Leos R. , Chow S. , Millard J. , Kirkpatrick L.
Published: August 2020

2571

Background: PX-12, a small-molecule inhibitor of Thioredoxin-1 (Trx-1) stimulates apoptosis, down-regulates HIF- 1α, VEGF in animal models. High levels of Trx-1 have been linked to chemoresistance in lung cancers. The phase 2 dose of PX-12 was 226 mg/m2 given by 3-h infusion IV x 5 days, q 21d (Ramanathan RK et al. CCR 13; 2109; 2007). Two Phase 1b trials of PX-12 in patients with advanced solid tumors have been completed to determine the safety, tolerability and optimal biologic dose when delivered by prolonged infusion. Methods: PX-12 was administered as a 24-h infusion every q7- 14d starting at 150 mg/m2/day (n=18); or a 72-h infusion q 21d, starting at 300 mg/m2/day (n=14) using a portable delivery pump. Results: Both the 24- or 72-h infusion of PX-12 were well tolerated in patients at doses up to 400 mg/m2/day. Common grade 1/2 AE's included fatigue, taste alteration, and odor caused by expired drug metabolite. In the 24 h study the maximal dose evaluated was 450 mg/m2. No DLTs were observed in this study. Since no MTD was reached on 24-h infusion up to 450 mg/m2 dose level, additional higher doses were explored utilizing 72-h infusion. DLT in the 72-h study at the highest dose administered (500 mg/m2/day) included reversible hypoxia with or without pneumonitis. Best response was stable disease in 3 pts (SD): liver cancer and colon cancer (24-h infusion) and rectal cancer (72-h infusion). Pharmacodynamics (PD): PX- 12 lowered circulating Trx-1 levels in patients who had starting Trx-1 levels 3-fold greater than that of the normal population (5.4 ng/mL) including all three SD. Circulating VEGF and FGF-2 levels were also lowered over multiple courses of treatment in these patients. The pharmacokinetics of PX-12 showed a dose dependent increase of Cmax and no accumulation over multiple cycles following a 24 h infusion. Conclusions: Dosing at 400 mg/m2/day appears safe and tolerable as a 24–72-h infusion. Extending the infusion time to 72h appears to decrease the intensity of cough and odor compared to bolus 1–3 h infusion. The PD effect produced by PX-12 was apparent only in those patients with elevated plasma Trx-1 levels. Patients with elevated TRX-1 levels appear to have the best probability of having SD. Supported by ProlX Pharmaceuticals/Oncothyreon through an award from the NCI.

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A phase I study of the safety and pharmacokinetics (PK) of XMT-1001 given as an intravenous (IV) infusion once every three weeks to patients with advanced solid tumors
Authors: Sausville E. , Garbo L. , Weiss G. J. , Anthony S. , Shkolny D. , Yurkovetskiy A. V. , Bethune C. , Fram R. J.
Published: August 2020

2574

Background: XMT-1001 is a water soluble macromolecular conjugate of camptothecin (CPT). In this novel CPT pro- drug, CPT is conjugated with a 70 kDa biodegradable hydrophilic polyacetal, poly (1-hydroxymethylethylene hydroxymethylformal). XMT-1001 demonstrated an improved therapeutic window as compared with CPT and irinotecan in human tumor xenograft models, providing a compelling rationale for its clinical development. Methods: This is an open label, dose escalation study of XMT- 1001 administered as an IV infusion once every 3 weeks. The objectives of this phase I study are to determine the maximum tolerated dose and to assess safety and PK of XMT-1001. Initially 3 patients (pts) are entered at each dose level. The cohort is expanded to 6 pts if a patient experiences a dose limiting toxicity. Analyses of plasma and urine were performed for XMT-1001 (conjugated CPT), 2 major drug release products, and for unconjugated (free) CPT. Results: Thirty two pts with refractory solid tumors have received 82 cycles of XMT-1001 at 8 dose levels ranging from 1.0 to 20.5 mg CPT equivalents/m2. Two pts had Gr 3 infusion reactions consistent with hypersensitivity to study drug. Symptoms reversed upon discontinuation of study drug. After the introduction of new clinical trial material with an improved formulation, to date, no infusion reactions suggestive of hypersensitivity have occurred (11 patients, 22 cycles). No hemorrhagic cystitis or ≥ Gr 3 diarrhea was noted. Myelosuppression was observed in 3 pts treated at 15.4 mg CPT equiv/m2 dose level. Stable disease was observed in 7 pts with the following tumor types and dose levels expressed in mg CPT equivalents/m2: NSCLC (1.0 mg/m2, 6 wks), ovarian (4.9 mg/m2, 12 wks), pancreas (4.9 mg/m2, 36 wks), appendiceal (7.3 mg/m2, 12 wks), bile duct (9.1 mg/m2, 18 wks), basal cell (11.6 mg/m2, 6 wks), and colon (15.4 mg/m2, 6 wks). PK demonstrates dose proportional increases in plasma levels of XMT-1001 (conjugated CPT) and confirms the formation of its expected release products. To date, levels of free CPT in urine are low. Conclusions: 1. XMT-1001 can be given safely to patients; 2. XMT-1001 has a favorable PK profile; 3. Prolonged stable disease was observed in patients with refractory tumors.

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Phase I study of combination treatment with PTK 787/ZK 222584 (PTK/ZK) and cetuximab for patients with advanced solid tumors: Safety, pharmacokinetics, pharmacodynamics, and toxicity analysis
Authors: Langenberg M. H. , Witteveen P. O. , Lankheet N. , Roodhart J. M. , Rosing H. , Beijnen J. H. , Voest E. E.
Published: August 2020

2575

Background: Based on the current knowledge of tumor biology there is a rationale to combine targeted therapies that block different growth factor pathways. Here we combined PTK/ZK, a small molecule inhibitor of all three vascular endothelial growth factor receptors, PDGFR and c-kit, with cetuximab, a monoclonal antibody against the epidermal growth factor receptor. Methods: In this phase I study patients were treated with PTK/ZK daily (cohort 1; 750 mg od, cohort 2; 1250 mg od, cohort 3; 250 mg [morning] and 500 mg [evening], cohort 4; 500 mg [morning] and 750 mg [evening]) combined with cetuximab 250mg/m2 weekly in cycles of 28 days in cohorts of 3 patients. Toxicity was evaluated conform CTCAE classification version 3.0. Pharmacokinetics and circulating endothelial (progenitor) (CE(P)) cell analysis by flow cytometry were performed. Response was assessed using RECIST criteria. Results: Safety and tolerability were evaluated in 16 out of 18 treated patients (median age 61, range 43–78) with advanced tumors of the colon (8), lung (1), chordoma (2), biliary tract (1), cervix (1), ovarian (1), breast (1) and pancreatic cancer (1). The most frequently reported adverse events (all CTCAE grades) were acne (87%), dry skin (81%), fatigue (69%), nausea (63%), ataxia/dizziness (50%), vomiting (50%), headache (38%) and diarrhea (31%). One dose limiting toxicity (DLT) occurred in cohort 3 (grade 3 transaminitis (AST)). The study was terminated after cohort 4 because the predefined maximum doses for vatalanib and cetuximab were attained. Preliminary PK analysis revealed no significant changes in PTK/ZK exposure upon coadministration with cetuximab. Biomarker analysis showed stabilized CE(P)Cs levels during treatment. 7 out of 14 patients evaluable for efficacy analysis (50%) showed SD for at least 2 months and 1 patient (colon cancer) a PR for 11.5 months. Conclusions: This study shows that the combination of PTK/ZK and cetuximab is well tolerated with only slightly overlapping toxicity profiles and has anti tumor activity. No MTD was defined; the recommended phase II dose is the predefined maximum combination dose: weekly cetuximab 250 mg/m2 combined with twice daily PTK/ZK 500/750 mg.

No significant financial relationships to disclose.
Phase I study of infusion of HER2/neu (HER2) specific T cells in patients with advanced-stage HER2 overexpressing cancers who have received a HER2 vaccine
Authors: Disis M. L. , Salazar L. G. , Coveler A. , Waisman J. , Higgins D. , Childs J. , Bates N. , Dang Y.
Published: August 2020

3000

Background: Adoptive T-cell therapy has shown promise in the treatment of advanced-stage melanoma. We have previously reported that expansion of HER2-specific T cells from peripheral blood mononuclear cells (PBMC) can be greatly facilitated by vaccine-priming. In this study, we evaluated the safety and clinical efficacy of infusion of HER2-specific T cells in patients with advanced HER2 overexpressing cancers. Methods: 10 patients with progressive HER2+ metastatic breast and ovarian cancer, not considered curable by conventional therapies, will be enrolled in this study. The patients must have been pre-immunized with a HER2-specific vaccine. Three escalating doses of T cells are given at 10-day intervals. Cyclophosphamide or denileukin diftitox is administrated before the first dose of T cells. Results: To date, 5 of 10 subjects have been enrolled. T cells were expanded with HER2-specific class II restricted peptides. After in vitro expansion cell products were >95% CD3+ with an average of 35% CD4+ and 60% CD8+ T cells. The maximal doses infused were 1x109-41x109 cells (median 10x109). Subjects tolerated the infusions well with the primary toxicity being related to the conditioning agent. Objective tumor regression has been observed in 2 of the 5 treated patients. One other patient has had stable disease after treatment. In patients with tumor regression, the magnitude of HER2-specific T cells in the infused product was 8-fold higher than that in patients without clinical responses. The total number of HER2-specific T cells infused was 43-fold higher in responding patients than in nonresponding patients. Moreover, HER2-specific CD4+ and CD8+ T cells persisted over a year and even augmented in magnitude post-infusion in responding patients. Conclusions: Adoptive transfer of autologous HER2 specific polyclonal T cells generated from PBMC after vaccine-priming is well tolerated and has shown evidence of some clinical efficacy in patients with advanced-stage HER2+ cancers.

No significant financial relationships to disclose.
Persistent immunity and survival after immunization with a HER2/neu (HER2) vaccine
Authors: Salazar L. G. , Goodell V. , O'Meara M. , Knutson K. , Dang Y. , dela Rosa C. , Guthrie K. A. , Disis M. L.
Published: August 2020

3010

Background: Our initial vaccine studies showed that optimally treated breast cancer patients can be immunized against HER2 during active immunization. The majority of patients developed T-cell immunity to HER2 peptides and protein and also epitope spreading (ES). The goal of this study was to determine if patients previously immunized with a HER2 vaccine had persistent immunity years after active immunization and to assess their clinical outcome in terms of overall survival (OS). Methods: Subjects eligible for this IRB-approved long term follow-up (LTFU) study: (1) had HER2+ breast cancer and were immunized between 1996–1999 in a phase I HER2 peptide vaccine trial, (2) were at least 1 year out from their last vaccine, and (3) if donating blood samples could not be receiving chemotherapy. 52 patients (37 stage IV, 15 stage III) were identified and 21/52 patients (12 stage IV, 9 stage III) were determined to be living. All 21 subjects were contacted by letter and sent a LTFU Questionnaire. OS was defined as the time between date of vaccine study entry and death or last follow-up and was estimated using the Kaplan-Meier method. Cox proportional hazards were used to determine associations between OS and known clinical and vaccine-related immunologic factors; analyses included all 52 subjects. Long-term T-cell immunity was evaluated using IFN-γ ELISPOT assay. Results: Median follow-up time for the 21 patients still alive was 112 months (range, 104–126 months). Blood samples were collected in 10/21 subjects and 6/8 (75%) evaluble patients had persistent T-cell immunity to immunizing HER2 peptides; and 7/8 patients (88%) had T-cell immunity specific for HER2 protein and peptides not contained in their immunizing mix (defined as ES). In multivariate analysis, number of chemotherapy regimens prior to vaccination (HR=5.7 (CI 95%, 1.5–23; p=<0.001)), and development of ES after HER2 vaccination (HR=0.34 (CI 95%, 0.12–1.0; p=0.05)) were independent predictors of OS. Median OS for 33 subjects who developed ES was 84 months vs 25 months for 16 subjects who did not develop ES. Conclusions: HER2-specific T-cell immunity elicited with active immunization is durable years after vaccination has ended and the generation of ES is an independent predictor of OS.

No significant financial relationships to disclose.
Immunologic impact of anti-CTLA-4 therapy
Authors: Sharma P. , Tsavachidou D. , Kamat A. , Ng Tang D. , Chen H. , Fu T. , Troncoso P. , Wolchok J. , Logothetis C. J. , Allison J. P.
Published: August 2020

3019

Background: Blockade of the T-cell inhibitory molecule known as cytotoxic T lymphocyte antigen-4 (CTLA-4) results in antitumor responses. To date, trials have been conducted with over 4,000 patients with various malignancies in the metastatic disease setting, which allow for correlation of therapy with clinical outcome but do not provide analyses of relevant biomarkers in the systemic circulation that reflect changes within the tumor microenvironment. Approximately 10% of treated patients respond to therapy. Why some patients respond while others do not remains unknown. The identification of intermediate biomarkers are essential for us to understand whether anti-CTLA-4 antibody has “hit its target” to affect human immune responses and whether these identified immune responses can serve as predictive markers of clinical outcomes. Methods: We conducted a presurgical clinical trial with anti-CTLA-4 antibody. Patients with localized bladder cancer (N=10) were given two doses of antibody prior to undergoing surgery. Immunological analyses were conducted on patients’ tissues and blood samples. Results: Expression of the inducible costimulator (ICOS) molecule was increased on CD4 T cells within tumor tissues and systemic circulation. ICOS-expressing T-cells have not previously been reported to have a role in anti-tumor responses. We showed that CD4+ICOShi T cells produced IFNγ and could recognize the NY-ESO-1 tumor antigen. Pre- and post-therapy CD4 T cells were analyzed by reverse-phase protein array and microRNA array, which led to the identification of signaling pathways and regulatory mechanisms that play a role in enhanced T-cell function. Furthermore, murine models confirmed our initial findings and implied a role for ICOS-expressing T-cells in antitumor responses. Finally, we extended our findings to the metastatic disease setting of melanoma patients (N=14) and our preliminary data indicate an improved survival for anti-CTLA-4 treated patients who have a sustained increase in ICOS-expressing CD4 T cells. Conclusions: Our presurgical clinical trial allowed for the correlation of data from tumor tissues with data from peripheral blood, thus identifying ICOS-expressing T-cells as a relevant biomarker that can be used to monitor patients who receive anti-CTLA-4 therapy.

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Phase II study of recombinant IL-21 (rIL-21) plus sorafenib as second- or third-line therapy for metastatic renal cell cancer (mRCC): Final results
Authors: Bhatia S. , Heath E. , Puzanov I. , Miller W. , Curti B. , Gordon M. , Ernstoff M. , Hausman D. , Hunder N. , Thompson J.
Published: August 2020

3023

Background: Despite the positive impact of targeted therapies on treatment for mRCC, the efficacy of these agents appears to decrease beyond the first-line setting. There is an unmet need for novel therapies after failure of vascular endothelial growth factor (VEGF)-directed agents. rIL-21, a cytokine that enhances CD8+ T-cell and NK cell activity, has single-agent antitumor activity (J Clin Oncol. 2008;26:2034). Based on promising results of a phase I study of rIL-21 plus sorafenib, we initiated a phase II study to explore the safety and efficacy of this combination as second- or third-line treatment for mRCC. Methods: Patients with mRCC received second- or third-line therapy with sorafenib 400 mg PO BID continuously plus rIL-21 30 μg/kg IV on days 1–5 and 15–19 of each 7-week treatment course (TC). Efficacy endpoints included progression-free survival (PFS) and overall response rate (ORR) per RECIST. Response was assessed by the investigator and by independent radiologic review (IRR). Results: 33 patients were enrolled from 14 sites in the U.S. and Canada. Median age was 61 years (range, 46–75); ECOG performance status was 0 (n=15) or 1 (n=18). Patients had received 1 (n=25) or 2 (n=8) prior lines of therapy, including sunitinib (n=19), temsirolimus (n=5), bevacizumab (n=3), everolimus (n=2), IL-2 (n=11), or other (n=4). Grade ≥3 adverse events considered at least possibly related to study drug and occurring in ≥3 patients included hypophosphatemia (33%), hand-foot syndrome (24%), rash (24%), thrombocytopenia (8%), and neutropenia (8%). Twelve patients remain on study; 13 withdrew for progressive disease (PD), 6 for toxicity, and 2 for other reasons. IRR has been performed for the first 23 patients who completed at least 1 full TC, with 6 confirmed PR (26%), 1 unconfirmed PR (4%), 14 SD (61%), and 2 PD (9%). While median PFS cannot yet be determined, 14 of the first 29 patients have completed at least 3 TCs, equivalent to approximately 21 weeks, with SD or better. Conclusions: rIL-21 plus sorafenib is associated with an acceptable safety profile and promising antitumor efficacy in previously treated patients with mRCC. The observed ORR to date compares favorably with the rate previously reported for sorafenib in the first and second-line setting.

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A phase I, pharmacokinetic (PK), and preliminary efficacy assessment of ALD518, a humanized anti-IL-6 antibody, in patients with advanced cancer
Authors: Clarke S. J. , Smith J. T. , Gebbie C. , Sweeney C. , Olszewski N.
Published: August 2020

3025

Background: ALD518 is a humanized anti-IL-6 antibody being developed for the treatment of cancer cachexia and fatigue. The primary objective of the study was to determine the safety of ALD518. Methods: 9 patients (pts) with advanced cancer, ECOG 0–2, and C-reactive protein (CRP) >10mg/L were enrolled. Pts were assigned to 1 of 3 dose-escalating cohorts (n=3/cohort). ALD518 was given as a single i.v. infusion of 80mg, 160mg, or 320mg. Pts were followed up for 12 weeks. Data included lab safety tests (LSTs), vital signs, ECGs, adverse events, hand grip strength (HGS), FACIT-F, PK and C-reactive protein (CRP). Results: 9 pts were evaluable for dose limiting toxicity (DLT) assessment at week 4 and 5/9 pts completed all visits. Of the 4 pts who failed to complete every visit; 3 were withdrawn due to progressive disease and 1 to be treated with chemotherapy. There were no DLTs or infusion reactions. There were 4 SAEs: 3 disease progressions and 1 sepsis secondary to a blocked biliary stent. There were no grade 3/4 toxicities. Changes in LSTs, CRP, HGS and FACIT-F fatigue subscale (pooled ITT analysis) are shown (Table). Conclusions: ALD518 given to pts with advanced cancer was safe and well tolerated. ALD518 reversed fatigue, increased hemoglobin and albumin, and there was a trend to increased HGS. There was a mild decrease in platelet count that remained stable throughout the study.

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Biomarkers associated with clinical outcome in advanced non-small cell lung cancer patients treated with TG4010
Authors: Acres B. , Quoix E. , Ramlau R. , Lacoste G. , Marie Bastien B. , Tavernaro A. , Bettinger S. , Bizouarne N. , Limacher J. M. , Bonnefoy J. Y.
Published: August 2020

3027

Background: TG4010 is a targeted immunotherapy product. It was tested in combination with first-line chemotherapy in a randomized, controlled, multicenter phase II study in patients with advanced non small cell lung cancer (NSCLC) (ASCO 2008- Abstract No 8023) Methods: In addition to clinical endpoints, immune parameters were tested. Blood samples were drawn prior to therapy (day1) as well as at day 43 (after 6 injections of TG4010). Lymphocyte populations were assessed by 5-color flow cytometry. Plasma samples were tested for biochemical markers using multi-analyte profile technology. Results: Out of the 148 patients enrolled in the study, 138 were evaluable for immunological analyses. Baseline characteristics were similar in both arms. Day 1 blood samples show: i) a correlation between lower levels of inflammation-associated plasma proteins and a longer median survival in Arm 1 (TG4010 + chemotherapy) (p< 0.001); ii) an improved clinical outcome with TG4010 in patients having normal levels of lymphocytes with an activated NK phenotype. Day 43 blood samples show: i) an association between higher levels of activated T lymphocytes and longer patient survival in Arm 1 (p < 0.05). No such association was observed in patients in Arm 2 (chemotherapy alone); ii) a longer survival for patients with higher levels of Interferon γ in Arm 1 than in Arm 2 (p=0.0001). Patients in both Arm 1 and Arm 2 showed specific binding of MUC1 tetramers to circulating CD8+ lymphocytes. No significant association between either treatment arm or clinical outcome and MUC1 tetramer binding was detected. Conclusions: These results identify the level of activated NK cells at baseline as a predictive biomarker for selection of patients to be treated with TG4010. Biomarker data including Interferon γ support a Th1 dependent pathway of activity for TG4010.

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The antitumor effects of CIK cells combined with docetaxel against drug-resistant lung adenocarcinoma cell line SPC-A1/DTX in vitro and in vivo
Authors: Pengying L. , Longbang C. , Xiang H.
Published: August 2020

3039

Background: Cytokine-induced killer (CIK) cells transfer is now being considered the most promising adoptive cellular therapy strategy. Multidrug resistance (MDR) phenomenon is a major hindrance to the successful chemotherapy of cancer. In this study, the anti-tumor activity of CIK cells combined with docetaxel (DTX) against multidrug resistance SPC-A1/DTX cell line was evaluated in vitro and in vivo. Methods: MTT assay was employed to evaluate the cytotoxic activity of DTX, CIK cells, and DTX plused CIK cells against SPC-A1/DTX cells in vitro. In vivo assay, SPC-A1/DTX cells were injected to nude mice subcutaneously to establish tumor-bearing mice model. On the 14th day, normal saline, docetaxel, CIK cells, and CIK cells combined with docetaxel were administered intraperitoneally respectively. All the nude mice were sacrificed at day 15 after treatment and the tumor were weight out. Results: MTT assay showed that CIK cells possessed a higher antitumor cytotoxic activity against SPC-A1/DTX cells than SPC-A1 cells in vitro (p <0.05). The synergetic anti-tumor activity positively correlated with the E:T ratio and the concertration of docetaxel. The animal data also suggested that CIK cells combined with DTX had a stronger suppressive effect on the tumor growth in vivo. Conclusions: CIK cells plused with docetaxel demonstrated a prominent augmentation of anti-tumor activity against MDR lung adenocarcinoma cell lines both in vitro and in vivo.

No significant financial relationships to disclose.
Association of sTNF-R1 and the development of treatment-related symptoms in patients undergoing concurrent chemoradiation therapy for colorectal or esophageal cancer
Authors: Wang X. S. , Williams L. A. , Johnson V. E. , Mao L. , Krishnan S. , Liao Z. , Mobley G. , Cleeland C. S.
Published: August 2020

3041

Background: Cancer-treatment-induced dysregulation of proinflammatory cytokines may be a common mechanism underlying the development of symptom burden (e.g., pain, fatigue, distress, and disturbed sleep) during concurrent chemoradiation therapy (CXRT). Methods: Patients undergoing CXRT for locally advanced colorectal or esophageal cancer (N=97) reported symptoms weekly via the M. D. Anderson Symptom Inventory (MDASI). Serum samples were tested weekly during therapy for changes in concentration levels of inflammatory cytokines (interleukin [IL]-6, IL-8, IL-10, IL-1 receptor antagonist [IL-1RA], vascular endothelial growth factor [VEGF], and soluble tumor necrosis factor receptor type 1 [sTNF-R1]) via enzyme-linked immunosorbent assay (ELISA). Symptom responses were modeled using longitudinal ordinal probit regression functions that included these serum cytokine values, along with age, cancer type, prechemotherapy status, and race (non-Hispanic white vs. others), as explanatory variables. Results: The severity of multiple symptoms significantly increased at week 4 and peaked around the end of CXRT (weeks 5–7). We found that an increase in the serum level of sTNF-R1 was significantly associated with an increase in the severity of 14 of the 16 MDASI symptoms individually over the course of CXRT, as well as with each of the 6 interference items (all p<.001). Even when week of observation was added as a variable to account for concurrent systematic trends in symptom reports and cytokine levels, sTNF-R1 retained a significant positive association with 14 of 16 symptoms, and IL-6 also showed a significant positive association with 6 of 16 symptoms. Conclusions: Longitudinal analysis identified temporal associations between increases in level of serum sTNF-R1 (and, to a lesser degree, IL-6) and the development of multiple symptoms in patients undergoing CXRT for colorectal and esophageal cancer. The results may be indicative of these cytokines as potential intervention targets of reducing aggressive chemoradiation-induced symptom burden.

No significant financial relationships to disclose.
Radiation dose-benefit analysis of hematopoietic stem cell grafting for tolerence induction across MHC barriers in living related donor renal allograft recipients
Authors: Shankar V. , Haritha C. , Trivedi H. L. , Vanikar A. , Modi P. M. , Shah P. , Shah V.
Published: August 2020

3044

Background: Donor specific immunologic tolerance protects an allograft from chronic rejection and allows discontinuation of chronic immunosuppressive therapy. Ahmedabad-tolerance induction protocol (A-TIP) allows grafting in living related donor (LRD) renal allograft recipients with persistent low-level MLHC. Present study aims to define of the ideal radiation dose needed for tolerance induction in patients undergoing A-TIP. Methods: 210 consecutive end stage renal disease patients recruited between May '05 through Mar '07 underwent renal transplantation (RTx) following A-TIP and negative Lymphocytotoxicity cross match (LCM). A-TIP includes (a) 2 DLI's (b) low intensity conditioning, and (c) HSC grafting.The conditioning regimen included fractionated low dose target specific radiation, cyclosporine, cyclophosphamide, anti T-cell a.b and treosulfan. All patients underwent subtotal lymphoid irradiation (STLI) targeting spleen, abdominal, iliac and inguinal lymph nodes, thoraco-lumbar vertebra and 75% of pelvis. Patients were randomized into 3 groups of 70 each: STLI 600, STLI 800, STLI 1000, corresponding to doses of 600cgy, 800cgy and 1000cgy delivered conventionally using 6MV/15MV photons. Unfractionated HSC procured from donor BM was administered into portal circulation, within 24 hours of achieving CD4+/CD8+ T cell count ≤ 10% of baseline. Donor specific cytotoxic antibodies were eliminated before RTx. Immunosuppression (ISp) was withdrawn 3–6 mo after RTx for patients with consistently positive chimerism. Tolerance - Robust (R), Prope (P) and Metastable (M) is defined as RT: Stable allograft function (fn.) for >100 days without ISp; PT: Early adequate, stable grafts fn. with no rejection episodes on minimum ISp; MT: Adequate graft fn. on ISp with single episode of steroid responsive ac. rejection. Results: See Table. Conclusions: The safe and effective dose for tolerance induction in LRD renal transplantation is 1000 cGy.

[Table: see text]

No significant financial relationships to disclose.
Population pharmacokinetics (PK) of tremelimumab in patients (pts) with melanoma
Authors: Kang D. , Wang E. , Wang D. , Amantea M. , Hsyu P.
Published: August 2020

3048

Background: Tremelimumab is a fully human monoclonal antibody targeted against CTLA4, a protein on T cells critical for regulating T-cell activities, which is under development for treatment of various cancers, including melanoma. Population PK analysis was conducted using concentration-time data from 450 pts, most with melanoma or solid tumors, enrolled in four phase I or II studies that evaluated PK, tolerability, and efficacy of single-agent tremelimumab. Methods: Tremelimumab was administered intravenously either as single dose or multiple doses every 4 or 12 weeks; doses varied between 0.01 and 15 mg/kg. PK was determined using nonlinear mixed-effect modeling implemented in NONMEM VI. Baseline characteristics, including body weight, ECOG score, age, sex, serum creatinine, AST, ALT, and bilirubin, and formulation effects were investigated as potential factors affecting PK. Tremelimumab plasma concentrations were determined using a sensitive, specific, validated ELISA assay. Results: A two-compartment linear model adequately described tremelimumab concentration-time data; an additive residual error model was employed on log-transformed data. Initial and terminal half-lives were 2.5 days and 22 days, respectively. Estimated parameter values were: 0.0109 L/hr for CL (clearance), 3.72 L for V1 (central volume of distribution), 0.0172 L/hr for Q (intercompartment clearance), and 3.31 L for V2 (peripheral volume of distribution). Females had 29.6% smaller V2 compared with males. Both CL and central V1 increased with weight. An ECOG score of ≥1 showed 20.2% increase in CL compared with a score of 0. New commercial formulation decreased CL by 18.5%. The model-predicted area under concentration-time curve value in females was 13.3% greater than males (p=0.5). None of the other covariates tested significantly affected PK. Furthermore, tremelimumab was tolerated in most pts at all doses tested. Conclusions: PK of tremelimumab were shown to be affected by weight, baseline ECOG score, and formulation. However, no effects other than weight were considered clinically significant enough to warrant treatment regimen change. Further investigation of PK-response relationships is warranted.

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Relationship between pharmacokinetics and safety of tremelimumab in patients with melanoma
Authors: Wang E. , Kang D. , Wang D. , Bulanhagui C. , Hsyu P.
Published: August 2020

3049

Background: Tremelimumab is a fully human anti-CTLA4 monoclonal antibody that has antitumor activity in some patients with advanced melanoma. The most common adverse event associated with tremelimumab is diarrhea/colitis. This analysis investigated the relationship between pharmacokinetics (PK) and diarrhea or colitis in 450 patients enrolled in four phase I or II clinical studies. Methods: PK parameters including AUC during the first 90 days (AUC90), Cmax, concentration at day 29 (C29), and AUC of concentration >30 μg/mL (AUCG30) of tremelimumab were determined using nonlinear mixed-effect modeling. Severity and frequency of diarrhea and colitis during the 90 days after the first dose were considered in relation to each individual PK parameter. Frequency of diarrhea was further analyzed by logistic regression analysis. Frequencies of diarrhea and colitis were combined for logistic analysis. Results: The PK/safety analysis included 450 patients (445 with advanced melanoma). In this analysis, the severity of diarrhea and colitis appeared to be independent of PK (AUC90, Cmax, C29, and AUCG30) of tremelimumab. Although frequency of diarrhea was positively related to AUC (AUC or AUCG30), Cmax, and C29, AUC appeared to be best correlated to frequency of diarrhea. Logistic regression analysis of change in AUC on probability of having diarrhea indicated that the frequency of diarrhea increased initially with increasing AUC, but reached a plateau quickly at approximately AUC value of 50,000 μg × hr/mL (20th percentile). Results of the combined diarrhea and colitis analysis were similar to those of diarrhea alone. Conclusions: Severity of diarrhea and colitis is independent of AUC in patients with melanoma treated with tremelimumab. Frequency of diarrhea and colitis initially increases with increasing AUC, but plateaus quickly.

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A prospective observational clinical study involving an alternative cancer treatment, psorinum therapy, in treating stomach, gallbladder, pancreas, and liver cancers
Authors: Chatterjee A. , Bhattacharya S. , Chatterjee A. K. , Biswas J. , Mukhopadhyay B.
Published: August 2020

3050

Background: The prospective observational clinical study was conducted to know the efficacy of an alternative cancer treatment, ‘psorinum therapy,‘ in treating liver, gall bladder, pancreatic, and stomach cancers. The primary outcome measures of the study were (1) to assess the radiological tumor response; (2) to assess how many participants survived at least 1 year, 2 years, 3 years, 4 years, and finally, 5 years after the beginning of the study. The secondary outcome measure of the study was to assess the side effects of the investigational anti-cancer drug (psorinum) if any. Methods: The drug psorinum (an alcoholic extract of scabies, scrub, slough, and pus cells) was administered orally at 0.01ml-0.02 ml/Kg body weight as a single dose in empty stomach per day and ongoing to all the participants along with allopathic and homeopathic supportive cares. Results: 158 histopathology or cytopathology proved participants (42 of stomach, 40 of gallbladder, 44 of pancreas, and 32 of liver cancers) were included in the final analysis at the end of the study. According to the AJCC/UICC TNM staging system, 7 (4.43%) of them diagnosed at stage II, 39 (24.68%) of them diagnosed at late stage II or early stage III and 112 (70.87%) of them diagnosed at late stage III or stage IV. According to the RECIST criteria, complete tumor response occurred in 28 (17.72%) cases and partial tumor response occurred in 56 (35.44%) cases. 126 (79.75%) of them survived at least 1 year, 99 (62.66%) of them survived at least 2 years, 87 (55.06%) of them survived at least 3 years, 76 (48.10%) of them survived at least 4 years, and 62 (39.24%) of them survived at least 5 years. These participants did not receive any other conventional or investigational cancer treatments. The participants report no side effects from the drug psorinum. Conclusions: Psorinum therapy is effective in treating stomach, gallbladder, pancreas, and liver cancers. Double-blinded randomized controlled clinical trial should be done for further investigation of this alternative cancer treatment.

No significant financial relationships to disclose.
Long-term safety of BLP25 liposome vaccine (L-BLP25) in patients (pts) with stage IIIB/IV non-small cell lung cancer (NSCLC)
Authors: Butts C. , Anderson H. , Maksymiuk A. , Vergidis D. , Soulières D. , Cormier Y. , Davis M. , Marshall E. , Falk M. , Goss G.
Published: August 2020

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Background: The BLP25 liposome vaccine (L-BLP25, Stimuvax) is an investigational innovative therapeutic cancer vaccine incorporating immunoadjuvant monophosphoryl lipid A and synthetic MUC1 lipopeptide in a liposomal delivery system. In an open-label phase IIb study in 171 pts with stage IIIB/IV NSCLC randomized to best supportive care (BSC) alone (n=83) or BSC + L-BLP25 (1000 μg lipopeptide) (n=88), L-BLP25 pts received weekly vaccinations for 8 weeks (wks) and could continue maintenance vaccinations every 6 wks from wk 13. Results were encouraging (Butts et al, JCO 2005) and a remarkable number of pts received prolonged treatment (tmt). As a result a global phase III study (START) has been initiated. Methods: Safety results for 16 pts from the phase IIb study treated for ≥2 years with L-BLP25 are reported. Results: In these 16 pts (median age 57.5 years, ECOG PS: 0 in 5/16 [31%] and 1 in 11/16 [69%]), there were more females (56% vs 44% [9/16 vs 76/171]) and locoregional stage IIIB disease at entry (81% vs 38% [13/16 vs 65/171]) vs the phase IIb study population. Pts received L-BLP25 for 2.0–7.7 years and 10 pts were treated for >5 years. Compliance with tmt was good: almost all (96%) maintenance vaccinations were given every 6 wks according to the tmt schedule. L-BLP25 was well tolerated: the most common tmt-emergent adverse events (TEAEs) were cough (n=12, 75%), fatigue (n=12, 75%), and dyspnea (n=11, 69%). The pattern of TEAEs did not change significantly over time and there was no rise in the incidence of TEAEs with increasing time on tmt. Among the most common TEAEs in years 1, 2, and >2 were nausea (44, 19, and 38%), fatigue (56, 18, and 38%), chest pain (38, 31, and 31%), and cough (38, 25, and 31%). Twelve pts (75%) had tmt-related TEAEs (grade 1/2 in 11/12 pts [92%] and grade 3 in 1/12 [8%]): the most common were injection-site reactions. The occurrence of tmt-related TEAEs decreased with increasing tmt duration. There was no evidence of any TEAEs related to autoimmunity. Analysis of laboratory data did not indicate any long-term renal, liver, or other toxicity. Conclusions: Long-term use of L-BLP25 was without any identifiable safety issues. In particular, there was no evidence of autoimmune reactions with prolonged use.

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Antitumor activity of patient-derived renal cell carcinoma cells fused with allogeneic dendritic cells: In vitro results and clinical responses
Authors: Xia J. , Zhou J.
Published: August 2020

3056

Background: Renal cell carcinoma (RCC) has been shown to be highly susceptible to immune-based treatment strategies. Methods: In the present study, patient-derived tumor cells were fused with allogeneic dendritic cells (DC) to elicit antitumor activity against RCC. DC from HLA-A2+ healthy donors were fused with primary RCC cells from 10 patients. Phenotype of fusion cells was characterized by flow cytometer and confocal microscopy. In vitro, T-cell proliferation, IFN-γ secretion, and cytotocic T lymphocytes (CTL) activity elicited by allogeneic DC/RCC fusion cells were assessed. Clinically, 10 patients were vaccinated with allogeneic DC/RCC fusion vaccine. The adverse effects and toxicity were observed. The clinical response was evaluated by CT scans. Results: After fusion, the created hybrids expressed both tumor-associated antigen and DC-derived molecules and could stimulate the proliferation and IFN-γ secretion of T-cells as well as elicit strong CTL activity against RCC cells in vitro. In vivo, neither serious adverse effects nor signs of autoimmune disease were observed after vaccination therapy. Percentage of T lymphocyte subsets in peripheral blood of patients was increased significantly. One of 10 patients exhibited a partial response with regression of lung metastases. Six patients showed stable disease with stabilization of previously progressive disease (follow-up 1.5 year). Conclusions: The data suggest that allogeneic DC/RCC fusion vaccine is safe and can elicit immunological responses in patients with RCC.

No significant financial relationships to disclose.
Analysis of immunological and clinical data resulting from four phase I and II trials of MVA-5T4 in colorectal cancer patients
Authors: Harrop R. , Shingler W. H. , Goonewardena M. , de Belin J. , Kelleher M. , Drury N. , Treasure P. , Naylor S.
Published: August 2020

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Background: The attenuated vaccinia virus MVA has been engineered to deliver the tumor antigen 5T4 (MVA-5T4; TroVax). 5T4 is a surface glycoprotein expressed by most solid tumors. MVA-5T4 has been tested in one phase I/II and three phase II clinical trials in colorectal cancer patients. All trials demonstrated that MVA-5T4 was well tolerated when administered alone (1 trial), as adjuvant/neoadjuvant to surgery (1 trial), or in combination with chemotherapy (FOLFOX or FOLFIRI; 2 trials). We have now collated data from all four trials, determined the incidence of immune responses across trials, and looked for associations with improved survival. Methods: Patients with histologically proven CRC were recruited to 4 independent trials in which 3 to 6 vaccinations of MVA-5T4 were scheduled to be administered either as a monotherapy, as adjuvant/neoadjuvant to surgery for respectable liver metastases or alongside treatment with FOLFIRI or FOLFOX. Antibody responses specific for 5T4 and MVA were monitored by ELISA. Survival data were collated from each hospital site. Immunological and survival data were analyzed using proportional hazards regression adjusting for age and gender. Results: Survival and immunological response data were available for 73 patients (median age 63), who received a median of 5 MVA-5T4 vaccinations (range 1–6). Of 69 patients tested for antibody responses post-vaccination (4 patients had no post-vaccination blood sample available), 54 (78%) and 65 (94%) showed positive responses for 5T4 and MVA respectively. Exploratory analyses demonstrated significant associations between immune responses and overall survival across trials. Indeed, a Cox proportional hazards model showed that a doubling in the geometric mean 5T4 antibody titre (injections 1 to 3) was associated with a 19.9% reduction in relative risk, adjusted for age and gender (p<1%). Conclusions: MVA-5T4 induced 5T4-specific immune responses in the majority of patients. Although the studies described here were uncontrolled, there were encouraging signs of activity which associated with the presence of 5T4-specific immune responses.

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Effect on humoral and cellular immunity and on apoptosis in CIN2, CIN3, and HPV16+ cervical cancer of therapeutic divalent genetic vaccination with CMV replicon system (CRS) delivering HPV16 recombinantly mutated E6 and E7 viral oncogenes targeting p53 and Rb, respectively
Authors: Giannios J. , Peristeris J. , Alexandropoulos N. , Kononas T. , Ginopoulos P.
Published: August 2020

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Background: Prophylactic vaccines have no therapeutic capacity for all the women who are already infected with HPV16 and have developed cervical intraepithelial neoplasia (CIN) or cervical cancer. Approximately 300 million women with CIN and cervical cancer will require therapy in the next decades. Thus, there is a great demand for a therapeutic HPV vaccine. Methods: We developed a cytomegalovirus (CMV) replicon system (CRS) for delivery of the HPV16 recombinantly mutated E6 and E7 genes replacing part of the CMV genome for the HPV genes, which were genetically altered to block binding sites for p53 and Rb.The replicon-vectors infected and co-transfected CIN and cervical cancer cells in animal models derived from HPV16(+) CIN, and cervical Ca cells obtained from patients. The genetic vaccine was administered subcutaneously (SC) with a needless injection system. Results: After vaccination,the viral E6 oncogene did not degrade apoptotic p53, and it blocked activation of telomerase. This induced apoptosis and DNA repair in CIN and cervical cancer cells. Furthermore, the E7 viral oncogene did not degrade the retinoblastoma oncogene (Rb) protein releasing transcription factor E2F. This vaccination led to scheduled cell cycle entry, genetic stability, and mortalization of tumor cells. Humoral and cellular immune responses were exhibited, which led to irreversible D2 apoptotic stage of PCD type I leading to a bystander killing effect of CIN, and cervical cancer cells. BrdU and MTT analysis exhibited inhibition of DNA synthesis and metabolic activity of vaccinated tumor cells compared to controls. Conclusions: This genetic divalent vaccine coding for E6 and E7 mutations designed to prevent p53 and Rb binding sites activated humoral and cellular immune responses leading to apoptosis of CIN and cervical cancer cells. It is up to translational medicine to bring this therapeutic vaccine into the clinic for patients with CIN2, CIN3, and cervical cancer patients.

No significant financial relationships to disclose.
A phase II trial of an adenovirus/PSA vaccine for prostate cancer
Authors: Lubaroff D. M. , Vaena D. A. , Williams R. D. , Joudi F. N. , Smith M. C. , Zehr P. S. , Eastman J. , Griffith K. , Madsen T. M. , Johnson K.
Published: August 2020

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Background: Our phase I adenovirus/PSA vaccine trial has proven the vaccine is safe. We are conducting a phase II clinical trial with two separate protocols for patients with recurrent or hormone-refractory prostate cancer assessing toxicity, immune responses, and change in PSA levels. Methods: In Protocol 1 men with recurrent prostate cancer after definitive initial treatment were randomized to arm A (vaccine injection alone at days 0, 30, and 60) or arm B (vaccine injection 14 days after initiation of androgen deprivation therapy). In Protocol 2 men with hormone-refractory disease receive the vaccine alone at days 0, 30, and 60. Each injection consists of 108 pfu of Ad/PSA vaccine suspended in a collagen matrix. All patients return at regular intervals for physical, chemical, radiologic, and immunologic evaluations. Twenty-five patients will be enrolled in arms A and B in Protocol 1 and 32 in Protocol 2. Results: To date 10 patients have completed 3 monthly injections and have been followed a median of 5 months. Median patient age is 70 years (range 61–84), and median enrollment PSA levels are 0.79 ng/ml (range 0.24–3.93) in Protocol 1 and 5.47 ng/ml (range 0.29–11.17) in Protocol 2. Preliminary results show 86% in both protocols demonstrating anti-PSA T cell responses above preinjection levels. 25% have stable serum PSA levels, 50% have decreased levels, and 25% have increased levels. 11% have stable serum prostatic acid phosphatase (PAP) levels, 56% have decreased levels, and 33% have increased levels. Conclusions: These early results from the first few months of this phase II trial demonstrate the induction of anti-PSA T-cell responses in a high percentage of the vaccinated patients and stabilization or declines in serum PSA and PAP levels. No serious vaccine-related toxicities have been identified.

No significant financial relationships to disclose.