scholarly journals Local administration of submicron particle paclitaxel to solid carcinomas induces direct cytotoxicity and immune-mediated tumoricidal effects without local or systemic toxicity: preclinical and clinical studies

2020 ◽  
Author(s):  
Shelagh Verco ◽  
Holly Maulhardt ◽  
Michael Baltezor ◽  
Emily Williams ◽  
Marc Iacobucci ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Systemic Toxicity ◽  
Local Administration ◽  
Submicron Particle ◽  
Tumor Cell Death ◽  
Primary Tumors ◽  
Clinical Investigations ◽  
Immune Mediated ◽  
Direct Cytotoxicity ◽  
Preclinical And Clinical Studies

Abstract This report describes local administration of submicron particle paclitaxel (SPP) (NanoPac®: ~ 800-nm-sized particles with high relative surface area with each particle containing ~ 2 billion molecules of paclitaxel) in preclinical models and clinical trials evaluating treatment of carcinomas. Paclitaxel is active in the treatment of epithelial solid tumors including ovarian, peritoneal, pancreatic, breast, esophageal, prostate, and non-small cell lung cancer. SPP has been delivered directly to solid tumors, where the particles are retained and continuously release the drug, exposing primary tumors to high, therapeutic levels of paclitaxel for several weeks. As a result, tumor cell death shifts from primarily apoptosis to both apoptosis and necroptosis. Direct local tumoricidal effects of paclitaxel, as well as stimulation of innate and adaptive immune responses, contribute to antineoplastic effects. Local administration of SPP may facilitate tumor response to systemically administered chemotherapy, targeted therapy, or immunotherapy without contributing to systemic toxicity. Results of preclinical and clinical investigations described here suggest that local administration of SPP achieves clinical benefit with negligible toxicity and may complement standard treatments for metastatic disease. Graphical abstract

scholarly journals Challenges and Recent Advances in NK Cell-Targeted Immunotherapies in Solid Tumors

2021 ◽  
Vol 23 (1) ◽  
pp. 164
Author(s):  
Guang-Yu Lian ◽  
Thomas Shiu-Kwong Mak ◽  
Xue-Qing Yu ◽  
Hui-Yao Lan
Keyword(s):  
Solid Tumors ◽  
Antigen Processing ◽  
Nk Cell ◽  
Residual Disease ◽  
Hematologic Malignancies ◽  
Great Success ◽  
Direct Cytotoxicity ◽  
Early Tumor ◽  
Immunosuppressive Microenvironment ◽  
Preclinical And Clinical Studies

Natural killer (NK) cell is a powerful malignant cells killer, providing rapid immune responses via direct cytotoxicity without the need of antigen processing and presentation. It plays an essential role in preventing early tumor, metastasis and minimal residual disease. Although adoptive NK therapies achieved great success in clinical trials against hematologic malignancies, their accumulation, activation, cytotoxic and immunoregulatory functions are severely impaired in the immunosuppressive microenvironment of solid tumors. Now with better understandings of the tumor evasive mechanisms from NK-mediated immunosurveillance, immunotherapies targeting the key molecules for NK cell dysfunction and exhaustion have been developed and tested in both preclinical and clinical studies. In this review, we introduce the challenges that NK cells encountered in solid tumor microenvironment (TME) and the therapeutic approaches to overcome these limitations, followed by an outline of the recent preclinical advances and the latest clinical outcomes of NK-based immunotherapies, as well as promising strategies to optimize current NK-targeted immunotherapies for solid tumors.

scholarly journals Foetal Cell Transplantation for Parkinson’s Disease: Focus on Graft-Induced Dyskinesia

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Elisabetta Tronci ◽  
Camino Fidalgo ◽  
Manolo Carta
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Transplantation ◽  
Open Label ◽  
Double Blind ◽  
Clinical Investigations ◽  
Serotonin Neurons ◽  
Ventral Mesencephalic ◽  
Preclinical And Clinical Studies ◽  
Foetal Cell

Transplantation of dopamine- (DA-) rich foetal ventral mesencephalic cells emerged as a promising therapy for Parkinson’s disease (PD), as it allowed significant improvement of motor symptoms in several PD patients in open-label studies. However, double-blind clinical trials have been largely disappointing. The general agreement in the field is that the lack of standardization of tissue collection and preparation, together with the absence of postsurgical immunosuppression, played a key role in the failure of these studies. Moreover, a further complication that emerged in previous studies is the appearance of the so-called graft-induced dyskinesia (GID), in a subset of grafted patients, which resembles dyskinesia induced by L-DOPA but in the absence of medication. Preclinical evidence pointed to the serotonin neurons as possible players in the appearance of GID. In agreement, clinical investigations have shown that grafted tissue may contain a large number of serotonin neurons, in the order of half of the DA cells; moreover, the serotonin 5-HT1A receptor agonist buspirone has been found to produce significant dampening of GID in grafted patients. In this paper, we will review the recent preclinical and clinical studies focusing on cell transplantation for PD and on the mechanisms underlying GID.

scholarly journals Immune Activation and Anemia Are Associated with Decreased Quality of Life in Patients with Solid Tumors

2020 ◽  
Vol 9 (10) ◽  
pp. 3248
Author(s):  
Patricia Kink ◽  
Eva Maria Egger ◽  
Lukas Lanser ◽  
Michaela Klaunzner ◽  
Bernhard Holzner ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Cancer Patients ◽  
Solid Tumors ◽  
Immune Activation ◽  
Inflammatory Markers ◽  
Mild Depression ◽  
Tryptophan Degradation ◽  
Immune Mediated ◽  
Phenylalanine Metabolism

Anemia often coincides with depression and impaired quality of life (QoL) in cancer patients. Sustained immune activation can lead to the development of anemia. Furthermore, it also may go along with changes in tryptophan and phenylalanine metabolism. The aim of our pilot study was to study the relationship between anemia, immune-mediated changes in amino acid metabolism, and the QoL and mood of cancer patients. Questionnaires to measure QoL and depression were completed by 152 patients with solid tumors. Hemoglobin, parameters of immune activation as well as tryptophan and phenylalanine metabolism were determined in the patients’ sera. Anemic patients (51.7%) presented with higher inflammatory markers, and a higher tryptophan breakdown with lower tryptophan concentrations. They reported an impaired QoL and had higher depression scores. Patients with an impaired QoL (65.8%) also suffered from more fatigue and impaired physical, emotional, and social functioning. They, furthermore, presented with higher concentrations of inflammatory markers (C-reactive protein (CRP) and neopterin) as well as higher tryptophan degradation (in men) and higher phenylalanine concentrations (in women). Sixty-one patients (40.1%) had (mostly mild) depression. In these patients, a higher degree of Th1 immune activation was found. The results of our study suggest that cancer-related anemia goes along with an impaired QoL, which is also associated with immune-mediated disturbances of tryptophan and phenylalanine metabolism.

scholarly journals αvβ3-integrin regulates PD-L1 expression and is involved in cancer immune evasion

2019 ◽  
Vol 116 (40) ◽  
pp. 20141-20150 ◽  
Author(s):  
Andrea Vannini ◽  
Valerio Leoni ◽  
Catia Barboni ◽  
Mara Sanapo ◽  
Anna Zaghini ◽  
...  
Keyword(s):  
Immune Evasion ◽  
Αvβ3 Integrin ◽  
Primary Tumors ◽  
Effective Strategies ◽  
Immune Mediated ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Β3 Integrin ◽  
Immunotherapy Target ◽  
Immunosuppressive Microenvironment

Tumors utilize a number of effective strategies, including the programmed death 1/PD ligand 1 (PD-1/PD-L1) axis, to evade immune-mediated control of their growth. PD-L1 expression is mainly induced by IFN receptor signaling or constitutively induced. Integrins are an abundantly expressed class of proteins which play multiple deleterious roles in cancer and exert proangiogenic and prosurvival activities. We asked whether αvβ3-integrin positively regulates PD-L1 expression and the anticancer immune response. We report that αvβ3-integrin regulated constitutive and IFN-induced PD-L1 expression in human and murine cancerous and noncancerous cells. αvβ3-integrin targeted STAT1 through its signaling C tail. The implantation of β3-integrin–depleted tumor cells led to a dramatic decrease in the growth of primary tumors, which exhibited reduced PD-L1 expression and became immunologically hot, with increased IFNγ content and CD8+ cell infiltration. In addition, the implantation of β3-integrin–depleted tumors elicited an abscopal immunotherapeutic effect measured as protection from the challenge tumor and durable splenocyte and serum reactivity to B16 cell antigens. These modifications to the immunosuppressive microenvironment primed cells for checkpoint (CP) blockade. When combined with anti–PD-1, β3-integrin depletion led to durable therapy and elicited an abscopal immunotherapeutic effect. We conclude that in addition to its previously known roles, αvβ3-integrin serves as a critical component of the cancer immune evasion strategy and can be an effective immunotherapy target.

Cabazitaxel plus cisplatin coadministration and drug-interaction study in patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e15116-e15116
Author(s):  
Alain C. Mita ◽  
Shankar Sundaram ◽  
John Sarantopoulos ◽  
Monica M. Mita ◽  
Alex R. Lane ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Solid Tumors ◽  
Dose Level ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Primary Tumors ◽  
Grade 3 ◽  
Ecog Ps ◽  
Cyp3a Inhibitor

e15116 Background: Cabazitaxel (Cbz) is a novel taxane with in vivo efficacy in taxane-sensitive and -resistant tumors. Therapeutic synergism of Cbz/cisplatin (Cis) has been shown in tumor-bearing mice. Since Cbz is primarily metabolized by CYP3A, drug interactions may occur with modulators of CYP3A. Methods: The primary objective of part 1 of this phase I study (NCT00925743) was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of Cbz/Cis. Secondary objectives included safety, pharmacokinetics (PK) and efficacy. The objective of part 2 was to assess efficacy at the MTD. The effect of the antiemetic aprepitant (a moderate CYP3A inhibitor) on the PK of Cbz was also examined. Eligible patients (pts) had ECOG PS ≤ 1 and confirmed metastatic or unresectable solid tumors for which Cis therapy was considered appropriate. A 3 + 3 dose escalation at a starting dose (level 0) of 20/75 mg/m2 (Cbz/Cis), administered IV Q3W, was used. The MTD was the highest dose at which 0/3 or ≤ 1/6 pts experienced a DLT in Cycle 1. Results: Pts (n = 25; 10 in part 1; 15 in part 2) with a median age of 56 yrs were enrolled. The most frequent primary tumors were lung (n = 4), prostate, ovary and pancreas (each n = 2). Of 6 evaluable pts, 2 had a DLT at dose level 0 (Grade 3 acute renal failure; febrile neutropenia). The MTD was 15/75 mg/m2 as no DLTs were observed; 18 pts were treated at the MTD and 60 cycles were administered (median = 3; range 1–8). The most frequent non-hematologic treatment-related adverse events (all grades/grade 3–4) were nausea (78%/22%), vomiting (72%/11%), fatigue (61%/17%), anorexia (67%/11%) and diarrhea (44%/0%). Incidence of grade 3–4 neutropenia was 78%; 1 pt had febrile neutropenia. The combined PK profile of Cbz/Cis did not appear to differ vs those of the single agents. The ratio of Cbz clearance with vs without aprepitant co-administration was 0.81 (90% CI 0.36–1.85). Stable disease was seen in 11 pts; 1 pt (prostate carcinoma) had an unconfirmed partial response. Conclusions: The MTD of Cbz/Cis was 15/75 mg/m2. The combination had a manageable safety profile consistent with a platinum/taxane combination. No PK interactions between Cis and Cbz were seen; aprepitant did not appear to alter the PK of Cbz.

A phase I study to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activities of BAL101553, a novel tumor checkpoint controller (TCC), administered as 48-hour infusion in adult patients with advanced solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS2602-TPS2602
Author(s):  
Markus Joerger ◽  
Anastasios Stathis ◽  
Ioannis Metaxas ◽  
Dagmar Hess ◽  
Aurelius Gabriel Omlin ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Spindle Assembly Checkpoint ◽  
Phase 1 ◽  
Therapeutic Window ◽  
Tumor Cell Death ◽  
Antitumor Activities ◽  
Dose Escalation Study ◽  
Vascular Toxicity

TPS2602 Background: BAL101553 (prodrug of BAL27862), is a novel TCC that promotes tumor cell death by modulating the spindle assembly checkpoint. BAL27862 has shown potent antitumor activity in diverse preclinical tumor models, including models refractory to standard therapies. In a completed Phase 1 study using 2-h IV infusions (Days 1, 8, 15, q28d, NCT01397929 , CDI-CS-001, Lopez et al. JCO 34, 2016 suppl; 2525) dose-limiting vascular effects were observed and appeared Cmax related. The recommended Phase 2 dose for 2-h IV BAL101553 is 30 mg/m2. Vascular toxicity was not observed in an ongoing study with oral BAL101553 (NCT02490800, CDI-CS-002) at daily doses up to 30 mg (QD). Preclinical data suggest that antiproliferative effects of BAL101553/27862 are driven by exposure (AUC); thus vascular toxicity and antitumor activity are mediated by different PK drivers. BAL27862 has a half-life of ~15 h. Based on PK-modeling, extending the infusion from 2 h to 48 h was expected to result in ~4-fold higher AUC at a given Cmaxlevel and thereby improve the therapeutic window. Methods: This is an ongoing multicenter, open-label, Phase 1 dose-escalation study (NCT02895360, CDI-CS-003/SAKK67/15) using a 3+3 design to determine the MTD, characterize dose-limiting toxicities and assess the PK, PD and antitumor activities of 48-h infusions of BAL101553 in consecutive 28-day cycles at a starting dose of 30 mg/m2 administered on Day 1, 8 and 15 (q28d). The dose escalation scheme foresees up to ~ 50% dose increments depending on observed toxicities. During cycle 2, patients receive 7 days oral (QD) BAL101553 (Day 15–21) instead of the weekly IV infusion to assess absolute oral bioavailability. Patients with histologically-confirmed advanced or recurrent solid tumors are eligible for enrollment. Adverse events are assessed using CTCAEv4; tumor response by RECIST 1.1 (every 2 cycles). PD assessments include optional tumor biopsies and circulating tumor cells. PK profiles are assessed during the first 2 cycles. Two dose cohorts (30 and 45 mg/m2) have completed without DLTs or signs of vascular toxicity. Clinical trial information: NCT02895360.

Pilot study on outcome and antitumor efficacy of an autologous cancer cell vaccine applied in patients with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3000-3000 ◽  
Author(s):  
Eglys Gonzalez Marcano ◽  
Leona Kröhle ◽  
Joachim Ahlers ◽  
Joachim Drevs
Keyword(s):  
Pilot Study ◽  
Side Effects ◽  
Tumor Marker ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Cell Vaccine ◽  
Advanced Solid Tumors ◽  
Tumor Cell Death ◽  
Informed Consent Form

3000 Background: In the last decade cancer immunotherapy has emerged as the most promising anti-tumor approach. The most commonly used immunotherapies are vaccines and checkpoint inhibitors. An autologous cell vaccine is made with the patient's own tumor cells processed in vitro, which may elicit a cytotoxic T-lymphocytic immune response against tumor cells antigens, resulting in tumor cell death. We performed a pilot study to evaluate the clinical relevance and general outcome of an autologous vaccine as a treatment in different types of cancer. Methods: A total of 31 patients (n=31) with advanced solid tumors and the lack of standard treatments were treated with an immunotherapy protocol consisting of 6 intradermal doses of the vaccine, given the first two doses at day 1 and 2, and the rest every two weeks. All patients signed an informed consent form. Response evaluation was assessed by PET/CT identified as metric (iRECIST) response and in some cases tumor markers where available. Results: Out of 31 patients treated, 2 patients suffered from pancreatic cancer, 2 from sarcoma, 1 from lung cancer, 13 from breast cancer, 2 from ovarian cancer, 1 from prostate cancer, 1 from cholangiocarcinoma, 4 from colorectal cancer, 1 from non-Hodgkin lymphoma, 1 from gastric cancer, 1 from laryngeal and hypopharyngeal cancer, 1 from fallopian tube cancer, 1 from peritoneal cancer. Side effects related to the therapy were rare including light redness in the area of injection and in one case inflammation of the tumor area. 26 patients were evaluated for metric response and 5 for tumor marker response assessment. For tumor marker follow up 9.6 % had a SD of > 3 month and 6.5 % a PD. For metric follow up 12.9 % had a CR, 6.5 % a PR, 25.8 % a SD of > 3 month and 38.7 % a PD. Conclusions: This study have confirmed an anti-tumor response in the majority of patients treated, with none to very low side effects and a good quality of life during the treatment. To obtain more detailed and significant data on the efficacy of this therapy, a further controlled clinical phase study should be performed.

scholarly journals Fe2P nanorods based photothermal therapy combined with immune checkpoint inhibitors for pancreatic cancer

Nanophotonics ◽  
2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Shanshan Liu ◽  
Jiawen He ◽  
Ruixiang Song ◽  
Mengmeng Zhang ◽  
Lianghao Huang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Death ◽  
Photothermal Therapy ◽  
Pancreatic Tumor ◽  
Local Treatment ◽  
Advanced Pancreatic Cancer ◽  
Tumor Model ◽  
Pancreatic Tumors ◽  
Tumor Cell Death ◽  
Primary Tumors

Abstract Treatment of pancreatic cancer is faced with great difficulties and challenges due to high lethality and metastasis. Synergism of targeted therapy and immunotherapy has been considered as ideal strategy to both eliminate primary tumors and control metastases. For the treatment of advanced pancreatic cancer, we demonstrated a local photothermal therapy (PTT) following administration of monoclonal antibody of programmed death ligand 1 (αPD-L1). Fe2P nanorods were employed as a Fenton agent and photothermal agent, which modified with DSPE-PEG2000-Mal for improved biocompatibility and Mal mediated-antigen presentation. Under a low dose laser irradiation at 980 nm, Fe2P-PEG-Mal nanorods (NRs) mediated PTT could induce immunogenic tumor cell death that can cause dendritic cells (DCs) infiltration and maturation. In a bilateral pancreatic tumor model, the local treatment of NRs-PTT on primary tumor could cause the increased infiltration of cytotoxic T lymphocytes (CTLs) and decreased residential of M2 macrophages in untreated distal tumors. Furthermore, subsequently intervened αPD-L1 could enhance cell death triggered by CTLs in distal tumors through reversing immunosuppression. An orthotopic pancreatic tumor model was used to further confirm the therapeutic outcome. Finally, the combination of NRs based PTT and αPD-L1 based immunotherapy was able to significantly eliminate orthotopic pancreatic tumors and reduce mesentery metastases. Thus, the strategy may provide a more effective treatment for pancreatic cancer.

Phase I and pharmacokinetic evaluation of enzastaurin combined with gemcitabine and cisplatin in advanced cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2046-2046 ◽  
Author(s):  
L. Beerepoot ◽  
J. Rademaker-Lakhai ◽  
E. Witteveen ◽  
S. Radema ◽  
C. Viseren-Grul ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Phase I ◽  
Solid Tumors ◽  
Pancreatic Head ◽  
Low Grade ◽  
Qtc Interval ◽  
Tumor Cell Death ◽  
Clinical Benefits ◽  
Recommended Phase Ii Dose ◽  
Dose Levels

2046 Background: Enzastaurin (Enz), an oral PKC inhibitor that also suppresses PI3K/AKT pathways, blocks tumor angiogenesis and tumor cell proliferation and induces tumor cell death. Gemcitabine (Gem) and cisplatin (Cis) combination is often used for treatment of solid tumors. Addition of Enz to the regimen has the potential for enhanced clinical benefits without increasing toxicity. Methods: In this phase I, dose-escalation trial, patients (pts) with advanced, refractory, solid tumors received a lead-in treatment (cycle 1) with oral Enz for 14 days to achieve steady-state exposures. Starting with cycle 2, pts received Enz orally (350 mg qd to 500 mg bid) on days 1–21 combined with Gem (1000 or 1250 mg/m2) as a 30-min iv infusion on days 1,8 and Cis (60 or 75 mg/m2) as a 3-h iv infusion on day 1, every 21 days, for up to 7 cycles. Results: 33 pts (22 males, 11 females; ECOG: 0–2), with a median age of 58 yrs (range: 38–79 yrs), were enrolled in 7 dose levels. The MTD was not identified. Two DLTs were reported, 1 grade (Gr) 2 QTc interval prolongation and 1 Gr 3 fatigue, both during cycle 1 in bid cohorts. Laboratory toxicities included Gr 3/4 neutropenia (3/6 pts), thrombocytopenia (1/6 pts), and Gr 3 leukopenia (2 pts), hyperglycemia (1 pt), and creatinine (1 pt). Gr 3 toxicity reported in >1 pt was fatigue (5 pts). Enz bid (≥ 250 mg bid) was associated with more discontinuations in early cycles, more Enz dose adjustments, higher numbers of possibly-related SAEs, and increased numbers of low-grade CTC toxicities compared to the corresponding qd dosing. Exposures of Enz in the presence of Gem and Cis decreased slightly but the decrease was not clinically significant as the mean exposure remained above the targeted exposure of 1400 nM. Gem and Cis exposures were not altered when given in combination with enz, as compared to historical data. Of 24 evaluable pts, 3 pts (pancreatic, head/neck, and ovarian cancer) achieved a partial response, whereas 13 achieved stable disease for ≥ 2 cycles. Conclusions: Based on safety and PK data, the recommended phase II dose is Enz 500 mg qd, Gem 1250 mg/m2, and Cis 75 mg/m2. This regimen is generally well tolerated across all dose levels and there are no significant alterations in PK parameters of any drug, when given in combination. [Table: see text]

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