scholarly journals 411 Novel intratumoral agent, INT230–6 induces cancer cell death, increases tumor infiltrates and results in durable benefit alone or in combination with pembrolizumab in refractory patients

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A436-A436
Author(s):  
Anthony El-Khoueiry ◽  
Jacob Thomas ◽  
Anthony Olszanski ◽  
Nilofer Azad ◽  
Lewis Bender ◽  
...  
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Cancer Cells ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Single Agent ◽  
Systemic Exposure ◽  
Systemic Circulation ◽  
Cancer Center ◽  
Advanced Malignancy

BackgroundINT230-6 is a novel formulation of cisplatin and vinblastine with an amphiphilic cell penetration enhancer that has been shown to enhance dispersion of the drug throughout tumors and allow diffusion into cells when given intratumorally. In preclinical models, INT230-6 has resulted in cell death, dendritic cell influx, antigen presentation and T-cell engagement with strong synergy when combined with checkpoint inhibitorsMethodsThis phase 1/2 study evaluated Q2week injections of INT230-6 x 5 dosed by tumor volume alone or with 200 mg pembrolizumab IV Q3 weeks. Eligble patients had any advanced malignancy refractory to standard therapy with an injectable tumor.ResultsSixty subjects (median 3 prior therapies (range 0–10)) were enrolled (53 monotherapy, 7 combo). Median age was 60 (42–85). 19 different cancer types were accrued with breast cancer and sarcoma being the most frequent. Over 200 deep tumor injections were administered at doses of up to 172 ml of INT230-6 (86 mg of CIS, 17 mg of Vin). PK analysis revealed <5% of the drugs were measured in systemic circulation, indicative of minimal systemic exposure. There was no dose limiting toxicity. The most frequent monotherapy drug related AE’s reported were: injection-site pain 58%, nausea 37%, fatigue 33%, and vomiting 27% with only 18% of subjects experiencing a grade 3 AE (no grade 4 or 5). Rates were comparable for the single agent INT230-6 and the combination with pembrolizumab. In the overall monotherapy cohort, patients completing all 5 doses of INT230-6 over 56 days (n=16), the median overall survival has not yet been reached. after a median followup of 408 days. In the 5 evaluable patients who received the pembrolizumab combination, the median TTP has not been reached with a median follow up of 6 mo. Paired biopsies (pre, 1 month) were available in 10 monotherapy patients and revealed a median of 63% reduction in viable cancer cells on H&E (30% had no viable cancer) that was also associated with qualitative decreases in Ki67, increases of CD4 and CD8 T-cells and reduction in FoxP3 Tregs. Despite receiving only 2 month of monotherapy, short half lives of the active agents, and no subsequent therapies, 8 injected tumors continued to regress past 1 year.ConclusionsINT230-6 is well tolerated when administered intratumorally alone or in combination with pembrolizumab. Pharmacodynamic assessments provides proof of concept that this drug can reduce viable cancer cells and increases CD4/CD8 T-cell infiltrates leading to durable clinical benefit off treatment.Trial RegistrationNCT 03058289Ethics ApprovalThe study was approved by USC, Princess Margaret Cancer Center, Fox Chase, UMass, Columbia, and Johns Hopkins Institution’s Ethics BoardConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal

scholarly journals Current Clinical Applications and Future Perspectives of Immune Checkpoint Inhibitors in Non-Hodgkin Lymphoma

2020 ◽  
Vol 2020 ◽  
pp. 1-18
Author(s):  
John Apostolidis ◽  
Ayman Sayyed ◽  
Mohammed Darweesh ◽  
Panayotis Kaloyannidis ◽  
Hani Al Hashmi
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
B Cell ◽  
Cancer Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors

Cancer cells escape immune recognition by exploiting the programmed cell-death protein 1 (PD-1)/programmed cell-death 1 ligand 1 (PD-L1) immune checkpoint axis. Immune checkpoint inhibitors that target PD-1/PD-L1 unleash the properties of effector T cells that are licensed to kill cancer cells. Immune checkpoint blockade has dramatically changed the treatment landscape of many cancers. Following the cancer paradigm, preliminary results of clinical trials in lymphoma have demonstrated that immune checkpoint inhibitors induce remarkable responses in specific subtypes, most notably classical Hodgkin lymphoma and primary mediastinal B-cell lymphoma, while in other subtypes, the results vary considerably, from promising to disappointing. Lymphomas that respond to immune checkpoint inhibitors tend to exhibit tumor cells that reside in a T-cell-rich immune microenvironment and display constitutive transcriptional upregulation of genes that facilitate innate immune resistance, such as structural variations of the PD-L1 locus, collectively referred to as T-cell-inflamed lymphomas, while those lacking such characteristics are referred to as noninflamed lymphomas. This distinction is not necessarily a sine qua non of response to immune checkpoint inhibitors, but rather a framework to move the field forward with a more rational approach. In this article, we provide insights on our current understanding of the biological mechanisms of immune checkpoint evasion in specific subtypes of B-cell and T-cell non-Hodgkin lymphomas and summarize the clinical experience of using inhibitors that target immune checkpoints in these subtypes. We also discuss the phenomenon of hyperprogression in T-cell lymphomas, related to the use of such inhibitors when T cells themselves are the target cells, and consider future approaches to refine clinical trials with immune checkpoint inhibitors in non-Hodgkin lymphomas.

scholarly journals A Phase 1 Study Evaluating BI 765063, a First in Class Selective Myeloid Sirpa Inhibitor, As Stand-Alone and in Combination with BI 754091, a Programmed Death-1 (PD-1) Inhibitor, in Patients with Advanced Solid Tumours

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1040-1040
Author(s):  
Jean-Pierre Delord ◽  
Nuria Kotecki ◽  
Aurelien Marabelle ◽  
Armelle Vinceneux ◽  
Iphigenie Korakis ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Research Funding ◽  
Cell Activation ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Regulatory Protein ◽  
Single Agent ◽  
Solid Tumours

Introduction: Signal Regulatory Protein α [SIRPα] is a polymorphic protein, strongly expressed on myeloid suppressive cells. BI 765063 (OSE172), a humanized IgG4 monoclonal antibody (mAb), is a selective antagonist of SIRPα/CD47 interaction, it does not bind to SIRP ɣ, known to assist T cell co-stimulation and migration. BI 765063 strongly binds V1 allele, one of the 2 major functional allele of SIRPα expressed in more than 80% of general population and Asian (in 60%). Anti-tumor effect was shown in various in vivo cancer models using the validated anti-mouse SIRPα mAbs surrogate, as single agent. The effect was more pronounced in combination with T checkpoint inhibitors (Gauttier V et al, 2018). BI 765063 mechanism of action includes promotion of tumor-antigen-presentation while preserving T-cell activation and increase tumor phagocytosis. This first in human (FIH) study is aiming at evaluating the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of BI 765063 as monotherapy and in combination a mAb antagonist to PD-1 receptor (with BI 754091), in patients with advanced solid tumours. Methods: This study comprises a dose escalation (step 1) to determine the Dose-Limiting Toxicities, Maximum Tolerated Dose (MTD), and Recommended Phase 2 Dose (RP2Ds) of BI 765063 monotherapy and with BI 754091, and dose-confirmation expansion cohorts (step 2). In Step 1, ascending dose of BI 763063 once every 3 weeks intravenously (iv) using a Bayesian approach with overdose control are tested. When MTD determined, BI 763063 will be tested with BI 754091, a PD1 mAb inhibitor. In step 2, 2 parallel randomized, non-comparative mono and combination cohorts will further confirm the RP2Ds and assess the safety and preliminary efficacy (RECIST 1.1 and iRECIST). Patients ≥ 18 years, PS:0-1, with advanced solid tumor who failed or are not eligible to standard therapy will be included. V1/V1 and V1/V2 patients (central testing) are evaluated in separate cohorts in step 1. In step 2 selected population of V1/V1 patients with advanced-stage cancers (e.g. non-small cell lung cancer, triple negative breast cancer, or gastro-intestinal cancers) will be included. Pharmacokinetics (PK), SIRPα receptor occupancy (RO) and a comprehensive translational program (in blood and tumour) will assess PK/PD profile and biomarkers of activity. A total of 116 (56 in step 1 and 60 in step 2) patients will be enrolled. Results: This trial is currently in progress. Conclusions: The trial is currently active and plans to assess the safety profile and preliminary efficacy of BI 765063, a first in class myeloid check point inhibitor antagonist of SIRPα on myeloid cells. Disclosures Marabelle: Merck Serono: Honoraria, Speakers Bureau; Merus: Research Funding; Sotio: Honoraria; Imcheck: Honoraria; Bayer: Honoraria; GSK: Honoraria; Boehringer Ingelheim: Honoraria, Research Funding; Deerfield: Honoraria; Amgen: Honoraria, Speakers Bureau; Astra Zeneca/Medimmune: Honoraria, Other: Travel expenses, Speakers Bureau; Transgene: Honoraria, Research Funding; Corus: Honoraria; Imaxio: Honoraria; Bioncotech: Honoraria; Roche/Genentech: Honoraria, Other, Speakers Bureau; Servier: Honoraria; Daichii: Honoraria; BMS: Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; T3 Pharma: Honoraria; OSE Immunotherapeutics: Honoraria; MSD: Honoraria, Other, Research Funding, Speakers Bureau; Oncovir: Honoraria; Molecular Partners: Honoraria; Novartis: Honoraria; Genticel: Honoraria; System Analytics: Honoraria; Eisei: Honoraria; GLG: Honoraria; Pillar Partners: Honoraria; Sanofi: Honoraria, Speakers Bureau; Rigontel: Honoraria; BioNtech: Honoraria; Pierre Fabre: Honoraria; Innate Pharma: Honoraria; Edimark: Honoraria; Onxeo: Honoraria; Guide Point Global: Honoraria. Vinceneux:UBS: Consultancy. Champiat:Astra Zeneca: Honoraria, Research Funding; BMS: Honoraria, Research Funding; MSD: Honoraria, Research Funding; Sanofi: Research Funding; Boehringer Ingelheim: Research Funding; Amgen: Honoraria; Novartis: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Pfizer: Research Funding. Huhn:Boehringer Ingelheim Pharmaceuticals: Employment. Poirier:OSE Immunotherapeutics: Employment. Costantini:OSE Immunotherapeutics: Employment, Membership on an entity's Board of Directors or advisory committees. Vasseur:OSE Immunotherapeutics: Employment. Cassier:Blueprint Medecine: Honoraria, Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Roche/Genentech: Honoraria, Other, Research Funding; Astra Zeneca: Research Funding; BMS: Other: Travel expenses, Research Funding; Innate Pharma: Research Funding; Plexxikon: Research Funding; Merck Sereno: Research Funding; Taiho Pharmaceuticals: Research Funding; Transgene: Research Funding; Toray industries: Honoraria; Janssen: Research Funding; MSD: Other: Travel expenses, Research Funding; Novartis: Honoraria, Other: travel expenses, Research Funding; Amgen: Honoraria, Other: travel expenses; Lilly: Research Funding; Bayer: Research Funding; Loxo: Research Funding; GSK: Research Funding.

405 CDX1140–01, a phase 1 dose-escalation/expansion study of CDX-1140 alone (Part 1) and in combination with CDX-301 (Part 2) or pembrolizumab (Part 3)

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A430-A430
Author(s):  
Rachel Sanborn ◽  
Ralph Hauke ◽  
Nashat Gabrail ◽  
Mark O’Hara ◽  
Nina Bhardwaj ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Metabolic Response ◽  
Phase 1 ◽  
Safety Data ◽  
Systemic Exposure ◽  
University Of Pennsylvania ◽  
Cancer Center ◽  
Low Grade ◽  
Metastatic Pancreatic Adenocarcinoma ◽  
Expansion Cohort

BackgroundCDX-1140 is an agonist anti-CD40 mAb selected to optimize systemic exposure and hence tumor microenvironment (TME) ingress. CDX-1140 activity may be enhanced by combining with CDX-301 (recombinant Flt3L), a dendritic cell growth factor, or with pembrolizumab, an anti-PD-1 mAb.MethodsPatients with advanced solid or hematologic (Part 1 only) tumors are enrolled. Part 1 dose-escalation results have been presented (SITC 2019). In Part 2, CDX-1140 dose-escalation (0.09–1.5 mg/kg q4w) is in combination with CDX-301 (75 mcg/kg sc QD x 5 for 2 cycles). In Part 3, CDX-1140 dose-escalation (0.72–1.5 mg/kg q3w) is in combination with pembrolizumab 200 mg q3w. Part 1 and 2 expansion cohorts are dosed at the CDX-1140 MTD, 1.5 mg/kg q4w. Part 3 expansion cohorts are planned. Peripheral blood and tumor biomarkers analysis are ongoing.Results92 patients have been treated (Part 1 n=57, Part 2 n=31, Part 3 n=4). Part 1 expansion cohorts in SCCHN (n=7) and RCC (n=5) are fully enrolled. Part 2 dose-escalation completed to the highest CDX-1140 dose and a SCCHN expansion cohort is ongoing. Part 3 dose-escalation recently initiated. Safety data is available for 23 and 10 patients at the MTD in Part 1 and 2, respectively. In general, the safety profiles were similar, with arthralgia (52% vs. 50%), pyrexia (44% vs 50%), fatigue (30% vs. 50%), chills (39% vs. 40%), vomiting (30% vs. 20%), nausea (26% vs 40%), myalgia (22% vs. 30%), increased ALT (22% vs. 20%), and increased AST (22% vs. 30%) being the most common drug related AEs at the MTD in Part 1 and 2, respectively. Most AEs were low grade. Across all cohorts, cytokine release syndrome (CRS) (G2 n=4, G3 n=2) occurred in 6 (Part 1 n=2; Part 2 n=4) and pneumonitis (G3) occurred in 5 (Part 1 n=4; Part 2 n=1) patients. Immune activation in the TME consistent with CD40 agonism and increases serum inflammatory cytokines were observed. Evidence of anti-tumor activity/clinical benefit include SD (n=13), tumor cavitation (n=2) and a uPR in solid tumors. A patient with follicular lymphoma has an ongoing durable complete metabolic response.ConclusionsThe CDX-1140 MTD dose of 1.5 mg/kg, a dose level expected to provide good systemic exposure and TME penetration, is generally well tolerated alone and with CDX-301. Transaminitis and CRS have generally been low grade and infrequent. A cohort combining CDX-1140 with chemotherapy will be initiated in patients with previously untreated metastatic pancreatic adenocarcinoma.Trial RegistrationNCT03329950Ethics ApprovalThe study was approved by the following: Providence St. Joseph Health IRB, approval number MOD2020001128; WIRB, approval number 1188814 (Hauke, Gabrail, Bordoni & Gordon); University of Pennsylvania IRB, approval number UPCC 18917; Mount Sinai School of Medicine IRB, approval number 18-00202; Memorial Sloan Kettering Cancer Center IRB, approval number 18-225A; Houston Methodist IRB, approval number MOD00000836

KY1044 to target the ICOS pathways inducing intratumoral Treg depletion and agonism of effector T cells: Preliminary pharmacodynamic markers from a phase 1/2 multicenter trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2626-2626
Author(s):  
Chia-Chi Lin ◽  
Aung Naing ◽  
Manish R. Patel ◽  
Howard A. Burris III ◽  
Giuseppe Curigliano ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Phase 1 ◽  
Single Agent ◽  
Effector T Cells ◽  
Post Treatment ◽  
Target Engagement ◽  
Treg Depletion ◽  
Gm Csf ◽  
Tumor Biopsies

2626 Background: Inducible T-cell co-stimulator (ICOS) is an important co-stimulatory receptor on effector T cells (Teffs) that also promotes tumor growth due to its high expression on regulatory T cells (Tregs). KY1044 is a fully human IgG1 that targets ICOS, acting via a dual mode of action (MoA) by depleting ICOShigh Tregs and stimulating ICOSLow Teffs. A Phase 1/2 clinical trial (NCT03829501) is currently assessing the safety and preliminary efficacy of KY1044, as a single agent and in combination with atezolizumab, in subjects with advanced relapsed/refractory malignancies. Using longitudinal blood samples and tumor biopsies, we aim to correlate KY1044 target engagement levels with pharmacodynamic (PD) properties (e.g. dual MoA) in the tumor microenvironment (TME) and the circulation. Methods: Phase 1 subjects were enrolled in dose escalation and enrichment cohorts to evaluate the effect of KY1044 as monotherapy (0.8 – 240 mg) Q3W and in combination (0.8 – 80 mg) with atezolizumab (1200 mg) Q3W. PBMCs, plasma and tumor biopsies were collected over the first 3 cycles to confirm target engagement and KY1044 MoA. The sample analysis included: immunohistochemistry (IHC) of tumor samples (ICOS, FOXP3 and CD8); circulating T cell immunoprofiling and receptor occupancy by chip-cytometry; PBMC and tumor sample pre- and post-treatment transcriptomic analysis; and the assessment of circulating cytokines (e.g. GM-CSF). Results: As assessed in PBMCs, full/prolonged ICOS target engagement on T cells was confirmed in subjects receiving a flat dose of 8 to 240 mg, while partial/transient saturation was observed at lower doses (0.8-2.4 mg). The target engagement was not affected by atezolizumab. The immune cell profiling showed changes in some populations, but there was no significant depletion of peripheral ICOS+ cells. In contrast, pre- and post-treatment IHC analysis of ICOS+/FOXP3+ cells in tumor biopsies confirmed a KY1044-dose dependent reduction of ICOS+ Tregs and maintenance of CD8+ T cells in the TME. Together, this resulted in an increased intratumoral CD8+/ICOS+ Treg ratio at all doses, plateauing from subjects receiving a flat KY1044 dose of 8 mg. KY1044-dependent agonism was indirectly assessed by measuring circulating cytokine levels. A post-dosing transient induction of GM-CSF was evident in subjects dosed with KY1044 at the 0.8 and 2.4 mg dose, whereas minimal induction was observed at dose of 8 mg and higher. Conclusions: LongitudinalPDdata confirmed the expected KY1044 MoA, namely ICOS Treg depletion and increased CD8/ICOS Treg ratio in the TME as well as T cell co-stimulation. The observed PD responses are currently being further explored in a more homogenous patient population.

Differentiated activity profile for the PD-1 inhibitor balstilimab.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5529-5529
Author(s):  
Cailin Joyce ◽  
Dhan Chand ◽  
Benjamin Duckless ◽  
Manuel Hidalgo ◽  
Joseph Elan Grossman ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Culture System ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Activity Profile ◽  
Double Positive ◽  
Programmed Death

5529 Background: The development and clinical application of immune checkpoint inhibitors has transformed the therapeutic landscape for cancer treatment in recent years. Balstilimab (AGEN2034) is a fully human, monoclonal IgG4 antibody that binds with high affinity to programmed death 1 (PD-1), thus preventing the interaction between this receptor and its ligands programmed death ligand 1 and 2 (PD-L1, PD-L2). Emerging evidence suggests that balstilimab exhibits a differentiated activity profile compared to currently approved anti-PD-1 agents, including pembrolizumab and nivolumab. Methods: Balstilimab as monotherapy was evaluated in a large phase 2 study in patients (pts) with recurrent/metastatic cervical cancer who had relapsed after a platinum-based treatment regimen for advanced disease. Pts were dosed at 3 mg/kg once every 2 weeks for up to 24 months and antitumor activity was assessed using RECIST v1.1. The tumor cell killing activity of balstilimab was evaluated preclinically in a human co-culture system of (1) primary T cells engineered to recognize NY-ESO-1 and (2) NY-ESO-1+ cancer cell lines, including PD-L1 and/or PD-L2-deficient engineered lines. The co-culture system was maintained for ̃ two weeks to drive partial T cell exhaustion; a state where cytotoxicity is compromised but recoverable with PD-1 blockade. Cytotoxicity of these partially exhausted T cells was quantified against PD-L1/L2 double positive, single positive, or double negative cancer cells in the presence or absence of PD-(L)1 antibodies. Results: In the second-line treatment setting for pts with advanced cervical cancer, balstilimab showed a numerically higher objective response rate (ORR) in subjects with PD-L1+, squamous cell carcinoma (SCC) tumors (21%, 95% CI, 12.7-32.6%) than those reported for pembrolizumab. Unlike pembrolizumab, balstilimab showed activity in PD-L1(-) pts, and irrespective of tumor histology (ORR 7.9%, 95% CI, 2.7-20.8%). Despite lower overall PD-L1 positivity compared to SCC (41.7 v 72.9%), an ORR of 12.5% (95% CI, 5.9-24.7%) was observed in the subset of pts with a poorer prognosis, those with cervical adenocarcinoma. Concordant with clinical observations, balstilimab demonstrated superior rescue of antigen-specific T cell cytotoxicity in vitro relative to pembrolizumab, nivolumab, or atezolizumab. Balstilimab also induced cytotoxicity against PD-L1 and/or PD-L2 deficient target cancer cells. Conclusions: Taken together, these data suggest functional differentiation of balstilimab from other PD-1 inhibitors with potentially important implications for extending the therapeutic reach of anti-PD-1 therapy. Investigation of the underlying mechanistic basis for these findings is ongoing. Clinical trial information: NCT03104699.

scholarly journals Sourcing the immune system to induce immunogenic cell death in Kras-colorectal cancer cells

2019 ◽  
Vol 121 (9) ◽  
pp. 768-775
Author(s):  
Mara Cirone ◽  
Lavinia Vittoria Lotti ◽  
Marisa Granato ◽  
Livia Di Renzo ◽  
Ida Biunno ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Cell Activation ◽  
Cytotoxic T Cells ◽  
Single Agent ◽  
Atp Release ◽  
Immunogenic Cell Death ◽  
Dendritic Cell Activation ◽  
Colorectal Cancer Cells

Abstract Background Current approaches aimed at inducing immunogenic cell death (ICD) to incite an immune response against cancer neoantigens are based on the use of chemotherapeutics and other agents. Results are hampered by issues of efficacy, combinatorial approaches, dosing and toxicity. Here, we adopted a strategy based on the use of an immunomolecule that overcomes pharmachemical limitations. Methods Cytofluorometry, electron microscopy, RT-PCR, western blotting, apotome immunofluorescence, MLR and xenografts. Results We report that an ICD process can be activated without the use of pharmacological compounds. We show that in Kras-mut/TP53-mut colorectal cancer cells the 15 kDa βGBP cytokine, a T cell effector with onco-suppressor properties and a potential role in cancer immunosurveillance, induces key canonical events required for ICD induction. We document ER stress, autophagy that extends from cancer cells to the corresponding xenograft tumours, CRT cell surface shifting, ATP release and evidence of dendritic cell activation, a process required for priming cytotoxic T cells into a specific anticancer immunogenic response. Conclusions Our findings provide experimental evidence for a rationale to explore a strategy based on the use of an immunomolecule that as a single agent couples oncosuppression with the activation of procedures necessary for the induction of long term response to cancer.

scholarly journals Cordyceps militaris Induces Immunogenic Cell Death and Enhances Antitumor Immunogenic Response in Breast Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Xingguo Quan ◽  
Beom Seok Kwak ◽  
Ji-Young Lee ◽  
Jin Hee Park ◽  
Anbok Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Checkpoint Inhibitors ◽  
Apoptotic Cell ◽  
Annexin V ◽  
Cfse Dilution ◽  
Mouse Breast Cancer ◽  
Treated Breast

Cordyceps militaris has been widely used as a traditional medicine in East Asia. Its effects against breast cancer have been reported previously. However, whether C. militaris-induced breast cancer cell death is immunogenic remains unelucidated. This study aimed to determine whether ethanolic extracts of C. militaris (CM-EE) could induce immunogenic cell death (ICD) in breast cancer immunotherapy to improve the efficacy of immune checkpoint inhibitors. Human and mouse breast cancer cells were treated with various concentrations of CM-EE for 72 h, and cytotoxicity was measured using the sulforhodamine B assay. Flow cytometry was used to assess cell death with annexin V/7-AAD staining and measure the surface exposure of damage-associated molecular pattern (DAMP) molecules including calreticulin, HSP70, and HSP90. Western blot for cleaved poly (ADP-ribose) polymerase (PARP) was used to confirm apoptotic cell death. The immunogenicity of CM-EE-induced dead cells was evaluated using the CFSE dilution assay. CM-EE reduced the viability of human (MCF7, MDA-MB-231, HS578T, and SKBR3) and mouse (4T1-neu-HA, TUBO-HA, and TUBO-P2J-HA) breast cancer cells. The IC50 was 25–50 µg/ml in human breast cancer cells and 10–50 µg/ml in mouse breast cancer cells at 72 h. CM-EE-treated breast cancer cells were positively stained by annexin V, cleaved PARP, and cleaved caspase 3/7 which were increased upon CM-EE treatment. Surface exposure of DAMP molecules was increased in dose- and time-dependent manners. The CFSE dilution assay revealed that dendritic cells fed with CM-EE-treated breast cancer cells successfully stimulated tumor-specific T cell proliferation without inhibiting DC function and T cell proliferation. The expression of PD-L1 mRNA and protein level was increased in dose-dependent manners. In addition, CM-EE also potentiated the cytotoxic activity of tumor-specific T cells. CM-EE can induce immunogenic and apoptotic cell death in breast cancer cells, and it is a good candidate for cancer immunotherapy and may improve the efficacy of immune checkpoint inhibitors.

Sarcoidosis-like syndrome and lymphadenopathy due to checkpoint inhibitors

2016 ◽  
Vol 23 (8) ◽  
pp. 620-624 ◽  
Author(s):  
Belal Firwana ◽  
Rahul Ravilla ◽  
Mihir Raval ◽  
Laura Hutchins ◽  
Fade Mahmoud
Keyword(s):  
Cell Death ◽  
Adverse Event ◽  
T Cell ◽  
Metastatic Melanoma ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Stage Iv ◽  
Stage Iii ◽  
Lymphocyte Antigen

Immunotherapy with checkpoint inhibitors has revolutionized the management of metastatic melanoma. These checkpoints, namely the cytotoxic T lymphocyte antigen 4 and the programmed T cell death 1 receptor, possess an inhibitory effect on the T cell function. Pharmacologic inhibition of cytotoxic T lymphocyte antigen 4 with ipilimumab and programmed T cell death 1 with either pembrolizumab or nivolumab has resulted in long-term sustained responses among patients with metastatic melanoma. The adverse events of these medications are predominantly immune related. Sarcoidosis-like syndrome/lymphadenopathy represents a challenging adverse event to the oncologist as it can be mistaken for progressive disease. Hence, awareness of such adverse event and obtaining a biopsy of the enlarged lymph nodes will confirm the diagnosis and avoid the unnecessary change of current therapies for those with stage IV disease or adding new ones for those with stage III disease. We report three cases of immunotherapy-related sarcoidosis-like syndrome/lymphadenopathy; two cases occurred during adjuvant ipilimumab for stage III surgically resected melanoma and one case during pemprolizumab for stage IV metastatic melanoma.

Pralatrexate Is Active in Cutaneous T-Cell Lymphoma (CTCL): Results of a Multicenter, Dose-Finding Trial.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 919-919
Author(s):  
Steven M. Horwitz ◽  
Madeleine Duvic ◽  
Youn Kim ◽  
Jasmine M Zain ◽  
Mary Jo Lechowicz ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Dose Reduction ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Single Agent ◽  
Optimal Dose ◽  
T Cell Lymphoma ◽  
Grade 3

Abstract Abstract 919 Background: Pralatrexate enters cancer cells via the reduced folate carrier-1 (RFC-1) and is efficiently polyglutamated by folylpolyglutamyl synthetase (FPGS), leading to high intracellular retention. In a Phase 1/2 study of patients with hematologic malignancies, pralatrexate demonstrated activity in aggressive T-cell lymphoma with a maximum tolerated dose (MTD) of 30 mg/m2 once weekly for 6 of 7 weeks. The generally indolent course of CTCL may be better treated at lower doses in a maintenance fashion if a lower incidence and severity of adverse events can be achieved while preserving activity. PDX-010 is an open-label, single-agent, multicenter, Phase 1 dose-reduction trial in patients with relapsed or refractory CTCL. The primary objective is to identify an optimal dose and schedule of pralatrexate for these patients. Methods: Eligibility included mycosis fungoides (MF), Sézary syndrome (SS), and primary cutaneous anaplastic large cell lymphoma (ALCL); with disease progression after at least 1 prior systemic therapy. The pralatrexate dose and schedule started at 30 mg/m2 by IV push on 3 of 4 weeks and subsequent cohorts received reduced doses (20, 15, 10 mg/m2) and/or schedules (3/4 or 2/3 weeks) of pralatrexate based on tolerability. All patients received supplementation with vitamin B12 1 mg intramuscularly every 8-10 weeks and folic acid 1 mg orally once daily. As we sought a well tolerated regimen the definition of DLTs to trigger dose reduction included toxicities such as grade ≥ 3 neutropenia, grade ≥ 2 thrombocytopenia, febrile neutropenia, grade ≥ 2 mucositis/stomatitis, and any toxicity leading to dose omission or reduction in cycle 1. If DLT occurred and a response was seen, the following cohort was opened at the next lower dose or next less frequent schedule. Response was evaluated by modified severity-weighted adjustment tool (SWAT) every 2 cycles for 6 months and then every 4 cycles. For patients with lymph node involvement, scans were completed at baseline and upon clinical response or end of treatment, whichever occurred first. Results: Thirty-one patients received pralatrexate, with 18 (58%) men and median age of 57 yrs (range, 30-81). Patients had received a median of 6 prior therapies (range, 1-25). Cohorts at the following doses/schedules were enrolled: 30 mg/m2 x 3/4 weeks (n=2), 20 mg/m2 x 3/4 weeks (n=3), 20 mg/m2 x 2/3 weeks (n=7), 15 mg/m2 x 3/4 weeks (n=6), 15 mg/m2 x 2/3 weeks (n=3), and 10 mg/m2 x 3/4 weeks (n=10). Patients received pralatrexate for a median of 72 days (range, 7-491+); 4 patients received >10 cycles of treatment. The most common treatment-related adverse events (all grades) were mucositis (18 patients [58%]), nausea (14 patients [45%]), fatigue (14 patients [45%]), pyrexia (7 patients [23%]), vomiting (6 patients [19%]), anemia (6 patients [19%]), and edema (5 patients [16%]). Grade 3-4 treatment-related toxicities in >1 patient each were mucositis (4 patients [13%]) and anemia (2 patients [6%]). Mucositis was dose limiting (≥ grade 2) in 8 patients (26%). A total of 11 responses were observed, including 2 complete responses and 9 partial responses. In the 18 patients who received pralatrexate at a dose intensity of 15 mg/m2 x 3/4 weeks or greater, the objective response rate was 56% (10/18 patients). This appeared to be the threshold dose for substantial activity in CTCL, below which the incidence of responses decreased in this dose de-escalation trial. Conclusion: Pralatrexate shows impressive activity in the treatment of relapsed CTCL. The optimal dose and schedule that provided activity with tolerability for CTCL was determined to be pralatrexate 15 mg/m2 weekly on 3 of 4 weeks. This cohort is being expanded to better assess efficacy and durability. Disclosures: Horwitz: Allos Therapeutics, Inc: Consultancy, Research Funding. Duvic:Allos Therapeutics, Inc.: Research Funding. Lechowicz:Allos Therapeutics, Inc.: Consultancy. Fruchtman:Allos Therapeutics, Inc.: Employment.

Phase I/II dose escalation and expansion study of FLX475 alone and in combination with pembrolizumab in advanced cancer.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. TPS24-TPS24
Author(s):  
William Ho ◽  
Nicole Nasrah ◽  
Dan Johnson
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
Dose Escalation ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Single Agent ◽  
Safety Data ◽  
Receptor Occupancy ◽  
Open Label ◽  
Ligand Expression

TPS24 Background: Regulatory T cells (Treg) can dampen anti-tumor immune responses in the tumor microenvironment (TME). The predominant chemokine receptor on human Treg is CCR4, the receptor for the chemokines CCL17 and CCL22, which are produced by tumor cells, tumor-associated macrophages and dendritic cells, as well as by effector T cells (Teff) in the setting of an inflammatory anti-tumor response. Preclinical studies with orally-available CCR4 antagonists have demonstrated potent inhibition of Treg migration into tumors, an increase in the intratumoral Teff/Treg ratio, and anti-tumor efficacy as a single agent and in combination with checkpoint inhibitors. In a first-in-human trial conducted in healthy volunteers, the oral CCR4 antagonist FLX475 was demonstrated to be well tolerated with outstanding PK properties. A robust PD assay measuring receptor occupancy on circulating Treg demonstrated the ability to safely achieve exposure levels predicted to maximally inhibit Treg recruitment into tumors via CCR4 signaling. These human PK, PD, and safety data have enabled a streamlined design of a Phase 1/2 study of FLX475 in cancer patients both as monotherapy and in combination with checkpoint inhibitor. Methods: This clinical trial is a Phase 1/2, open-label, dose-escalation and cohort expansion study to determine the safety and preliminary anti-tumor activity of FLX475 as monotherapy and in combination with pembrolizumab. The study is being conducted in 2 parts, a dose-escalation phase (Part 1) and a cohort expansion phase (Part 2). In Part 1 (Phase 1) of the study, at least 3 to 6 eligible subjects will be enrolled in sequential cohorts treated with successively higher doses of FLX475 as monotherapy or in combination with pembrolizumab (Part 1b). In Part 2 (Phase 2) of the study, expansion cohorts of both checkpoint-naïve and checkpoint-experienced patients with tumor types predicted to be enriched for Treg and/or CCR4 ligand expression (i.e. “charged tumors”) -- including both EBV+ and HPV+ tumors and NSCLC, HNSCC, and TNBC -- will be enrolled using a Simon 2-stage design. As of November 6, 2018, Cohort 1 has been completed without DLT. Clinical trial information: NCT03674567.

Sign in / Sign up

Export Citation Format

Share Document