ADMINISTRATION OF MOST CLOSELY MATCHED THIRD PARTY RAPIDLY GENERATED LMP, BARF1 and EBNA1 SPECIFIC CYTOTOXIC T-LYMPHOCYTES TO PATIENTS WITH EBV-POSITIVE LYMPHOMA AND OTHER EBV-POSITIVE MALIGNANCIES

The subject has a type of cancer or lymph gland disease associated with a virus called Epstein Barr Virus (EBV), which has come back, is at risk of coming back, or has not gone away after standard treatments. This research study uses special immune system cells called LMP, BARF-1 and EBNA1- specific cytotoxic T lymphocytes (MABEL CTLs).
Some patients with Lymphoma (such as Hodgkin (HD) or non-Hodgkin Lymphoma (NHL)), T/NK-lymphoproliferative disease, or CAEBV, or solid tumors such as nasopharyngeal carcinoma (NPC), smooth muscle tumors, and leiomyosarcomas show signs of a virus called EBV before or at the time of their diagnosis. EBV causes mononucleosis or glandular fever ("mono" or the "kissing disease"). EBV is found in the cancer cells of up to half the patients with HD and NHL, suggesting that it may play a role in causing Lymphoma. The cancer cells (in lymphoma) and some immune system cells (in CAEBV) infected by EBV are able to hide from the body's immune system and escape destruction. EBV is also found in the majority of NPC and smooth muscle tumors, and some leiomyosarcomas. We want to see if special white blood cells (MABEL CTLs) that have been trained to kill EBV infected cells can survive in your blood and affect the tumor.
In previous studies, EBV CTLs were generated from the blood of the patient, which was often difficult if the patient had recently received chemotherapy. Also, it took up to 1-2 months to make the cells, which is not practical when a patient needs more urgent treatment. To address these issues, the MABEL CTLs were made in the lab in a simpler, faster, and safer way. The MABEL CTLs will still see LMP proteins but also two other EBV proteins called EBNA-1 and BARF. To ensure these cells are available for use in patients in urgent clinical need, we have generated MABEL CTLs from the blood of healthy donors and created a bank of these cells, which are frozen until ready for use. We have previously successfully used frozen T cells from healthy donors to treat EBV lymphoma and virus infections and we now have improved our production method to make it faster.
In this study, we want to find out if we can use banked MABEL CTLs to treat HD, NHL, T/NK-lymphoproliferative disease, CAEBV, NPC, smooth muscle tumors or leiomyosarcoma. We will search the bank to find a MABEL CTL line that is a partial match with the subject.
MABEL CTLs are investigational and not approved by the Food and Drug Administration.

Start Date01 Feb 2015

Sponsor / Collaborator

Baylor College of Medicine

[+2]

NCT02578641 / CompletedPhase 3

A Multicentre, Randomized, Open-Label, Phase III Clinical Trial Of Gemcitabine And Carboplatin Followed By Epstein-Barr Virus-Specific Autologous Cytotoxic T Lymphocytes Versus Gemcitabine And Carboplatin As First Line Treatment For Advanced Nasopharyngeal Carcinoma(NPC) Patients

This study is a multi-center, randomized, open label, Phase III clinical trial for advanced Nasopharyngeal Carcinoma(NPC) Patients.
Drugs used in chemotherapy, such as gemcitabine and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving an infusion of a person's cytotoxic T cells (CTL) that have been treated in the laboratory may help the body build an effective immune response to kill tumor cells. Giving combination chemotherapy together with laboratory-treated T cells may kill more tumor cells. This Phase III trial is to assess if combined gemcitabine-carboplatin (GC) followed by adoptive T-cell therapy would improve clinical outcome for patients with advanced nasopharyngeal carcinoma (NPC). It is also the world's first, and largest, Phase 3 T-cell therapy cancer trial ever conducted, and enrollment is ongoing for 330 patients from 30 hospital centers across Asia and the United States.
This clinical trial is conducted on the back of a successful Phase 2 NPC trial involving 38 patients at the National Cancer Centre, Singapore. This trial produced the best published 2-year (62.9%), and median overall survival (OS) data (29.9 months) in 35 patients with advanced NPC who received autologous EBV-specific CTL. Kindly see https://www-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/pmc/articles/PMC3978790/ for the Phase 2 publication titled "Adoptive T-cell Transfer and Chemotherapy in the First line treatment of Metastatic and/or Locally Recurrent Nasopharyngeal Carcinoma".

Start Date01 Jul 2014

Sponsor / Collaborator

Tessa Therapeutics Ltd

NCT00058773 / TerminatedPhase 1IIT

Administration of Autologous Neomycin Resistant Gene Marked EBV Specific Cytotoxic T-Lymphocytes as Therapy for Patients Receiving Autologous Bone Marrow Transplant for Relapsed EBV-Positive Lymphoma.

Subjects have a type of lymph gland cancer called Hodgkin or non-Hodgkin Lymphoma, which has come back or not gone away after treatment, including the best treatment we know for relapsed Lymphoma. We are asking subjects to volunteer to be in a research study using Epstein Barr virus (EBV) specific cytotoxic T lymphocytes, a new experimental therapy. This therapy has never been used in patients with Hodgkin disease or this type of non-Hodgkin Lymphoma but it has been used successfully in children with other types of blood cancer caused by EBV after bone marrow transplantation.
Some patients with Hodgkin disease or non-Hodgkin Lymphoma show evidence of infection with the virus that causes infectious mononucleosis Epstein Barr virus (EBV) before or at the time of their diagnosis of Lymphoma. EBV is often found in the cancer cells suggesting that it may play a role in causing Lymphoma. The cancer cells infected by EBV are very clever because they are able to hide from the body's immune system and escape destruction. We want to see if we can grow special white blood cells, called T cells, that have been trained to kill EBV infected cells and give them back to subjects.

Start Date01 Jan 1996

Sponsor / Collaborator

Baylor College of Medicine

[+2]

100 Clinical Results associated with TT-10x

100 Translational Medicine associated with TT-10x

100 Patents (Medical) associated with TT-10x

Literatures (Medical) associated with TT-10x

01 Mar 2021·European Journal of Pharmaceutical SciencesQ2 · MEDICINE

Mechanistic prediction of first-in-human dose for bispecific CD3/EpCAM T-cell engager antibody M701, using an integrated PK/PD modeling method

Q2 · MEDICINE

Review

Author: Zhang, Jing ; Liu, Dongyang ; Li, Si ; Xue, Junsheng ; Zhou, Tianyan ; Song, Ling

AIMM701 is a bispecific CD3/EpCAM T-cell engager antibody to treat malignant ascites. This study aimed to predict in vivo exposure-cytotoxicity relationship and human pharmacokinetics (PK) characteristics of M701, as well as to design optimal starting dose and effective dose for M701 first-in-human (FIH) study.METHODMechanistic in vitro PK/PD model was firstly developed based on in vitro data of M701's cytotoxicity and binding affinities with targeting receptors. The cell killing effect of M701 in vitro was driven by tri-molecular synapse, which formed by binding drug to both CD3 receptor on T cells and EpCAM receptor on tumor cells. Human exposure-response (E-R) curve in ascites was estimated using the same model structure with clinical systemic model parameters. Human PK was predicted by allometrically scaling monkey PK data, which was characterized using a two compartment model. Human PK model was integrated into in vivo synapse-based cell killing model to provide human PK/PD characteristics. Integrated human PK/PD model was applied in FIH dose design. Clinical starting dose and effective dose were suggested as the simulated drug concentration in human ascites that achieved the estimated in vivo minimally anticipated biological effect level (MABEL) and pharmacologically active level. Other approaches including PK-driven and receptor occupancy calculation were also employed in this study to verify the starting dose prediction.RESULTSIn vitro M701 cytotoxicity curves under 24, 48, 72 h incubations were well captured by mechanistic synapse-based cell killing model. Human E-R curve in ascites was obtained based on in vitro model structure and clinical systematic parameters. We defined 10~20% and 80% of maximum cytotoxicity effect as in vivo MABEL and pharmacologically active level. Human E-R curve indicated in vivo EC₁₀, EC₂₀ and EC₈₀ were 0.56, 1.26 and 31.6 ng/mL. For human PK model, clearance (CL, CL_d), distribution volumes (V_c, V_p) and absorption rate were allometrically scaled using exponent of 0.9, 1 and -0.25. Predicted clearance and volume were 0.53- and 1.19-fold of observed data. Simulated average ascites M701 concentrations (calculated as C_{ave_ ascites} = AUC_τ/τ) were 0.81 and 32.5 ng/mL under dose of 5 and 200 μg within 2-hour i.p. infusion. By integrating human E-R curve and the simulated PK profile in ascites, we suggested 5 and 200 μg within 2-hour i.p. infusion as MABEL dose and pharmacologically active dose (PAD) for M701 FIH study. PK-driven approach predicted a starting dose of 5 μg, which was comparable to that predicted via PK/PD-driven approach.CONCLUSIONSThis study predicted human ascites PK and E-R curve by integrating human PK model into in vivo synapse-based cell killing model. Optimal clinical MABEL dose and PAD of bispecific T cell engager antibody M701 were suggested based on current integrated PK/PD approach.

01 May 2019·The Journal of Clinical PharmacologyQ3 · MEDICINE

Pharmacokinetics, Pharmacodynamics, and Safety of E6011, a Novel Humanized Antifractalkine (CX3CL1) Monoclonal Antibody: A Randomized, Double‐Blind, Placebo‐Controlled Single‐Ascending‐Dose Study

Q3 · MEDICINE

Article

Author: Yasuda, Nobuyuki ; Ieiri, Ichiro ; Imai, Toshio ; Aoyama, Muneo ; Katsurabara, Toshinori ; Obara, Takashi ; Kawano, Tetsu ; Kumagai, Yuji ; Tabuchi, Hiroko ; Mori, Masahiko

AbstractE6011 is a novel humanized antifractalkine (FKN) monoclonal antibody being developed as a therapeutic target for Crohn's disease, rheumatoid arthritis, and primary biliary cholangitis. This study was a randomized, double‐blind, placebo‐controlled single‐ascending‐dose study of intravenous administration of E6011 (0.0006‐10 mg/kg) in healthy Japanese adult men (n = 64). The starting dose was the minimum anticipated biological effect level (MABEL). MABEL was estimated by extrapolating results of a pharmacokinetic/pharmacodynamic (PK/PD) model relating E6011 exposure and suppression of free soluble FKN using data obtained from cynomolgus monkeys. Safety assessments consisted of monitoring and recording adverse events, laboratory tests, vital signs, intensive electrocardiograms, and chest x‐rays. Blood samples to determine PK, PD (serum total FKN concentration), and serum anti‐E6011 antibody were collected. Noncompartmental analysis was used to derive PK parameters. Single intravenous infusions of E6011 were safe and well tolerated in healthy subjects. Serum E6011 concentrations showed triphasic elimination. An increase in serum total FKN concentration was observed, confirming target engagement. The dose strategy for patient studies is to select regimens that will attain a minimum serum E6011 exposure of 10 μg/mL, identified as the minimum concentration needed to saturate the target‐mediated elimination pathway. Model‐based drug development from preclinical stage was successful in identifying dose regimens for clinical testing.

01 Sep 2016·Clinical Pharmacology & TherapeuticsQ2 · MEDICINE

Mechanistic Projection of First‐in‐Human Dose for Bispecific Immunomodulatory P‐Cadherin LP‐DART: An Integrated PK/PD Modeling Approach

Q2 · MEDICINE

Article

Author: Barletta, F ; Li, H ; Clark, T ; Chen, X ; Betts, AM ; Xuan, D ; Haddish‐Berhane, N ; Moore, P ; Yang, Y ; Barton, HA

A bispecific immunomodulatory biotherapeutic molecule (P‐cadherin LP‐DART) based on the Dual Affinity Re‐Targeting (DART) scaffold has been developed as a potential antitumor treatment showing efficacy in preclinical testing. A minimal anticipated biological effect level (MABEL) approach was applied to project the first‐in‐human (FIH) dose, because of its immune agonistic properties following target engagement. The pharmacological activity of P‐cadherin LP‐DART is driven by binding to both P‐cadherin on the tumor cells and CD3 on T cells. Therefore, the concentration of the tri‐molecular synapse formed between drug, T cell, and tumor cell, rather than drug concentration, is responsible for efficacy. A mechanistic pharmacokinetic/pharmacodynamic (PK/PD)‐driven approach was explored to understand the exposure–response relationship based on the synapse concentration to project the MABEL dose. Orthogonal approaches including PK‐driven and receptor occupancy calculations were also investigated. This study showcases the application of PK/PD modeling in immune‐oncology, and could potentially be implemented for other bispecific biotherapeutics.

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced Nasopharyngeal Carcinoma	Phase 3	TH	Tessa Therapeutics Ltd	01 Jul 2014
Advanced Nasopharyngeal Carcinoma	Phase 3	TW	Tessa Therapeutics Ltd	01 Jul 2014
Advanced Nasopharyngeal Carcinoma	Phase 3	US	Tessa Therapeutics Ltd	01 Jul 2014
Advanced Nasopharyngeal Carcinoma	Phase 3	MY	Tessa Therapeutics Ltd	01 Jul 2014
Advanced Nasopharyngeal Carcinoma	Phase 3	SG	Tessa Therapeutics Ltd	01 Jul 2014
Nasopharyngeal Carcinoma	Phase 3	TW	Tessa Therapeutics Ltd	01 Jul 2014
Nasopharyngeal Carcinoma	Phase 3	TH	Tessa Therapeutics Ltd	01 Jul 2014
Nasopharyngeal Carcinoma	Phase 3	SG	Tessa Therapeutics Ltd	01 Jul 2014
Nasopharyngeal Carcinoma	Phase 3	MY	Tessa Therapeutics Ltd	01 Jul 2014
Nasopharyngeal Carcinoma	Phase 3	US	Tessa Therapeutics Ltd	01 Jul 2014

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02578641 (VANCE, Pubmed \| Ann Oncol) Manual	Phase 3	Nasopharyngeal Carcinoma First line	330	Gemcitabine + carboplatin + EBV-CTL	(ponckpdhfk) = sztnqytvir yeccaupqqx (zkdfbvmuii )	Negative	01 Sep 2024
				Gemcitabine+carboplatin	(ponckpdhfk) = halmyedjef yeccaupqqx (zkdfbvmuii )

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