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1 injection One of the following 4 dose levels: 2x 10\^7 cells/m2, 1x 10\^8 cells/m2, 3 x 10\^8 cells/m2, 1 x 10\^9 cells/m2

LMP1 SPECIFIC CYTOTOXIC T-LYMPHOCYTES

LMP2-SPECIFIC CYTOTOXIC T-LYMPHOCYTES

MALCOLM K BRENNER, MD

The purpose of this study is to obtain blood (up to 90 ml or 18-teaspoonfuls on one or two occasions) to make LMP1- and LMP2-cytotoxic T-lymphocytes and grow them in the laboratory in such a way that they are able to attack LMP1- and LMP2-positive cells in the laboratory.

If we are successful in growing these cells and if we feel they would be helpful to the donor, we would then give the cells back to the donor.

This trial is for patients that have a type of lymph gland cancer called Hodgkin or non-Hodgkin lymphoma, or chronic active Epstein Barr virus (EBV) infection, which has come back or not gone away after treatment, including the best treatment we know.

This is a research study using special immune system cells called LMP1- and LMP2-specific cytotoxic T lymphocytes (LMP1- and LMP2-CTLs), a new experimental therapy. As in chronic active EBV infection, some patients with Hodgkin or non-Hodgkin lymphoma show evidence of infection with the virus that causes infectious mononucleosis (EBV) before or at the time of their diagnosis of the Lymphoma. EBV is found in the cancer cells of up to half the patients with lymphoma, suggesting that it may play a role in causing lymphoma. The cancer cells infected by EBV are able to hide from the body's immune system and escape destruction. We want to see if special white blood cells, called T cells, that have been trained to kill EBV infected cells can survive in the patient's blood and affect EBV-positive cells. In this present study we are trying to find out if we can improve this treatment by growing T cells that only recognize two of the proteins expressed on lymphoma cells called LMP1 and LMP2. These special T cells are called LMP1- and LMP2-specific cytotoxic CTLs.

Infusions of CD45 MAbs A fixed dose of CD45 MAbs will be used determined from our previous and ongoing studies in stem cell transplant recipients will be used 40, 400ug/kg over 6 to 8 hrs daily x 4 given as daily intravenous infusions that will be completed 48-72 hours prior to CTL infusion. Patients will be premedicated prior to CD45 infusions and monitored as per the SOP for CD45 MAbs infusion.

Day 1 through Day 4: YTH 24/54 400ug/kg over 6 to 8 hr; Day 5: Rest; Day 6, 7 or 8: CTL Infusion (provided CD45 Mab level \<100 ng/ml)

Preparation of the Patient:

Oxygen and suction equipment must be available in the room. Emergency drugs (Benadryl, Epinephrine, solucortef to solumedrol) in appropriate doses must be preordered by the physician prior to initiation of each infusion with doses available. A code card containing the appropriate doses of each medicine according to the patient's weight will also be available. Continuous telemetric monitoring by pulse oximeter and EKG will begin prior to and for 6 hours after each antibody infusion has taken place. Baseline vital signs are taken and recorded and monitored as per the SOP for antibody infusions.

MAbs Infusion:

The antibody aliquot to be infused will arrive in the treatment area hand-carried by the attending physician or appointed designate.

The antibody aliquot will be diluted in minimal amounts of normal saline. The resulting solution is stable for 24 hours.

The antibody solution is administered by a syringe pump in incremental doses, 0.2-0.8 mg in the first hour and up to 10 mg/hr thereafter, for a maximum infusion time of 8 hrs. A registered nurse and a physician must be readily available

Antibody toxicity:

Volume Overload: This is of particular importance in small recipients and will be monitored carefully.

Inflammatory mediator release from damaged circulating white cells and allergic reactions: Fever, chills, rigors, pruritis, urticaria, nausea, vomiting, throat tightness and dyspnea may occur. These reactions usually respond to slowing or stopping the infusion and/or the parenteral administration of diphenhydramine, hydrocortisone, meperidine or anti-emetics. Administration of O2, epinephrine, bronchodilators or IPPB may be necessary.

Adverse effects of CD45 MAbs on CTL Our experience to date has shown rapid clearance of CD45 MAbs from the plasma, such that levels are undetectable by 24-48hrs after infusion. However, the MAb levels will be measured before CTL infusion and if free plasma CD45 MAbs are present CTL infusion will be deferred for 24 hours

CTL Infusion:

Dose Levels of CTLs: The following dose levels will be evaluated: Each patient will receive 1 injection, according to the following dosing schedules:

Dose level I: 2 x 10e7 cells/m2; Dose level II: 1 x 10e8 cells/m2; Dose level III: 3 x 10e8 cells/m2; Dose level IV: 1 x 10e9 cells/m2. Patients will be pre-medicated with Benadryl 1mg/kg IV (max 50mg) and Tylenol 10mg/kg po (max 650mg).

Cell Administration: LMP1- and LMP2-specific T cells will be given by intravenous injection over 1-10 minutes through either a peripheral or a central line.

Lmp1 and Lmp2 Specific CTLs Following Cd45 Antibody for Relapsed Ebv-Positive Hodgkin's Or Non-Hodgkin's Lymphoma

Administration of LMP1- and LMP2- Specific Cytotoxic T-Lymphocytes Following CD45 Antibody to Patients With Relapsed EBV-Positive Hodgkin's or Non-Hodgkin's Lymphoma or Chronic Active EBV Infection (ALDI)

The Methodist Hospital Research Institute

Baylor College of Medicine

Principal Investigator

Hematologic Neoplasms

Disease Attributes

Hematologic Diseases

Each subject receive LMP1 CAR T-cells by intravenous infusion

LMP1 CAR T-cells

He Huang, PhD

Yongxian Hu, PhD

A study of LMP1 CAR-T for patients with LMP1 positive infectious diseases and hematological malignancies

This is a single arm, open-label, single-center study. This study is indicated for LMP1 positive infectious diseases and hematological malignancies. The selections of dose levels and the number of subjects are based on clinical trials of similar foreign products. 144 patients will be enrolled. Primary objective is to explore the safety, main consideration is dose-related safety.

LMP1 CAR-T for Patients With LMP1 Positive Infectious Diseases and Hematological Malignancies

Clinical Trial for the Safety and Efficacy of Sequential of LMP1 CAR-T for Patients With LMP1 Positive Infectious Diseases and Hematological Malignancies

Adverse events assessed according to NCI-CTCAE v5.0 criteria

Incidence of treatment-emergent adverse events \[Safety and Tolerability\]

Assessment of ORR (ORR = CR + PR) at Month 1, 3, 6, 12, 18 and 24

From the first remission after LMP1 CAR-T cells to relapse, death or the last visit

From the first infusion of LMP1 CAR-T cells to death or the last visit

From the first remission after LMP1 CAR-T cells to relapse or the last visit

From the first infusion of LMP1 CAR-T cells to the occurrence of any event, including death, relapse or gene relapse, disease progression (any one occurs first), and the last visit

Assessment using European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) scale \[For item1-28: max score: 112, min score: 28, higher scores mean a better outcome; for item 28-29: max score: 14, min score: 2, higher scores mean a worse outcome\] to measure Quality of life at Baseline, Month 1, 3, 6, 9 and 12

Assessment using Activities of Daily Living (ADL) scale (Barthel Index) \[max score: 100, min score: 0, higher scores mean a better outcome\] at Baseline, Month 1, 3, 6, 9 and 12

Assessment of Instrumental Activities of Daily Living (IADL) scale \[max score: 56, min score: 14, higher scores mean a worse outcome\] at Baseline, Month 1, 3, 6, 9 and 12

Assessment using Hospital Anxiety and Depression Scale (HADS) \[max score: 42, min score: 0, higher scores mean a worse outcome\] at Baseline, Month 1, 3, 6, 9 and 12

Yake Biotechnology Ltd.

Zhejiang University

Clinical Professor

Mouth and Tooth Diseases

Ear, Nose, and Throat Diseases

Carcinoma

Nasopharyngeal Carcinoma

Neoplasms, Glandular and Epithelial

Nasopharyngeal Neoplasms

Pharyngeal Neoplasms

Otorhinolaryngologic Neoplasms

Head and Neck Neoplasms

Nasopharyngeal Diseases

Pharyngeal Diseases

Stomatognathic Diseases

Otorhinolaryngologic Diseases

DZ1 group receives DZ1 intratumoral injection in combination with radiation therapy.

Placebo group receives saline injection in combination with radiation therapy.

DZ1 in saline is administrated by intratumoral injection two hours prior to radiation therapy from week 1 to week 7 on Monday and Thursday. Dosage for each injection is 12 mg in 0.1 mL (200 micrograms per kilogram body weight.

The radical radiotherapy is given to patients 5 times per week with 2 Gy of each treatment. The entire procedure lasts seven weeks.

DNAzyme targeting EBV-LMP1 (DZ1)

0.1 mL of saline is administrated by intratumoral injection two hours prior to radiation therapy from week 1 to week 7 on Monday and Thursday.

The radical radiotherapy is given to patients 5 times per week with 2 Gy of each treatment. The entire procedure lasts seven weeks.

Saline

Lun-Quan Sun, PhD

The purpose of this study is to determine whether an EBV-LMP1 targeted DNAzyme is effective in radiosensitization of nasopharyngeal carcinoma in combination with standard radiation therapy.

INTRODUCTION Nasopharyngeal carcinoma (NPC) is a serious health problems worldwide, particularly in the southern Chinese population, with an incidence rate ranging from 15 to 50 per 100 000. NPC is an epithelial malignancy with a striking racial and geographic distribution differences. High incidence rates are observed in the southeast Chinese population, and similar rates have been reported in these people wherever they have migrated, including Singapore, Taiwan, and Hong Kong. This incidence is almost 100 fold higher than in white populations. The most unique feature of NPC is its almost universal association with the infection of Epstein-Barr virus (EBV), which is the first human virus identified to be involved in the pathogenesis of several malignancies and has a particularly close association with NPC, as EBV genome can be detected in virtually all NPC cells. While radiotherapy has been the first-line treatments for NPC, radio-resistance remains a significant clinical issue for the NPC radiotherapy. Thus, there is unmet medical needs to discover and develop novel radiosensitizers for NPC therapy.

EBV infection in NPC is classified as type II latent infection in which only EBV nuclear antigen-1(EBNA-1), latent membrane protein-1(LMP1), LMP2, and EBV early RNA (EBER) expressions can be detected. Among these proteins, LMP1 is thought to play a key role in the pathogenesis of NPC. As a 60kD integral membrane protein, LMP1 functions as a constitutively active tumor necrosis factor receptor (TNFR), and contributes to multiple aspects of NPC through activating a number of signaling pathways including nuclear factor NF-κB, activator protein-1(AP-1), and Janus kinase/signal transducer and activator of transcription(JAK/STAT). Activation of NF-kB or AP-1 by LMP1 has been linked to the upregulation of some cellular proteins and inhibition of apoptosis. Depending on the cell types, expression of LMP1 has been shown to play different roles in response to biological and physiological stimulus. It acts as a primary oncoprotein for human cell immortalization and is also shown as the only EBV-coded product that can transform rodent fibroblast cell line, human epithelial cells and keratinocytes.

Given the critical role of viral oncoproteins in transformation and apoptosis, suppression of some viral oncoproteins would provide a sensible strategy to genetically treat NPC. Indeed, antisense oligonucleotides against LMP1 or EBNA1 have been shown to inhibit viral oncoprotein expression, induce apoptosis, and sensitize the EBV-positive cells to cytotoxic agents. Recently, some experimental studies indicated that the RNA interference against LMP1 exhibited an anti-proliferative and anti-metastasis effect in LMP1 expressing NPCs. These results suggested that EBV-encoded LMP1 may present a potential molecular target for treatment of EBV-associated carcinomas.

DNAzymes are synthetic, single-stranded DNA oligonucleotides that can be engineered to bind to their complementary sequence in a target messenger RNA (mRNA) through Watson-Crick base pairing and cleave the mRNA at predetermined phosphodiester linkages. A general model for the DNAzyme has been proposed, and is known as the ''10-23'' model. A ''10-23'' DNAzyme has a catalytic domain of 15 deoxyribonucleotides, flanked by two substrate-recognition domains of seven to nine deoxyribonucleotides at each arm. In vitro analyses showed that this type of DNAzyme could effectively cleave its substrate RNA at purine: pyrimidine junctions under physiological conditions. These agents have been used in a number of in vitro and in vivo applications to inhibit the expression of their target genes and the dependent genes. Their capacity to block development of a diverse range of pathologies in animal models suggests that DNAzymes can be used as therapeutic agents.

To develop EBV-LMP1 targeted DNAzymes for NPC treatment, we showed that the phosphorothioate-modified ''10-23'' DNAzymes specifically targeted at the LMP1 mRNA could significantly down-regulate the expression of LMP1 in a nasopharyngeal carcinoma cell (NPC) and affected the down-stream pathways activated by LMP1, including the NF-κB pathway. It was also demonstrated that suppression of the LMP1 expression by the LMP1-targeted DNAzyme DZ1 could enhance radiosensitivity both in vivo and vitro. Radio-resistance has been one of the impediments in clinical settings for effective cancer therapy, which is thought to be associated with multiple signaling pathways in different cancer types. ATM (ataxia telangiectasia mutated) is a nuclear 350-kDa protein kinase with a carboxylterminal phosphatidylinositol 3-kinase-like kinase domain\[1\]. It functions as a member of a coordinated system that detects DNA breaks; arrests the cells temporarily at G1, S, or G2 checkpoints; and activates DNA repair. Cells lacking functional ATM protein show increased sensitivity to ionizing radiation (IR) and other genotoxic events. NF-κB (nuclear factor kappa B) can activate a great number of genes involved in stress responses, inflammation, and programmed cell death (apoptosis). P50 homodimers or p50/p65 or p50/c-Rel heterodimers bind to the NF-κB DNA binding sites in the promoter regions of many stress-responsive genes, suggesting a complex gene and physiological regulation network controlled by NF-κB in stress response. The elevated basal NF-κB activity in certain cancers has been linked to tumor resistance to chemotherapy and radiation. Inhibition of NF-κB blocked the adaptive radioresistance. Our studies for the molecular mechanism of the LMP1-DNAzyme mediated radiosensitization revealed that LMP1 activated the ATM expression through the NF-κB pathway and inhibition of LMP1 expression by the DNAzyme attenuated the binding of NF-κB transcription factor to the ATM promoter. Further evidence showed that the radiosensitivity was recovered when the ATM expression was knocked down by siRNA in NPCs. Together, all our data support our hypothesis and provide solid experimental basis for the use of LMP1-targeted DNAzymes as potential radiosensitizers for treatment of the EBV-associated carcinomas.

Toxicological studies in mice showed that no morbidity or mortality was observed in any of the dosing groups during the course of the study (50mg, 100mg, and 200mg/kg). All hematological values and biochemistry results from tests of hepatic and renal function were normal. No microscopic lesion that could be attributed to the modified DNAzyme oligonucleotide treatment was found in liver, spleen and kidney in any groups. After i.v. administration of 100 mg/kg DNAzyme oligonucleotide in mice, the peak plasma concentration of 24.13±2.6μg/ml was achieved. The decrease in plasma concentration of DNAzyme followed a bi-exponential pattern with initial distribution half-life (t1/2α) of 0.18±0.03 h and a terminal half-life (t1/2β) of 2.55±1.0 h, and area under the plasma concentration-time curve (AUC) was 54.17±9.1μg.h/ml.

STUDY DESIGN This study will be a randomized, double-blinded and placebo controlled Phase I/II clinical trial. Forty (40) patients will be randomized to one of two groups of equal size: placebo group receiving saline by intra-tumor injection and standard radiotherapy; or DZ1 group receiving LMP1 DNAzyme (DZ1) and standard radiotherapy. The placebo group will provide the basis for assessment of safety and efficacy of DZ1.

Patients receive placebo or DZ1 injection two (2) hours prior to radical radiation therapy on Monday and Thursday over seven weeks. The radical radiotherapy is given to patients 5 times per week with 2 Gy of each treatment. The entire procedure lasts seven weeks.

All patients will complete the study at 104 weeks post-first injection. The patients will undergo assessment and testing every week in the first seven weeks, then every three months from the weeks 8 to week 104.

The study will include evaluations of safety and tolerability:

Clinical Study of EBV-LMP1 Targeted DNAzyme to Treat Nasopharyngeal Carcinoma

Phase I/II Study of EBV-LMP1 Targeted DNAzyme in Nasopharyngeal Carcinoma

Tumor growth is measured using MRI weekly from week 1 to week 7, followed by six-monthly measures until week 104.

Tumor vasculature permeability is measured using DCE-MRI from week 1 to week 52. EBV DNA copies are measured monthly up to 24 months.EBV cpoies are measured by quantitative PCR.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Lmp1 and Lmp2 Specific CTLs Following Cd45 Antibody for Relapsed Ebv-Positive Hodgkin's Or Non-Hodgkin's Lymphoma	NCT00383097	Hodgkins Lympho... Non-Hodgkin Lym...	LMP1 SPECIFIC C... LMP2-SPECIFIC C...	-	Baylor College of Medicine
LMP1 CAR-T for Patients With LMP1 Positive Infectious Diseases and Hematological Malignancies	NCT04657965	Infectious Dise... Hematological M...	LMP1 CAR T-cell...	-	Zhejiang University
Clinical Study of EBV-LMP1 Targeted DNAzyme to Treat Nasopharyngeal Carcinoma	NCT01449942	Nasopharyngeal ...	DNAzyme targeti... Saline	-	Xiangya Hospital of Central South University

Spots Global Cancer Trial Database for lmp1

Every month we try and update this database with for lmp1 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for lmp1

Every month we try and update this database with for lmp1 cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for lmp1 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.