Neoplasms

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Rare Diseases

Lymphoma

Lymphoma, Non-Hodgkin

Hodgkin Disease

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphosarcoma

Hodgkin Lymphoma

Camurati-Engelmann Disease

CTLs be given by intravenous injection over 1-10 minutes through either a peripheral or a central line.

If patients with active disease have stable disease or a partial response at their 6 week or subsequent evaluations they will be eligible to receive up to 6 additional doses of CTLs at 1-2 monthly intervals-each of which will consist of the same cell number as their second injection.

Each patient will receive 2 injections, 14 days apart, according to the following dosing schedules:

Group One:

Day 0 2 x 10\^7 cells/m2 Day 14 2 x 10\^7 cells/m2

Group Two:

Day 0 6 x 10\^7 cells/m2 Day 14 6 x 10\^7 cells/m2

Group Three:

Day 0 1.5 x 10\^8 cells/m2 Day 14 1.5 x 10\^8 cells/m2

TGFbeta resistant LMP-specific CTLs

Helen E Heslop, MD

Patients have a type of lymph gland cancer called HD, NHL or lymphoepithelioma (these 3 diseases will be referred to as "Lymphoma"). The lymphoma has come back or has not gone away after treatment. This is a research study using special immune system cells called TGFb-resistant LMP-specific cytotoxic T lymphocytes (DNR-CTL), a new experimental therapy.

Some patients with Lymphoma show signs of infection with the Epstein Barr virus (EBV) before or at the time of their Lymphoma diagnosis. EBV is found in the cancer cells of up to 1/2 the patients with Lymphoma, suggesting 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 being killed by releasing a substance called Transforming Growth Factor-beta (TGFb). The investigators want to see if special white blood cells (called T cells) that have been given a gene that they hope will let them survive against TGFb and that have been trained to kill EBV infected cells can also survive in the blood and kill the tumor.

Investigators have used this sort of therapy with specially trained T cells to treat a different type of cancer that occurs after bone marrow and solid organ transplant called post transplant lymphoma. In this type of cancer they were able to successfully prevent and treat post transplant lymphoma. However when they used a similar approach in HD some patients had a partial response to this therapy, but no patients had a complete response. In a follow-up study they tried to find out if they could improve this treatment by growing T cells that recognize 2 of the proteins expressed on Lymphoma cells called LMP-1 and LMP2a. These special T cells were called LMP-specific cytotoxic T-lymphocytes (CTLs). Although some patients had tumor responses, CTL therapy alone did not cure those who had a lot of disease. Investigators think that a reason for this is that the tumor cells are releasing TGFb. For this reason, they want to find out if they can make the CTL resistant to TGFb by putting in a new gene called TGFb resistance gene. Investigators hope that this will improve this treatment for relapsed lymphoma. These TGFb-resistant LMP-specific CTLs are an investigational product not approved by FDA.

The purpose of this study is to find the largest safe dose of TGFb resistant LMP-specific CTLs, to learn what the side effects are and to see whether this therapy might help patients with Lymphoma.

Investigators will test a biopsy of the tumor to see if the tumor cells are EBV positive and to see if the subject is eligible for this study. Then they will take some blood from the donor, which is used to grow T cells. First they will grow a special type of cell called dendritic cells (or monocytes), which stimulates the T cells and add a specially produced human adenovirus that carries the LMP1 and LMP-2a genes into the dendritic cells(or monocytes). Addition of a gene to the cells is known as gene transfer. These dendritic cells (or monocytes) are then used to stimulate T cells. The stimulation trains the T cells to kill cells with LMP on their surface. Investigators will then make more LMP-specific CTLs by stimulating them with EBV infected cells (which we will make from the subject's blood or the donor's blood by infecting them with EBV in the laboratory). They also will put the adenovirus that carries the LMP1 and LMP2 genes into these EBV infected cells so that they increase the amount of LMP1 and LMP2, which these cells have.

These EBV infected cells are treated with radiation so they cannot grow. Once sufficient numbers of T cells are made, investigators test them to see if they kill cells with LMP on their surface. To make sure that these cells won't attack the subjects tissues they test the cells against the skin cells or against T cells that they grow in the laboratory.

To make these CTL resistant to the effects of the TGFb released by the tumor we put in a new gene called a mutant TGFb receptor. Investigators used a mouse retrovirus that had been changed to stop it from causing infection to add the mutant TGFb receptor to the cells.

WHAT THE INFUSION WILL BE LIKE:

After the cells are made, they will be frozen. If the subject agrees to participate in this study, at the time they are scheduled to be treated, the cells will then be thawed and injected into the subject over 10 minutes.

Initially two doses of T cells will be given two weeks apart. If after the second infusion, there is a reduction in the size of the subject's lymphoma (or no increase) on CT or MRI scans as assessed by a radiologist, the subject can receive up to six additional doses if it would be to their benefit, if they would like to receive more doses, and if there is enough product remaining to give them additional doses.

This is a dose escalation study as investigators don't know what the highest dose of T cells with the new gene is safe. To find out, they will give the cells to 2 participants at one dose level. If that is safe they will raise the dose given to the next group of participants. The dose the subject will get will depend on how many participants get the agent before and how they react. The investigator will tell the subject this information.

All of the Treatments will be given by the Center for Cell and Gene Therapy at Texas Children's Hospital or Houston Methodist Hospital.

FOLLOW-UP STUDIES We will follow the subject after the injections. Total time participation for this study will be 15 years.

Autologous/Allogeneic TGFbeta-resistant LMP-specific CTL, Lymphoma (TGF-beta)

Administration of TGF-b Resistant LMP-Specific Cytotoxic T-Lymphocytes to Patients With Relapsed EBV-Positive Lymphoma

Number of patients with Dose-Limiting Toxicity (DLT).

Mean number of T cells transduced with vector.

Summarize tumor response by calculating overall response rates.

The Methodist Hospital Research Institute

Center for Cell and Gene Therapy, Baylor College of Medicine

Baylor College of Medicine

Professor

Infections

Symptoms and General Pathology

Leukemia

Hematologic Neoplasms

Communicable Diseases

Cytomegalovirus Infections

Herpesviridae Infections

Virus Diseases

DNA Virus Infections

Cytomegalic Inclusion Disease

CTL product given as single infusion within 72 hours of CMV reactivation. CTL dose infused will be at a maximum dose of 10e5 viable CD3+ T cells/kg.

Cytomegalovirus (CMV)-Specific Cytotoxic T Cells (CTLs)

Betul Oran, MD

The goal of this clinical research study is to learn if giving cytotoxic T lymphocytes (CTLs) can help control CMV when it reactivates (becomes active again) in patients who receive an allogeneic stem cell transplant. Researchers also want to learn about the safety of giving CTLs to patients who have had a stem cell transplant.

The CTLs:

Blood (about 34 tablespoons) will be drawn 1 time. The blood will be frozen and stored in a laboratory at MD Anderson for future use to make the CTLs. If CMV comes back after your transplant, the blood will be used to create CTLs. To create CTLs, blood cells are grown in the laboratory and trained to kill CMV. If the blood is not used to make the CTLs within 3 years, it will be destroyed.

CTL Administration:

If your CMV becomes active after your stem cell transplant, you will receive the CTLs through a needle in your vein over 1-5 minutes one time, within 72 hours after CMV becomes active again. Before you receive the CTLs, you will receive Benadryl (diphenhydramine) and Tylenol (acetaminophen) by mouth to help reduce the risk of side effects. This can be done in either the hospital (if not yet discharged after your transplant) or in the outpatient clinic (if you are discharged).

Your vital signs will be monitored at the end of the infusion, and then at 30 and 60 minutes after the infusion. Your oxygen level will be measured by pulse oximetry. For this test, a clothespin-shaped clip will be placed on your finger for at least 30 minutes. If you are an outpatient, you will remain in the clinic for at least 1 hour after the CTL infusion.

If the CMV does not become active again after your stem cell transplant, you will not receive the CTL infusion.

Study Visits:

If the CMV does not become active again after your stem cell transplant, you will not receive the CTL infusion and your follow-up care will be done as per post-transplant standard of care.

If you receive the CTL infusion, you will have the tests/procedures listed below.

Within 48 hours before the CTL infusion:

* You will have a physical exam.
* Blood (about 6 tablespoons) will be drawn for routine tests and to check your kidney and liver function. Part of blood draw will be used for a pregnancy test for women who are able to become pregnant. To take part in this study, you must not be pregnant.

Once a week for 4 weeks, blood (about 4-8 tablespoons) will be drawn to check the level of CMV infection in your body. This may be done more often, if you doctor thinks it is needed.

About 1, 2, 3, and 4 weeks, and then about 3, 6, and 12 months after the CTL infusion:

* You will have a physical exam.
* Blood (about 4 tablespoons) will be drawn for routine tests and to check your kidney and liver function.

Blood (about 4 tablespoons) will be drawn for tests to learn more about the way the CTLs are working and how long they last in the body. This blood will be drawn before the CTL infusion, and then about 2 weeks, 4 weeks, 3 months, and 6 months after the CTL infusion. If possible, the blood needed for these tests will be collected during blood draws for routine tests so that no additional needle sticks will be needed.

Follow-Up Visits:

Once a week for 6 weeks, and then about 3, 6, 9, and 12 months after the CTL infusion, you will be checked for signs of graft-versus-host disease (GVHD) at every clinic visit. You were told about GVHD at the time of being prepared for transplant.

Length of Study:

Your participation on this study will end after your last follow-up visit about 12 months after the CTL infusion.

This is an investigational study. The use of CTLs to treat CMV infection is not FDA approved. At this time, CTLs are only being used to treat infections in research studies.

Up to 105 patients will take part in this study. All will be enrolled at MD Anderson.

Autologous Cytomegalovirus (CMV)-Specific Cytotoxic T Cells for Cytomegalovirus (CMV) Reactivation

The Pre-Emptive Use of Recipient-Derived Autologous Cytomegalovirus (CMV)-Specific Cytotoxic T Cells for Cytomegalovirus (CMV) Reactivation After Allogeneic Stem Cell Transplantation

Non-relapse mortality defined as death because of causes other than relapse of the underlying hematological malignancy.

Treatment considered a success if the patient does not require initiation of cytomegalovirus (CMV) anti-viral therapy.

Miltenyi Biotec B.V. & Co. KG

M.D. Anderson Cancer Center

Death, serious adverse events, and other (non-serious adverse events) were not assessed for the study.

CTL product given as single infusion within 72 hours of CMV reactivation. CTL dose infused will be at a maximum dose of 10e5 viable CD3+ T cells/kg.

Cytomegalovirus (CMV)-Specific Cytotoxic T Cells (CTLs): CTL product given as single infusion within 72 hours of CMV reactivation. CTL dose infused will be at a maximum dose of 10e5 viable CD3+ T cells/kg.

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

United States

Region of Enrollment

Dr. Betul Oran / Associate Professor, Stem Cell Transplantation

Number of Participants With Non-Relapse Mortality

Success Rate of Cytotoxic T Cells

Overall Study

Nervous System Diseases

Glioblastoma

Brain Neoplasms

Astrocytoma

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

All Drugs and Chemicals

Immunomodulating Agents

Immunologic Factors

3 doses of ALECSAT cell based immunotherapy planned for all enrolled patients

I.V. injected Cell Based Medicinal Product, containing between 10 million and one billion autologous Cytotoxic T cells and Natural Killer cells.

ALECSAT cell based immunotherapy

Martin R Jensen, PhD

It is the primary objective of this study to show safety and tolerability for administration of the cell based immunotherapy ALECSAT to patients with Glioblastoma brain cancer. It is a secondary objective to establish if any indications of positive therapeutic or palliative effects may be observed.

The primary objective for this study is to establish if any side effects or toxicity issues occur, that will prevent further clinical development of the autologous cell based immunotherapy ALECSAT in Glioblastoma (GBM) or to establish if there are side effects or toxicity issues, that will suggest that the further clinical development planned, has to change course significantly. It is a primary objective to show safety and tolerability for administration of ALECSAT, thus not meeting this endpoint, may stop further clinical development of ALECSAT.

The secondary objective for this study is to establish if any indications of a positive therapeutic or palliative effect may be observed. As this is a secondary objective, no observed significant positive clinical effect, will not prevent further clinical development or in itself, trigger changes in the further clinical development planned.

The overall endpoint of the study is to develop a new therapeutic approach that may slow down or stop disease progression in late stage GBM patients.

ALECSAT is an autologous cell based immunotherapy based on the patient's own Natural Killer cells and CytoToxic T cells. The cells are isolated from the patient's own blood - activated and expanded in number before re administering i. v.

A Phase I Study to Investigate Tolerability and Efficacy of ALECSAT Administered to Glioblastoma Multiforme Patients

A Phase I Study to Investigate Tolerability and Efficacy of Autologous Lymphoid Effector Cells Specific Against Tumour-cells (ALECSAT) Administered to Patients With Glioblastoma Multiforme (GBM)

A total of 4 scanannings are performed during the study: 2 PET-MRI scans and 2 SPECT (Single-photon emission computed tomography) scans.

CytoVac A/S

Mouth and Tooth Diseases

Ear, Nose, and Throat Diseases

Musculoskeletal Diseases

Respiratory Tract (Lung and Bronchial) Diseases

Carcinoma

Head and Neck Neoplasms

Epstein-Barr Virus Infections

Nasopharyngeal Carcinoma

Nose Neoplasms

Nasopharyngeal Neoplasms

Pharyngeal Neoplasms

Otorhinolaryngologic Neoplasms

Nasopharyngeal Diseases

Pharyngeal Diseases

Stomatognathic Diseases

Otorhinolaryngologic Diseases

Antineoplastic Agents

Carboplatin

Gemcitabine

Antimetabolites

4 cycles\* of combination IV Gemcitabine (1000 mg/m2) and IV carboplatin (AUC2) on Days 1, 8, 15 every 28 days, followed sequentially by T-cell immunotherapy (2 cycles) of autologous EBV specific Cytotoxic T cells every 2 weeks, followed by EBV-specific CTL immunotherapy (4 cycles) every 8 weeks after 6 weeks from the second cycle.

\*Additional 1-2 chemotherapy cycles (up to total 6 chemo cycles) might be given upon discretion of Investigator, if EBV-specific CTL infusions are not available in time for the 1st scheduled infusion.

As of 1 May 2020, patients who have not received the first infusion of EBV-specific CTLs, will instead continue to receive a total of 6 cycles combination of Gemcitabine (1000 mg/m2) and carboplatin (AUC2) on Days 1, 8, 15 every 28 days

6 cycles of combination IV gemcitabine (1000 mg/m2) and IV carboplatin (AUC2) on Days 1, 8, 15 every 28 days.

The CTL line will be prepared by co-cultivation of the irradiated EBV-LCL with patient PBMC. A proportion of peripheral blood will be used to generate EBV specific CTLs.

autologous EBV specific Cytotoxic T cells

4 cycles for Arm A and 6 cycles for Arm B

combination IV gemcitabine and IV carboplatin (AUC2)

Han Chong TOH

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/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".

330 patients will be randomized after their eligibility status has been fully determined and informed consent has been obtained. Patients will be randomly allocated to receive either Arm A (Gemcitabine and Carboplatin (GC) x 4\* cycles and EBV-specific CTL) or Arm B (GC x 6 cycles alone) in a 1:1 ratio using a stratified block randomization scheme. The stratification variables are country and disease stage (metastatic vs locally recurrent). \*Additional 1-2 chemotherapy cycles (up to total 6 chemo cycles) might be given upon discretion of Investigator, if EBV-specific CTL infusions are not available in time for the 1st scheduled infusion.

After randomization, patients in Arm A will have their peripheral blood taken for the establishment of cytotoxic T cell line and EBV transformed lymphoblastoid cell line (CTL). Within two weeks of enrollment, patients will commence combination GC chemotherapy for a total of 4 cycles. Patients in Stage 2 of study will receive the EBV-specific CTL immunotherapy.

As of 1 May 2020, patients who have not received the first infusion of EBV-specific CTLs, will instead continue to receive a total of 6 cycles combination of Gemcitabine (1000 mg/m2) and carboplatin (AUC2) on Days 1, 8, 15 every 28 days

A Phase III Trial Evaluating Chemotherapy and Immunotherapy for Advanced Nasopharyngeal Carcinoma (NPC) Patients

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

Efficacy of EBV-CTL following first line chemotherapy was compared to chemotherapy alone in terms of OS of subjects with advanced nasopharyngeal carcinoma. Overall survival was defined as the duration in months from the day of randomization until death from any cause for a subject known to be deceased, or censored at the last contact date that a subject was known to be alive or lost to follow-up.

Progression-free survival was defined as the duration from randomization to the first occurrence of documented disease progression \[based on imaging results\] or death from any cause, whichever occurred first.

Overall response rate was assessed by sites using computed tomography/magnetic resonance imaging based on RECIST version 1.1, which defined Complete Response (CR) as disappearance of all lesions and pathologic lymph nodes; Partial Response (PR) as \>=30% decrease in the sum of the longest diameter (SLD) of target lesions, no new lesions, no progression of non-target lesions; Stable disease (SD) as no PR and no progressive disease (PD); PD as \>=20% increase SLD compared to smallest SLD or progression of non-target lesions or new lesions. The ORR for each treatment arm was comprised of the proportion of subjects who achieved a best overall response of CR or PR while on treatment (until End of Treatment visit), taking as reference the tumor measurement at baseline. Subjects who achieved CR or PR are responders, otherwise are non-responders.

Clinical benefit rate (CBR) was assessed using computed tomography/magnetic resonance imaging based on RECIST version 1.1., which defined CR as disappearance of all lesions and pathologic lymph nodes; PR as \>=30% decrease in the sum of the longest diameter (SLD) of target lesions, no new lesions, no progression of non-target lesions; SD as no PR and no PD; PD as \>=20% increase SLD compared to smallest SLD or progression of non-target lesions or new lesions. CBR was defined as the proportion of subjects who achieved CR, PR, or SD while on treatment (until End of Treatment visit), taking as reference the tumor measurement at baseline.

Best overall response (BOR) was assessed using computed tomography/magnetic resonance imaging based on RECIST version 1.1., which defined CR as disappearance of all lesions and pathologic lymph nodes; PR as \>=30% decrease in the sum of the longest diameter (SLD) of target lesions, no new lesions, no progression of non-target lesions; SD as no PR and no PD; PD as \>=20% increase SLD compared to smallest SLD or progression of non-target lesions or new lesions. The BOR of each treatment arm consisted of CR, PR, SD, PD, NE, and NA while on treatment (until End of Treatment visit), taking as reference the tumor measurement at baseline. The ORR was comprised of the proportion of subjects who achieved a BOR of CR or PR.

Tessa Therapeutics

Safety analyses are based on the Safety Analysis Set, defined as all randomized subjects who received at least one dose of study treatment. Subjects were analyzed according to the treatment actually received.

Chemo + EBV-CTL

Chemo Only

Total

Age, Continuous

Race (NIH/OMB)

Singapore

Taiwan

Malaysia

Thailand

NPC staging by Investigator per 7th American Joint Committee on Cancer (AJCC); Tumor (T)1 Nasopharynx, oropharynx, nasal cavity without extension, T2 Parapharyngeal extension, T3 Skull base, paranasal sinuses, T4 Intracranial, cranial, hypopharynx, orbit, infratemporal fossa/masticator; Nodes (N)0 No lymph node metastasis, N1 Cervical, retropharyngeal nodes, ≤6 cm, N2 Bilateral metastasis, ≤6cm, N3 \>6 cm, supraclavicular fossa, Metastasis (M)0 No metastasis, M1 metastasis. Stage II:T2 N0-1 M0, T1 N1 M0; Stage III:T1-3 N2 M0, T3 N0-1 M0; Stage IVA:T4 N0-2 M0; Stage IVB:T N3 M0; Stage IVC:T N M1

Nasopharyngeal Cancer (NPC) stage at time of study entry

Disease Status per Randomization Stratification

ECOG PS Scale, as assessed by Investigator - Grade 0: Fully active, able to carry on all pre-disease performance without restriction; Grade 1: Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; Grade 2: Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours

Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)

Intent-to-treat Analysis Set - all subjects randomized to treatment.

Khong-Bee Kang, Senior Manager Clinical Development

Overall Survival (OS) of Subjects With Advanced Nasopharyngeal Carcinoma.

Progression-free Survival (PFS) of Subjects With Advanced Nasopharyngeal Carcinoma.

Overall Response Rate (ORR) of Subjects With Advanced Nasopharyngeal Carcinoma.

Clinical Benefit Rate (CBR) of Subjects With Advanced Nasopharyngeal Carcinoma.

Best Overall Response (BOR) of Subjects With Advanced Nasopharyngeal Carcinoma.

Two consecutive stages:

* 4 cycles of combination IV gemcitabine (1000 mg/m2) and IV carboplatin (AUC2) on Days 1, 8, 15 every 28 days. Option to add 1 to 2 cycles (i.e., up to 6 cycles total)
* 6 cycles of immunotherapy with EBV-specific CTL (1 x 10\^8 cells/m2) starting 2 to 4 weeks after last chemotherapy treatment. Subsequent chemotherapy cycles occurred 2 weeks after the first immunotherapy dose, 6 weeks after the second immunotherapy dose, and every 8 weeks thereafter

Syndrome

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Preleukemia

Myelodysplastic Syndromes

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Leukemia, Lymphocytic, Chronic, B-Cell

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Adenoviridae Infections

Hematologic Diseases

Bone Marrow Diseases

Leukemia, B-Cell

Chronic Disease

Disease Attributes

Myeloproliferative Disorders

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Chronic Graft Versus Host Disease

Chronic Lymphocytic Leukemia

Chronic Myeloid Leukemia

Acute Graft Versus Host Disease

Chronic Myeloproliferative Disorders

MVST

PBMCs will be collected by apheresis prior to mobilization for Hematopoietic stem cells collection, donor apheresis will be used partially to prepare DLIs per PI specification and remaining will be further processed by elutriation.

Monocytes and Lymphocytes are cryopreserved for further manufacture of MVSTr.

MVSTr

Minocher M Battiwalla, M.D.

Allogeneic hematopoetic stem cell transplantation (SCT) is frequently complicated by life threatening viral reactivation. Conventional antiviral therapy is suboptimal for cytomegalovirus (CMV), adenovirus (AdV) and Epstein-Barr virus (EBV) and nonexistent for BK virus (BKV). An alternative approach to prevent viral reactivation is to infuse virus-specific cytotoxic T cells (CTL) prepared from the donor early after SCT. Such multivirus-specific CTL cells (MVST) have been successfully used in a number of centers to prevent or treat CMV, Ad and EBV. Activity of BKV-reactive cells has not been studied. Multi virus-specific T cells (MVST) are donor lymphocytes that are highly enriched for viral antigens and expanded in vitro before infusion into the transplant recipient. Viral reactivation is a particular problem inT cell depleted SCT. Median time to CMV reactivation is estimated as 28 days post T-depleted transplant, but infusion of MVST within the immediate post-SCT period has not been previously studied. This protocol will be the first of a planned series of cellular therapies to be layered on our existing T lymphocyte depleted transplant platform protocol 13-H-0144.

The aim of this study is to determine the safety and efficacy of very early infusion of MVST directed against the four most common viruses causing complications after T-depleted SCT. GMP-grade allogeneic MVST from the stem cell donor will be generated using monocyte-derived donor dendritic cells (DCs) pulsed with overlapping peptide libraries of immunodominant antigens from CMV, EBV, Ad, and BKV and expanded in IL-7 and IL-15 followed by IL-2 for 10-14 days. A fraction of the routine donor leukapheresis for lymphocytes obtained prior to stem cell mobilization will be used to generate the MVST cells. MVST passing release criteria will be cryopreserved ready for infusion post SCT.

Eligible subjects on NHLBI protocol 13-H-0144 will receive a single early infusion of MVST within 30 days (target day +14, range 0-30 days) post SCT. Phase I safety monitoring will continue for 6 weeks. Viral reactivation (CMV, EBV, Ad, BK) will be monitored by PCR by serial blood sampling. The only antiviral prophylaxis given will be acyclovir to prevent herpes simplex and varicella zoster reactivation. Subjects with rising PCR exceeding threshold for treatment, or those with clinically overt viral disease will receive conventional antiviral treatment. Patients developing acute GVHD will receive standard treatment with systemic steroids. These patients are eligible for reinfusion of MVST when steroids are tapered.

The clinical trial is designed as a single institution, open label, non-randomized Phase I/II trial of MVST in transplant recipients, designed as 3-cohort dose escalation Phase I followed by a 20 subject extension Phase II at the maximum tolerated dose of cells. Safety will be monitored continuously for a period of 6 weeks post T cell transfer. The primary safety endpoint will be the occurrence of dose limiting toxicity, defined as the occurrence of Grade IV GVHD or any other SAE that is deemed to be at least probably or definitely related to the investigational product. The primary efficacy endpoint for the phase II will be the proportion of CMV reactivation requiring treatment at day 100 post transplant. Secondary endpoints are technical feasibility of MSVT manufacture, patterns of virus reactivation by PCR, and clinical disease from EBV, Ad, BK, day 100 non-relapse mortality.

Allogeneic hematopoetic stem cell transplantation (SCT) is frequently complicated by life threatening viral reactivation. Conventional antiviral therapy is suboptimal for cytomegalovirus (CMV), adenovirus (AdV) and Epstein-Barr virus (EBV) and nonexistent for BK virus (BKV). An alternative approach to prevent viral reactivation is to infuse virus-specific cytotoxic T cells (CTL) prepared from the donor early after SCT. Such multivirus-specific CTL cells (MVST) have been successfully used in a number of centers to prevent or treat CMV, Ad and EBV. Activity of BKV-reactive cells has not been studied. Multi virus-specific T cells (MVST) are donor lymphocytes that are highly enriched for viral antigens and expanded in vitro before infusion into the transplant recipient. Viral reactivation is a particular problem inT cell depleted SCT. Median time to CMV reactivation is estimated as 28 days post T-depleted transplant, but infusion of MVST within the immediate post-SCT period has not been previously studied. This protocol will be the first of a planned series of cellular therapies to be layered on our existing T lymphocyte depleted transplant platform protocol 13-H-0144.

The aim of this study is to determine the safety and efficacy of very early infusion of MVSTr cells directed against the four most common viruses causing complications after T-depleted SCT. GMP-grade allogeneic MVSTr from the stem cell donor will be generated using or peripheral blood mononuclear cells (PBMCs) pulsed with overlapping peptide libraries of immunodominant antigens from CMV, EBV, Ad, and BKV and expanded in IL-7 and IL-15 followed by IL-2 for 14 days. A fraction of the routine donor leukapheresis for lymphocytes obtained prior to stem cell mobilization will be used to generate the MVST cells. MVST passing release criteria will be cryopreserved ready for infusion post SCT.

Eligible subjects on NHLBI protocol 13-H-0144 will receive a single early infusion of MVSTr on day +7 post transplant range 0-14 days) post SCT. Phase I safety monitoring will continue for 6 weeks after infusion. Viral reactivation (CMV, EBV, Ad, BK) will be monitored by PCR by serial blood sampling. The only antiviral prophylaxis given will be acyclovir to prevent herpes simplex and varicella zoster reactivation. Subjects with rising PCR exceeding threshold for treatment, or those with clinically overt viral disease will receive conventional antiviral treatment. Patients developing acute GVHD will receive standard treatment with systemic steroids. These patients are eligible for reinfusion of MVST when steroids are tapered.

The clinical trial is designed as a single institution, open label, non-randomized Phase I trial of MVSTr in transplant recipients, designed as a single cohort Phase I study. Safety will be monitored continuously for a period of 6 weeks post MVSTr transfer. The primary safety endpoint will be the occurrence of dose limiting toxicity (DLT), defined as the occurrence of Grade IV GVHD, Grade III cytokine release syndrome (CRS), Grade III autoimmunity or any other SAE that is deemed to be at least probably or definitely related to the investigational product.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Autologous/Allogeneic TGFbeta-resistant LMP-specific CTL, Lymphoma (TGF-beta)	NCT00368082	Lymphoma Hodgkin's Disea... Relapse Lymphoma, Non-H...	TGFbeta resista...	-	Baylor College of Medicine
Autologous Cytomegalovirus (CMV)-Specific Cytotoxic T Cells for Cytomegalovirus (CMV) Reactivation	NCT02210065	Leukemia Lymphoma	Cytomegalovirus...	18 Years -	M.D. Anderson Cancer Center
A Phase I Study to Investigate Tolerability and Efficacy of ALECSAT Administered to Glioblastoma Multiforme Patients	NCT01588769	Glioblastoma Mu...	ALECSAT cell ba...	18 Years -	CytoVac A/S
A Phase III Trial Evaluating Chemotherapy and Immunotherapy for Advanced Nasopharyngeal Carcinoma (NPC) Patients	NCT02578641	Nasopharyngeal ...	autologous EBV ... combination IV ...	18 Years -	Tessa Therapeutics
Phase I/II Trial of Early Infusion of Rapidly-generated Multivirus Specific T Cells (MVST) to Prevent Post Transplant Viral Infections	NCT02231853	Chronic Lymphoc... CML (Chronic My... MDS (Myelodyspl... Acute Lymphobla... AML (Acute Myel...	MVST MVSTr	18 Years - 75 Years	National Institutes of Health Clinical Center (CC)
A Phase I Study to Investigate Tolerability and Efficacy of ALECSAT Administered to Glioblastoma Multiforme Patients	NCT01588769	Glioblastoma Mu...	ALECSAT cell ba...	18 Years -	CytoVac A/S

Spots Global Cancer Trial Database for cytotoxic t cells