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Immunologic Factors

Related and unrelated donors undergo lymphapheresis to prepare cellular vaccines and to donate lymphocytes for infusion.

Participants receive donor lymphocytes and vaccines prepared from donors.

WT1 Peptide-Pulsed Dendritic Cells

Lymphocytes from donors (related or unrelated) collected via lymphapheresis.

Donor Lymphocytes

water-soluble protein; this study will use GMCSF (granulocyte macrophage colony stimulating factor)/IL-4 generated monocyte derived dendritic cells

IL-4

Neoantigen known to induce helper responses; will be used concurrently as a vaccine adjuvant and control antigen.

WT1 Peptides

Purified lipopolysaccharide prepared from E.Coli 0:113

Endotoxin

Terry J Fry, M.D.

Background:

* Most patients with acute lymphoblastic leukemia (ALL) and many patients with acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML) and non-Hodgkin's lymphoma (NHL) have a protein called Wilm's Tumor 1 (WT1) in their cancer cells. This protein is thought to be able to influence the growth of these cancers.
* A vaccine made with the WT1 protein may boost the immune system to help fight these cancers in patients whose cancer cells contain the protein.

Objectives:

* To determine the safety, effectiveness and side effects of giving the WT1 vaccine and donor white blood cells to patients with AML, ALL, CML or NHL who have previously received standard treatment and undergone stem cell transplantation.
* To determine the immune response to the WT1 vaccine and donor white blood cells in these patients and to determine if the response is related to the amount of WT1 protein in the patient's cancer cells.

Eligibility:

* Patients between 1 and 75 years of age with the blood antigen human leukocyte antigen (HLA-A2) and the WT1 cancer protein who have persistent or recurrent blood cancers after stem cell transplantation.
* The prior stem cell transplant donor must be willing to provide additional cells, which will be used to prepare the cellular vaccines and for donor lymphocyte (white blood cell) infusions.

Design:

* Patients are given the WT1 vaccine every 2 weeks for 6 weeks (weeks 0, 2, 4, 6, 8, 10). Each vaccination consists of two injections in the upper arm or thigh.
* On weeks 0, 4 and 8, patients also receive white blood cells from a donor to enhance the immune response. The cells are also given as a 15- to 30-minute infusion through a vein about 1 hour after the vaccine injection. Donor infusions are given only to patients with mild or no graft-vs-host disease resulting from their prior stem cell transplantation.
* Periodic physical examinations, blood and urine tests, scans to evaluate disease and other tests as needed are done for 12 months after enrollment in the study.

Background:

* Efforts to incorporate anti-tumor immunotherapy at stages of minimal residual disease (MRD) burden are limited by profound host immune depletion associated with standard anti-cancer therapies.
* Allogeneic blood and marrow stem cell transplantation (SCT) can be curative for a number of hematologic malignancies. Part of the success of this approach is an allogeneic immunologic reaction that has been demonstrated to play a role in the eradication of residual malignant disease after transplant in certain cancers (the so called graft-versus-leukemia, GVL, or graft-versus-tumor, GVT, effect). Nonetheless, relapse remains the primary cause of treatment failure after allogeneic SCT.
* The Wilm's tumor 1 (WT1) gene product is a tumor-associated antigen that represents a potential target for immunotherapy in a wide array of cancers. WT1 is expressed in most cases of acute leukemia and in many cases of chronic myelogenous leukemia and myelodysplastic syndromes. Importantly, WT1 has limited expression in normal tissues beyond embryogenesis. This trial represents an attempt to incorporate antigen-specific immunotherapy in the setting of allogeneic adoptive cell transfer.

Objectives:

* To determine the safety, toxicity, and feasibility of donor-derived dendritic cell vaccination and donor lymphocyte infusion (DLI) after allogeneic SCT.
* To determine the frequency and severity of graft-vs.-host disease (GVHD) in patients treated with peptide-loaded donor-derived dendritic cell vaccination and donor lymphocyte infusion (DLI).
* To evaluate whether immunologic responses to WT1-specific peptides can be generated by peptide-loaded donor-derived dendritic cell vaccination and DLI after allogeneic SCT.
* To evaluate whether clinical responses to WT1-specific peptides can be generated by peptide-loaded donor-derived dendritic cell vaccination and DLI after allogeneic SCT.
* To evaluate whether immunologic and/or clinical responses may be associated with the degree of WT1 expression by malignant cells or pre-existing donor anti-WT1 immunity.

Eligibility:

* HLA-A2 plus patients may be enrolled on this trial if they have relapsed or residual disease following allogeneic SCT for a WT1 expressing hematologic malignancy.
* Donors from the previous SCT, related or unrelated, must be 5- or 6- antigen genotypic HLA-matched (single HLA-A or B locus mismatch allowed) and HLAA2 plus.

Design:

* This is a pilot study, the primary aim of which is to assess safety and feasibility of this novel vaccine strategy aimed to enhance the GVL effect after allogeneic SCT.
* Donor-derived dendritic cells prepared from peripheral blood monocytes will be loaded with a combination of three WT1-derived peptides. These peptides are each comprised of one WT1-derived oligomeric epitope known to bind to HLA-A2 and an 11-mer protein transduction epitope known to enhance peptide loading and antigen presentation.
* Patients will receive donor-derived dendritic cell vaccines every 14 days for 6 doses. Donor leukocyte infusions (DLI) will also be administered with the vaccine.
* Study endpoints will include toxicity, feasibility, antigen-specific immunity, and disease response.
* This is an exploratory pilot trial. Up to 12 patients will be treated.
* Stopping rules will take effect if excessive toxicity (e.g., GVHD) or inability to generate vaccines are observed.

Wilm's Tumor 1 Protein Vaccine to Treat Cancers of the Blood

A Pilot Trial of WT1 Peptide-Loaded Allogeneic Dendritic Cell Vaccine and Donor Lymphocyte Infusion for WT1-Expressing Hematologic Malignancies

Here is the number of participants with adverse events. For details of the adverse events, see the adverse event module.

Acute Graft versus Host Disease (GVHD) was graded by the modified Glucksberg scale. 0 = no GVHD normal, 4 = severe GVHD.

Immune response was monitored by use of interferon gamma Enzyme-Linked Immunospot (ELISpot) and by delayed-type hypersensitivity (DTH) testing.

WT1 expression of the hematologic malignancy was confirmed by either having greater than 15% of malignant cells react with anti-WT1 by immunohistochemistry or by having a positive quantitative reverse transcription polymerase chain reaction (RT-PCR) of WT1 compared with a negative control.

WT1 expression of the hematologic malignancy was confirmed by either having greater than 15% of malignant cells react with anti-WT1 by immunohistochemistry or by having a positive quantitative reverse transcription polymerase chain reaction (RT-PCR) of WT1 compared with a negative control. DTH skin testing was performed using KLH and with a cocktail of WT1 peptides as 2 separate injections. Enzyme-Linked Immunospot (ELISpot) was performed against each peptide and was considered positive if results were at least 10 spots above background on at least 2 measurements. DTH was considered positive if there was at least .5cm induration 48 to 72 hours after placement.

KLH is a neoantigen known to induce helper response was used concurrently as a vaccine adjuvant and control antigen. DTH skin testing was performed using KLH and with a cocktail of WT1 peptides as 2 separate injections. Enzyme-Linked Immunospot (ELISpot) was performed against each peptide and was considered positive if results were at least 10 spots above background on at least 2 measurements. DTH was considered positive if there was at least .5cm induration 48 to 72 hours after placement.

Progressive disease is at least a 20% increase in the sum of the longest diameter of all target lesions (i.e. tumor response). Response criteria for acute leukemia's is worse marrow classification (i.e., M status) with at least a 50% increase in the percentage of marrow blasts, or no change in marrow classification (i.e., M status), but a 50% or greater increase in absolute peripheral blast count or extent of medullary disease

National Cancer Institute (NCI)

Principal Investigator

Only recipients were monitored for adverse events.

Recipients

Donor lymphocyte collection via apheresis.

Donors

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Hodgkin

ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia.

Disease

MA x 2

NMA, nonmyeloablative; MA, myeloablative; MAx2, myeloablative conditioning. This is standard terminology in the transplant field and refers to pre-transplant chemotherapy/radiation doses that require stem cell rescue.

Transplantation Type

MRD*

MSD, matched sibling donor; MRD\*, matched related donor. MRD\* was a 10/10 matched related parent for both transplantations. the first used marrow and the second used peripheral blood stem cells.; MUD, matched unrelated donor.

Fludarabine/cyclophosphamide

Cyclophosphamide, TBI, thiotepa

HSCT1:cyclo,TBI;HSCT2:busulfan, melphalan, etop

Cyclophosphamide, TBI

TBI, total body irradiation; cyclo, cyclophosphamide; etop, etoposide; HSCT, hematopoietic stem cell transplant

Conditioning Regimen

Cyclosporine

Sirolimus/tacrolimus, methotrexate

None after second BMT

Immunosuppression

Patient 1

Patient 2

Patient 3

Patient 4

Patient 5

Time Off Immunosuppression before Protocol Enrollment

6%-8% blasts

Multiple 1-2cm lymph nodes

5%-10% blasts

2% blasts

5% blasts

Pre-Enrollment Disease Status

Time to HCT to Relapse, mo

Time to First Vaccine (from day 0 of HCT), mo

Dr. Terry Fry

Toxicity

Data for the frequency and severity of GVHD was captured as an endpoint for this trial. The donor arm is not included here because they were not evaluated for this outcome measure; recipients only.

Number of Participants With Graft Versus Host Disease (GVHD) Greater Than or Equal to Grade 3

Period 1 - Vaccine and donor lymphocyte prep Period 2 - Vaccine and donor lymphocyte administration.

The donor arm is not included here because they were not evaluated for this outcome measure; recipients only.

Time to Immune Response

Positive

Negative

Wilm's Tumor 1 (WT1) Enzyme-Linked Immunospot (ELISpot)

NA (Not available)

Wilm's Tumor (WT1) Delayed-type Hypersensitivity (DTH)

Keyhole Limpet Hemocyanin (KLH) Delayed-type Hypersensitivity (DTH)

Number of Participants With Progressive Disease

Period 1 -Donor lymphocyte collection via apheresis. Period 2 -Donor cell processing for vaccine and infusion.

Period 1

Period 2

Respiratory Tract (Lung and Bronchial) Diseases

Heart and Blood Diseases

Nutritional and Metabolic Diseases

Asthma

Atherosclerosis

Metabolic Syndrome

Insulin Resistance

Hyperinsulinism

Metabolic Diseases

Glucose Metabolism Disorders

Arteriosclerosis

Arterial Occlusive Diseases

Vascular Diseases

NIEHS Join A Study Recruitment Group

Michael B Fessler, M.D.

Background:

- Innate immunity is the process by which white blood cells and other parts of the immune system sense and respond to potential infections by causing an inflammation. Researchers are interested in studying how the body responds to certain environmental factors, and whether the body s response can contribute to chronic illnesses or diseases such as asthma and certain types of cancers.

Objectives:

- To examine how specific genes and proteins in blood cells respond to environmental exposures.

Eligibility:

- Healthy volunteers between 18 and 45 years of age.

Design:

* The study will involve one visit of 45 to 60 minutes.
* Participants will be screened with a brief physical examination and finger stick to determine if they are eligible to donate blood for the study, and will complete a questionnaire about any medications or other drugs (e.g., cigarettes) they may be taking.
* Participants will provide a blood sample for research purposes.

This research study will examine the role of innate immunity on the Inflammatory response of monocytes and macrophages to endotoxin. Approximately 1450 healthy participants aged 18 years and older will be identified and recruited from the Environmental Polymorphism Registry (EPR). The EPR is a long-term project to collect and store up to 15,000 DNA samples for use in research studies from individuals in the greater North Carolina Triangle Region. It is anticipated that approximately 50% of the participants contacted will enroll and about 15% of participants enrolled will withdraw.

This controlled, observational gene association study will recruit participants on the basis of genotype and then observe the phenotype of each participant. There are several SNPs of interest in the genes TIRAP, MyD88, ABCA1, CD14, CD44, ITIH3, ITIH4, TLR4, TNFa, TLR5, IRGM, and APOL1. In addition there are alleles of interest in the gene ApoE. These alleles taken together are considered a polymorphism. For each polymorphism of interest a separate group of participants will be recruited (including heterozygous and homozygous for both the minor and major alleles for each SNP). A maximum of 200 mLs of blood will be obtained from each participant during one visit lasting approximately 1-1.5 hours. Blood monocytes will be isolated from the donated blood samples and cultured to obtain macrophages. The macrophages will be exposed ex vivo to an endotoxin (LPS) and to PAM3CSK4 to determine cell response depending on genotype. In studies of APOL1, a urine specimen will also be collected to evaluate for protein filtration.

The primary objective is to determine associations between select polymorphisms in genes \[TIRAP (TIR Associated Protein), MyD88 (Myeloid Differentiation Primary Response Protein 88), ApoE (Apolipoprotein E), ABCA1 (ATP Binding Cassette Transporter A1), CD14, CD44, ITIH3, ITIH4, TLR4, TNFa, TLR5, IRGM, and APOL1\] and quantitative in vitro inflammatory functions of two cell types, the macrophage and neutrophil. The primary endpoints of this study for both cell types will be levels of 6 cytokines TNF alpha, IL-6, MIP-2, IL-8, MCP-1, and IFN-beta (ELISA) induced by LPS and by PAM3CSK4 plus baseline cytokine levels (no exposure to LPS or PAM3CSK4). Urinary levels of protein will be quantified in some studies as a measure of early kidney dysfunction.

We hope the results of this study may lead to discovery of important information regarding the role of MDC1 (Mediator of DNA damage Checkpoint protein 1) in human disease, potentially identifying new targets for future studies.

Study of the Effect of Innate on the Inflammatory Response to Endotoxin

Study of the Effect of Innate Immunity on the Inflammatory Response to Endotoxin

.It isn t known yet if there will be a plan to make IPD available

The primary endpoints of this study are for both cell types and will be levels of 6 cytokines \[TNF alpha, IL-6, MIP-2, IL-8, MCP-1, and IFN-beta (ELISA)\] induced by LPS and by PAM3CSK4 plus baseline cytokine levels (no exposure to LPS or PAM3CSK4).

National Institute of Environmental Health Sciences (NIEHS)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Wilm's Tumor 1 Protein Vaccine to Treat Cancers of the Blood	NCT00923910	Leukemia, Acute... Leukemia, Acute... Leukemia, Chron... Myelodysplastic... Non-Hodgkin's L...	WT1 Peptide-Pul... Donor Lymphocyt... IL-4 KLH WT1 Peptides Endotoxin Diphenhydramine Acetaminophen	1 Year - 74 Years	National Institutes of Health Clinical Center (CC)
Study of the Effect of Innate on the Inflammatory Response to Endotoxin	NCT01143480	Asthma Atherosclerosis Metabolic Syndr... Insulin Resista... Cancer		18 Years - 100 Years	National Institutes of Health Clinical Center (CC)
Study of the Effect of Innate on the Inflammatory Response to Endotoxin	NCT01143480	Asthma Atherosclerosis Metabolic Syndr... Insulin Resista... Cancer		18 Years - 100 Years	National Institutes of Health Clinical Center (CC)
Study of the Effect of Innate on the Inflammatory Response to Endotoxin	NCT01143480	Asthma Atherosclerosis Metabolic Syndr... Insulin Resista... Cancer		18 Years - 100 Years	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for endotoxin

Every month we try and update this database with for endotoxin 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 endotoxin

Every month we try and update this database with for endotoxin 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 endotoxin 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.