Using T-Cell Alloreactivity and Chimerism to Guide Immunosuppression Minimization in Intestinal Transplantation

NCT ID: NCT04804891

Last Updated: 2025-03-27

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1
• Total Enrollment: 6 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-10-22
• Study Completion Date: 2028-12-31

Brief Summary

The purpose of this study is to investigate the safety and feasibility of giving intestinal transplant patients CD34+ stem cells (the cells that make all the types of blood cells) obtained from their organ donor's bone marrow. The goal of this is to develop a post-transplant treatment strategy that controls rejection while reducing the high risk of infection and malignant disease associated with the high levels of immunosuppression medication(s) that intestinal and multi-organ transplant patients must take. Infusion of bone marrow cells from the same donor of the transplanted organ(s) could promote a state called "mixed chimerism" in which both donor cells and recipient cells coexist in the body with the ultimate goal of minimizing the amount of immunosuppression medication(s) needed.

Detailed Description

Abdominal trauma, congenital abnormalities and ischemic injury cause intestinal damage that prevents the digestion and absorption of fluids and nutrients essential for life. Intestinal transplantation is life-saving for patients with complications related to the administration of intravenous nutrients. Approximately 100-160 intestinal transplants (ITx) are performed in the US annually. However, patient survival rates are far from optimal, due to high rejection rates resulting from an immune attack of the recipient against the donor, termed host-vs-graft (HVG) reactivity The high levels of global immunosuppression used to prevent rejection come with a high risk of infections and malignant disease (i.e. lymphoma). Thus, there is an urgent need for a well-tolerated treatment strategy that controls rejection while reducing these risks. Immune tolerance, in which the immune system regards the donor as "self" so that long-term graft acceptance is achieved without life-long immunosuppression, would accomplish this goal . Infusion of bone marrow cells from the same donor of the solid organs could promote a state called "mixed chimerism" in which both donor cells and recipient cells coexist in the body. Mixed chimerism has been shown to induce tolerance to the transplanted organ in animal models and in patients receiving kidney transplants.

The investigators propose studies to promote tolerance induction in intestinal transplant recipients by administering donor bone marrow stem cells to promote lasting mixed chimerism. The investigators' proposal builds on their demonstration that mixed chimerism commonly occurs in intestinal transplant (ITx) recipients without bone marrow transplant, and that its presence correlates with reduced rejection rates. However, this mixed chimerism is not permanent. The investigators have discovered that there are bone marrow stem cells in the donor intestinal grafts and that some of these survive and enter the bone marrow of the recipient. This process is facilitated by a phenomenon called a "lymphohematopoietic graft-vs-host responses (LGVHR)", in which T lymphocytes from the ITx donor attack recipient blood-forming cells to make "space" for their own establishment in the bone marrow, but do not induce GVHD. The investigators have also obtained evidence that this immune response suppresses rejection of the graft.

Conditions

Intestinal Transplantation

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

Cell Therapy

Patients will receive an infusion containing 1x106/kg CD34+ cells. No more than 104 CD34+ T cells per kg recipient weight will be included in the infusion. Cadaveric donor CD34 cell infusion will occur at any time between post-operative day 11 to day 13 following transplantation.

Group Type: EXPERIMENTAL

Cell Therapy

Intervention Type: BIOLOGICAL

Infusion of containing 1x106/kg CD34+ cells from donor bone marrow selected using the CliniMACS® CD34 Reagent System.

Control

Patients who do not consent to receive donor CD34 cell infusion or whose donor family declines consent for research use of donor bone marrow will receive their usual standard of care.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Cell Therapy

Infusion of containing 1x106/kg CD34+ cells from donor bone marrow selected using the CliniMACS® CD34 Reagent System.

Intervention Type: BIOLOGICAL

Eligibility Criteria

Inclusion Criteria

• All patients actively listed as candidates for intestinal or multi-visceral transplant at the study site; while all patients who are actively listed in United Network for Organ Sharing (UNOS) for intestinal and/or multi-visceral transplantation, including those who have previously received a multi-visceral transplant and are re-listed, are eligible for participation, the following are examples of listing criteria suitable for enrollment in this clinical trial:

• Short Bowel Syndrome (SBS) due to:

• Trauma (multiple resections/explorations and/or vascular abdominal trauma superior mesenteric artery (SMA) / superior mesenteric vein (SMV) injuries)
• Gastroschisis
• Volvulus
• Necrotizing Enterocolitis
• Intestinal Atresia
• Crohn's Disease
• Hirschprung's Disease
• Chronic Intestinal Pseudo-Obstruction
• Malabsorption:

• Microvillus Inclusion Disease
• Tufting Enteropathy
• Complete portomesenteric thrombosis with cirrhosis
• Slow-growing, low-malignancy potential tumors infiltrating mesenteric root:

• Gardner's Syndrome
• Familial Adenomatous Polyposis
• Desmoid Tumor with Intra-Abdominal Infiltration
• Endocrine Tumors
• Re-transplant candidates who lost the first graft to rejection or patients who have higher risk of toxicity from chronic long term immunosuppression (i.e., patients with chronic kidney disease)
• Patient commits to planned follow up at a study site for the 48-month duration of study procedures
• Age ≥18 years old and ≤65 years old
• Subjects or capable of signing the informed consent document themselves

Exclusion Criteria

• Active systemic infection with hemodynamic instability and/or sepsis
• Patients with known immunodeficiency syndrome
• Carcinoma with metastasis (except neuro-endocrine tumors, even in the presence of metastasis these patients may undergo multivisceral/cluster transplantation)
• Severe cardiovascular and/or respiratory instability, as defined by requirement of pressors or ventilator
• Severe cerebral edema, with radiologic findings of effaced sulci and/or herniation
• Poorly controlled hypertension (systolic blood pressure > 170 on at least 2 occasions), diabetes mellitus (HbA1c > 8), or uncontrollable seizure disorders
• Age > 65 years
• Documented history of non-compliance with medical therapy and follow-up
• Substance addiction in the last six months
• Psychosocial Instability: absence of a consistent reliable social support system
• Significant or active psychiatric disorder associated with the inability to cooperate or comply with medical therapy
• In the judgement of the clinical team, severely limited functional status with poor rehabilitation potential
• Multi-organ failure and preceding CD34+ infusion
• Pre formed panel reactive antibodies (PRA) mean fluorescein intensity (MFI) > 5000 by Luminex
• Patients who are pregnant or breast-feeding or intend to get pregnant during the study period
• Patients who have developed moderate or severe rejection before post-transplant day 11
• Vulnerable populations, such as incarcerated or institutionalized individuals
• Subjects with clinical features suggestive of GVHD
• Subjects who are hemodynamically unstable (i.e., requiring vasopressor support)
• Female subjects of childbearing age and male patients who are not using and/or unwilling to use an effective method of birth control for the duration of the trial activities

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Ossium Health, Inc.

INDUSTRY

Sponsor Role: collaborator

Columbia University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Tomoaki Kato, MD

Role: PRINCIPAL_INVESTIGATOR

Columbia University

Locations

Columbia University Irving Medical Center/NYP

New York, New York, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Clinical Research Core

Role: CONTACT

tk2388@cumc.columbia.edu

212-305-3839

Facility Contacts

Clinical Research Core

Role: primary

tk2388@cumc.columbia.edu

212-305-3839

Other Identifiers

AAAS8908

Identifier Type: -

Identifier Source: org_study_id