Cell Therapy for Intestinal Transplant Recipients

Overseen By Clinical Research Core

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Columbia University

Disqualifiers: Infection, Immunodeficiency, Metastatic carcinoma, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

6 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new method to assist individuals who have undergone an intestinal transplant. It investigates whether administering certain stem cells (CD34+ stem cells) from the organ donor can enable safer use of fewer anti-rejection drugs, which often lead to infections and other complications. Participants should be those awaiting an intestinal or multi-organ transplant, particularly if they have conditions like Short Bowel Syndrome or other gut-related issues. The trial aims to determine if this approach can reduce rejection risk and enhance recovery. As a Phase 1 trial, the research focuses on understanding how the treatment functions in people, offering participants the chance to be among the first to receive this innovative treatment.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, since the study aims to reduce the amount of immunosuppression medication needed, it's possible that changes to your medication regimen might be part of the trial.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that CD34+ stem cells have been used safely in various medical situations. For example, studies have found that these stem cells can aid recovery after treatments like CAR T-cell therapy without causing major side effects. They have also been tested in other transplant settings, where careful monitoring revealed no serious problems directly related to the stem cell infusion.

Since this trial is in its early stages, researchers are still closely studying the treatment's safety in people. However, previous research provides some confidence that CD34+ stem cells are generally safe, as past studies have shown they are well-tolerated. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about using CD34+ stem cells for intestinal transplant recipients because they offer a novel approach to enhancing immune system tolerance. Unlike the standard treatments that primarily focus on managing rejection through immunosuppressive drugs, CD34+ stem cells potentially improve long-term transplant acceptance by promoting immune regulation. This approach could reduce reliance on heavy immunosuppression, which often comes with significant side effects. Additionally, the infusion of these cells shortly after transplantation may allow for quicker adaptation of the immune system, leading to better overall outcomes for patients.

What evidence suggests that CD34+ stem cells might be an effective treatment for intestinal transplant recipients?

Research has shown that CD34+ stem cells can help manage health issues after a transplant. These cells aid in the recovery of blood cell production, which is crucial following such procedures. For instance, CD34+ stem cells have helped patients with certain blood conditions recover more effectively. In this trial, some participants will receive an infusion of CD34+ stem cells to explore their potential to reduce the need for strong immune-suppressing drugs, which can have harmful side effects. Early studies suggest that using CD34+ cells can improve overall organ function and reduce some complications. ^{1 2 3 6 7}

Who Is on the Research Team?

Tomoaki Kato, MD

Principal Investigator

Columbia University

Are You a Good Fit for This Trial?

This trial is for adults aged 18-65 who need an intestinal transplant and can follow up for 48 months. It's open to those listed in UNOS, with conditions like Short Bowel Syndrome or specific tumors, but not for those with multi-organ failure, severe infections, or unstable health conditions. Pregnant women and individuals unable to use birth control are excluded.

Inclusion Criteria

I have Short Bowel Syndrome from surgery, injury, or a specific condition.

I can attend all study visits for the next 4 years.

All patients actively listed as candidates for intestinal or multi-visceral transplant at the study site

Exclusion Criteria

My cancer has spread, but it's not a neuro-endocrine tumor.

I have multiple organ failure and have received a CD34+ cell infusion.

I am older than 65.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Transplantation and Initial Treatment

Participants undergo intestinal transplantation and receive an infusion of donor CD34+ stem cells between post-operative day 11 to day 13

2 weeks

In-patient stay for transplantation and initial recovery

Follow-up

Participants are monitored for safety, effectiveness, and occurrence of GVHD after transplantation

Up to 4 years

Regular follow-up visits

Long-term Monitoring

Participants are monitored for retention and graft survival

Up to 3 years

What Are the Treatments Tested in This Trial?

Interventions

• CD34+ stem cells

Trial Overview The study tests the safety of using donor bone marrow cells (CD34+ stem cells) after an intestinal transplant to reduce rejection and lower immunosuppressant needs. The aim is achieving 'mixed chimerism,' where both recipient's and donor's cells coexist harmoniously.

How Is the Trial Designed?

Group I: Cell Therapy Experimental Treatment 1 Intervention

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 II: Control Active Control 1 Intervention

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.

CD34+ stem cells is already approved in United States, European Union for the following indications:

Approved in United States as Hematopoietic Stem Cells for:

• Autologous use in hematopoietic stem cell transplantation for certain conditions such as leukemia and lymphoma
• Investigational use in intestinal transplantation for minimizing immunosuppression

Approved in European Union as Hematopoietic Stem Cells for:

• Autologous use in hematopoietic stem cell transplantation for certain conditions such as leukemia and lymphoma
• Investigational use in various clinical trials including intestinal transplantation

Who Is Running the Clinical Trial?

Columbia University

Lead Sponsor

Trials

1,529

Recruited

2,832,000+

Ossium Health, Inc.

Industry Sponsor

Trials

11

Recruited

200+

Published Research Related to This Trial

In a study involving nine patients with advanced cancers, CD34+ marrow cells were successfully separated and infused after marrow ablative therapy, leading to engraftment in six patients, which indicates their potential for reconstituting blood cell production.

The engrafted patients achieved significant recovery of granulocyte and platelet counts within a few weeks, demonstrating the efficacy of CD34+ cell transplantation in supporting hematopoiesis, although some patients experienced complications related to their underlying disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engraftment after infusion of CD34+ marrow cells in patients with breast cancer or neuroblastoma. Berenson, RJ., Bensinger, WI., Hill, RS., et al.[2021]

The study successfully cultured and expanded CD34-positive cells from mobilized peripheral blood, demonstrating the feasibility of this method for clinical use.

Patients tolerated the infusions of these cells well, and successful engraftment was achieved, indicating a positive safety profile for this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical use of selected and expanded peripheral blood CD34+ cells: a preliminary report of feasibility and safety. Zimmerman, TM., Williams, SF., Bender, JG., et al.[2004]

Bone marrow-derived cells (BMDCs) can successfully differentiate into intestinal epithelial cells long-term in chimeric mice, demonstrating their potential role in intestinal regeneration without special treatment.

In a study involving 40 irradiated C57BL/6 mice, 93.3% survival was observed one week post-transplantation, and BMDCs were found to express epithelial markers, indicating their successful engraftment and differentiation into various intestinal cell types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term repopulation effects of donor BMDCs on intestinal epithelium. Liu, D., Wang, F., Zou, Z., et al.[2021]

Hematopoietic stem cell transplantation and mesenchymal stromal cell therapy are being explored as innovative treatments for inflammatory bowel diseases, with the potential to reset the immune system and improve responses to gut antigens.

Recent studies in animal models and early human trials indicate that ex vivo expanded mesenchymal stromal cells may effectively modulate immune responses, showing promise for conditions like Crohn's Disease and graft-versus-host disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stem cells as potential novel therapeutic strategy for inflammatory bowel disease. Duijvestein, M., van den Brink, GR., Hommes, DW.[2016]

Intestinal transplantation is the best treatment for patients with short bowel syndrome, and the study evaluated the effects of infusing autologous bone marrow mesenchymal stromal cells (BMSCs) in patients undergoing this procedure.

The results indicated a potential increase in epithelial chimerism with BMSC infusion, which could lead to better graft survival and reduced need for immunosuppressants, although further studies are needed to confirm these findings over time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of epithelial chimerism after bone marrow mesenchymal stromal cell infusion in intestinal transplant patients. Kilinc, S., Gurkan, UA., Guven, S., et al.[2018]

Transplanting intestinal mucosal stem cells from neonatal mice into adult mice showed that a seeding density of 10,000 organoids with 20 minutes of debridement resulted in the highest engraftment of new mucosal tissue, indicating an optimal condition for successful transplantation.

The study faced a high mortality rate of 70%, which limited the ability to fully explore all combinations of stem cell doses and debridement times, highlighting the need for careful consideration of experimental conditions in future research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engraftment of mucosal stem cells into murine jejunum is dependent on optimal dose of cells. Avansino, JR., Chen, DC., Woolman, JD., et al.[2019]

A minimum of 2.5 x 10^6 CD34+ cells is necessary for successful engraftment in autologous transplantation, but a target of 5.0 x 10^6 CD34+ cells is recommended for prompt engraftment of neutrophils and platelets.

While higher doses (>15 x 10^6 CD34+ cells) may improve engraftment and reduce hospitalization costs, they can also lead to complications like fever and engraftment syndrome, indicating a need for careful consideration of stem cell dosing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

What is the optimum number of CD34+ peripheral blood stem cells for an autologous transplant? Jillella, AP., Ustun, C.[2005]

Recent research indicates that some hematopoietic stem cells (HSC) in the bone marrow do not express the CD34 marker, which is traditionally used to identify and select these cells for transplantation.

Studies in various animal models have shown that these CD34-negative progenitor cells possess the ability to produce CD34+ cells in vitro and have long-term repopulating potential, suggesting that the current selection methods for stem cell transplantation may need to be reevaluated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Who is hematopoietic stem cell: CD34+ or CD34-? Pei, X.[2015]

A higher dose of CD34+ cells (> 8.5 × 10^6/kg) during allogeneic hematopoietic stem cell transplantation (allo-HSCT) is associated with improved progression-free survival (PFS), with a significant odds ratio of 0.36, indicating a lower risk of disease progression.

While higher CD34+ cell doses may enhance PFS, they also raise concerns about potential complications, such as graft-versus-host disease (GVHD), highlighting the need for careful consideration of cell dosing in transplantation protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of CD34+ Cell Dose with Progression-free Survival after Allogeneic Peripheral Blood Hematopoietic Cell Transplantation in Children with Hematologic Malignancies. Wang, YL., Chang, TY., Hsieh, HY., et al.[2023]

In a study of 21 patients over 5 years, it was found that intestinal transplants can lead to long-term mixed chimerism, where both donor and recipient blood cells coexist, indicating a potential for immune tolerance.

Donor-derived hematopoietic stem and progenitor cells (HSPCs) were identified in various tissues, including the intestines and liver, suggesting that these cells may play a role in promoting tolerance and immune acceptance in transplant recipients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human Intestinal Allografts Contain Functional Hematopoietic Stem and Progenitor Cells that Are Maintained by a Circulating Pool. Fu, J., Zuber, J., Martinez, M., et al.[2022]

CD34+ marrow cells can be purified to over 98% using specific techniques, allowing for the potential use of these cells in both autologous and allogeneic transplantation.

Distinct subsets of CD34+ cells exhibit different functions: CD34+/CD18- cells are less immunogenic and may be better for engrafting in allogeneic transplants, while CD34+/CD86+ cells have strong alloantigen presenting capabilities, suggesting tailored approaches could enhance transplantation success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alloantigen presenting function of normal human CD34+ hematopoietic cells. Rondelli, D., Andrews, RG., Hansen, JA., et al.[2021]

In a study involving 11 transplant recipients, it was found that those who received CD34(+)-selected transplants had a similar frequency of Lin(-)CD34(-) precursor cells compared to normal donors and recipients of other transplant types, suggesting no immediate difference in cell population.

However, the Lin(-)CD34(-) cells from CD34-enriched transplant recipients did not develop into CD34(+) cells or show colony-forming activity after 7 days in culture, indicating a potential defect in their ability to differentiate, which may have long-term clinical implications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Absence of a CD34- hematopoietic precursor population in recipients of CD34+ stem cell transplantation. Kato, S., Ando, K., Nakamura, Y., et al.[2006]

In a study involving 32 patients, CD34+ cell selection for transplantation showed comparable hematopoietic recovery to unmanipulated peripheral blood stem and progenitor cells (PBPCs), despite a lower efficiency in collecting certain cell types like burst-forming units-erythroid (BFU-E).

A critical dose of 5 x 10(6) CD34+ cells or 40 x 10(4) colony-forming units-granulocyte-macrophage (CFU-GM) per kg is necessary for ensuring rapid recovery of neutrophils and overall hematopoietic function post-transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematopoietic recovery in cancer patients after transplantation of autologous peripheral blood CD34+ cells or unmanipulated peripheral blood stem and progenitor cells. Beguin, Y., Baudoux, E., Sautois, B., et al.[2019]

A minimum threshold of 1-2 x 10^6 CD34+ cells/kg is necessary for adequate hematopoietic cell transplantation, while doses greater than 5 x 10^6 CD34+ cells/kg lead to faster engraftment and lower graft failure rates.

The timing and coordination of peripheral blood progenitor cell (PBPC) collection with chemotherapy cycles are crucial, as prior treatments can significantly affect the quality and quantity of CD34+ cells collected.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of CD34+ peripheral blood progenitor cell dose on hematopoietic recovery. Shpall, EJ., Champlin, R., Glaspy, JA.[2019]

Transplantation of allogeneic peripheral blood-derived CD34+ cells in 10 patients with advanced hematologic malignancies resulted in successful hematologic reconstitution, with neutrophil and platelet engraftment occurring within 10 and 16 days, respectively.

The procedure demonstrated a low incidence of acute graft-versus-host disease (GVHD), with only 4 out of 10 patients developing mild cases, indicating that this method is both feasible and safe for long-term engraftment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic transplantation of positively selected peripheral blood CD34+ progenitor cells from matched related donors. Finke, J., Brugger, W., Bertz, H., et al.[2015]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2693630/

Co-transplantation of Human Mesenchymal Stem Cells ... In the present study, we evaluated whether the efficacy of hematopoietic stem cell transplantation is improved by their co-transplantation with MSC, and whether ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S2666636723012952

Efficacy and Safety of CD34+ Stem Cell Boost for Delayed ... Autologous stem cell boosts can be effectively and safely used to promote hematopoietic recovery for post-CAR T cytopenias in patients with RRMM.

3. astctjournal.org astctjournal.org/article/S2666-6367(21)00628-X/fulltext

CD34+ Stem Cell Selection and CD3+ T Cell Add-Back ... The results we present show that an addback of 30 × 106 donor CD3+ cells/kg recipient BW to a MUD BM or PBSC-derived CD34+ selection gives promising results in ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2980678/

Autologous CD34+ and CD133+ stem cells transplantation ... RESULTS: Near normalization of liver enzymes and improvement in synthetic function were observed in 54.5% of the group 1 patients; 13.6% of the patients showed ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT03626285

Bone Marrow Transplantation Using CD34-Selected Stem ... This expanded access protocol studies bone marrow transplantation using CD34-selected stem cells from related or unrelated donors in treating participants with ...

6. recruit.cumc.columbia.edu recruit.cumc.columbia.edu/studyinfopage/2816

CD34+ Stem Cell Infusion in Post Intestinal Transplant Patients Additional Study Information: The purpose of this study is to study the safety and feasibility of giving intestinal transplant patients CD34+ stem cells ...

7. astctjournal.org astctjournal.org/article/S2666-6367(23)01295-2/pdf

Efficacy and Safety of CD34+ Stem Cell Boost for Delayed ... Patients were considered eligible for stem cell boost if they had CD34+ autologous hematopoietic stem cells available in storage, col- lected ...