CAR T-Cell Therapy for Chronic Graft Versus Host Disease

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must be taking: Corticosteroids, Tyrosine kinase inhibitors

Must not be taking: Immunosuppressive therapy, Vaccines

Disqualifiers: Active infection, Uncontrolled illness, Vascular disease, others

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

Compensation: Varies

Number of Visits: 2

Duration: 28 days per cycle

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment using CAR T-cell therapy for individuals with chronic graft versus host disease (cGVHD) following a donor stem cell transplant. In cGVHD, the donor's immune cells attack the patient's body, causing symptoms similar to autoimmune diseases. The trial tests whether modified immune cells (CD6-CAR Tregs) can safely control this reaction and improve patients' health. It suits those who, after a stem cell transplant, still experience moderate to severe cGVHD despite ongoing steroid treatments. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

Will I have to stop taking my current medications?

The trial requires that participants have a stable dose of corticosteroids for at least 14 days before enrolling, and they must not have taken immunosuppressive therapy (except corticosteroids) within 28 days prior to enrollment. This suggests that some medications may need to be adjusted or stopped before participating.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that CD6-CAR Tregs are undergoing safety testing for treating chronic graft versus host disease (cGVHD). This condition can occur after a stem cell transplant when the immune system attacks the body's own cells. In these early studies, researchers aim to assess how well patients tolerate these modified T cells and determine the optimal dose. As a Phase 1 trial, this marks the first time the treatment is tested in humans. So far, studies focus on ensuring the treatment does not cause harmful side effects and is safe to use. Detailed safety information is still being gathered, but reaching this stage suggests researchers believe it is safe enough for human testing. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about CD6-CAR Tregs for chronic graft versus host disease (cGVHD) because they offer a novel approach that could improve outcomes. Unlike standard immunosuppressive treatments that broadly suppress the immune system, CD6-CAR Tregs are engineered to specifically target and regulate immune responses, potentially reducing the risk of widespread immune suppression. This precise targeting could lead to more effective management of cGVHD symptoms with fewer side effects. Additionally, the use of tafasitamab, an antibody that targets B-cells, may enhance the treatment's ability to control problematic immune cells, offering a comprehensive strategy against cGVHD.

What evidence suggests that CD6-CAR Tregs might be an effective treatment for chronic graft versus host disease?

Research has shown that people with chronic graft versus host disease (cGVHD) often have low levels of T regulatory cells, which help manage the immune system. Animal studies suggest that increasing these cells might lessen the severity of cGVHD. In this trial, participants will receive CD6-CAR Tregs, a new type of T regulatory cell designed to boost these cells in the body. This treatment targets a protein called CD6 to help control the immune response. Although this research is in the early stages, the goal is to improve cGVHD by balancing the immune system and reducing harmful reactions. Initial results in animal studies are promising, but more research in humans is needed. ^{1 2 3 4 6}

Who Is on the Research Team?

Amandeep Salhotra

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

Adults with chronic graft versus host disease after a stem cell transplant from a related or haploidentical donor, who have tried at least one FDA-approved therapy and are not responding well to steroids. They must be in relatively good health otherwise, understand the study, consent to it, and agree to use birth control. People with uncontrolled illnesses, recent vaccines, other investigational treatments, unstable heart conditions or active infections can't join.

Inclusion Criteria

Women who can have children must have a recent negative pregnancy test before joining the study. If the urine test is positive or not clear, a blood test will be needed.

I have been treated with an FDA-approved TKI for cGVHD.

My heart's electrical activity is normal, with a QTc of ≤ 480 msec.

Exclusion Criteria

You are currently taking other experimental drugs or biologic treatments.

I have no active cancer except for skin cancer.

I am currently fighting an infection that needs strong medication.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Patients receive CD6-CAR Treg intravenously on day 0, with potential additional cycles of tafasitamab IV post Treg cell infusion

28 days per cycle

Multiple visits for infusion and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, with blood specimen collection and imaging as clinically indicated

Up to 15 years

Monthly for 1 year, then yearly

Dose-escalation and expansion

Dose-escalation study of CD6-CAR Treg cells followed by a dose-expansion study

Varies based on dose level

What Are the Treatments Tested in This Trial?

Interventions

• CD6-CAR Tregs

Trial Overview The trial is testing CD6-CAR T regulatory cells for patients with chronic GVHD post-transplantation. It aims to see if these engineered immune cells can help control autoimmune responses by increasing T regulatory cells that maintain immune balance. The process involves various assessments like MRI and CT scans before infusing the modified T cells back into the patient.

How Is the Trial Designed?

Group I: Treatment (CD6-CAR Treg, tafasitamab) Experimental Treatment 12 Interventions

Donors undergo leukapheresis over 2-4 hours for collection of PBMSc and the manufacturing of CD6-CAR Treg cells over 2 weeks. Patients then receive CD6-CAR Treg intravenously on day 0. Patients may also receive ablation tafasitamab IV post Treg cell infusion on days 1, 4, 8, 15, 22 for 1 cycle. If ablation is not complete by day 28, patients may receive an additional 1-2 cycles per investigator's discretion. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO, CT, and x-ray imaging during screening and as clinically indicated. Patients undergo blood specimen collection on study and during follow-up. Patients may undergo a biopsy on study as well as a lumbar puncture and MRI/CT as clinically indicated on study.

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study involving three children with severe, therapy-refractory graft-versus-host disease (GvHD), the adoptive transfer of polyclonally expanded regulatory T cells (Tregs) from the original stem cell donor led to significant clinical improvement and reduced GvHD activity.

The treatment was well tolerated, showing no signs of overimmunosuppression, but caution is advised for patients with invasive opportunistic infections, highlighting the need for further controlled studies to validate these promising results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive transfer of ex vivo expanded regulatory T cells improves immune cell engraftment and therapy-refractory chronic GvHD. Landwehr-Kenzel, S., Müller-Jensen, L., Kuehl, JS., et al.[2023]

In a study of 74 hematopoietic cell transplant recipients, high levels of skin-homing (CLA(+)) and gut-homing (α(4)β(7)(+)) regulatory T cells (Tregs) at the time of engraftment were associated with significantly lower incidences of acute graft-vs-host disease (aGVHD) in the skin and gut, respectively.

Patients with high frequencies of these tissue-specific Tregs had better overall survival rates (73.4%) and lower nonrelapse mortality (7.5%) compared to those with low Treg levels, suggesting that monitoring Treg levels could help predict patient outcomes and guide treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tissue-specific regulatory T cells: biomarker for acute graft-vs-host disease and survival. Engelhardt, BG., Sengsayadeth, SM., Jagasia, M., et al.[2021]

Treatment with naturally occurring CD4(+)CD25(+) T regulatory cells (Tregs) shows promise as a therapy for graft-versus-host disease (GvHD), a serious complication following bone marrow transplantation that can severely impact patient quality of life and is a leading cause of post-transplant mortality.

The review discusses the rationale for using Tregs, which help maintain immune tolerance and prevent tissue rejection, and highlights ongoing clinical trials that are exploring their effectiveness in treating GvHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of graft-versus-host disease with naturally occurring T regulatory cells. Trzonkowski, P., Dukat-Mazurek, A., Bieniaszewska, M., et al.[2022]

Blocking interleukin-6 (IL-6) in a bone marrow transplantation model led to lasting multi-lineage chimerism for about 12 weeks and significantly improved the survival of donor skin and heart grafts, suggesting a promising alternative to traditional Treg cell therapy.

The treatment with anti-IL-6 resulted in the expansion of endogenous regulatory T cells (Tregs) and inhibited dendritic cell activation, indicating that IL-6 blockade can effectively enhance graft acceptance without the need for irradiation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-Interleukin-6 Promotes Allogeneic Bone Marrow Engraftment and Prolonged Graft Survival in an Irradiation-Free Murine Transplant Model. Granofszky, N., Farkas, AM., Muckenhuber, M., et al.[2019]

A new method for isolating and expanding regulatory T cells (Treg) from donors was successfully developed, resulting in high-purity Treg preparations that were transfused into five patients with chronic graft-versus-host disease (cGvHD).

Two out of five patients showed clinical improvement in cGvHD symptoms after Treg transfusion, while three maintained stable symptoms for up to 21 months, indicating potential efficacy; however, there were also risks, as two patients developed skin cancers months after treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive transfer of allogeneic regulatory T cells into patients with chronic graft-versus-host disease. Theil, A., Tuve, S., Oelschlägel, U., et al.[2021]

Transducing human regulatory T cells (Tregs) with a chimeric antigen receptor (CAR) targeting the HLA class I molecule A2 allows these cells to be effectively activated and exert strong immunosuppressive effects in vitro.

In a mouse model of hematopoietic stem cell transplantation, CAR-modified Tregs were more effective than standard polyclonal Tregs in preventing graft-versus-host disease, suggesting a promising approach for improving transplant outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Driving allotolerance: CAR-expressing Tregs for tolerance induction in organ and stem cell transplantation. Edinger, M.[2018]

Adoptive immunotherapy using chimeric antigen receptor (CAR) technology to create insulin-specific regulatory T cells (cTregs) shows promise for treating graft-versus-host disease, demonstrating functional stability and long-term suppressive capabilities in vivo.

This approach allows for the redirection of T cell specificity and conversion of effector T cells into regulatory T cells, potentially overcoming limitations in isolating antigen-specific Tregs for autoimmune conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regulatory T cells engineered with a novel insulin-specific chimeric antigen receptor as a candidate immunotherapy for type 1 diabetes. Tenspolde, M., Zimmermann, K., Weber, LC., et al.[2020]

Regulatory T cells (Tregs) show promise in preventing and treating graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation, as they help maintain immune balance and promote tissue repair.

Genetic engineering of Tregs may enhance their effectiveness by improving their potency, specificity, and persistence, which could lead to better outcomes in GVHD management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regulatory T Cell Therapy of Graft-versus-Host Disease: Advances and Challenges. Hefazi, M., Bolivar-Wagers, S., Blazar, BR.[2022]

CCR6 plays a crucial role in modulating graft-versus-host disease (GVHD) responses, as shown by a study where CCR6-deficient T cells significantly reduced mortality and morbidity in GVHD models.

While CCR6-deficient regulatory T (Treg) cells can suppress T cell proliferation in lab tests, they are less effective in reducing tissue damage in live models, highlighting the importance of CCR6 for Treg function in GVHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CCR6 regulates the function of alloreactive and regulatory CD4+ T cells during acute graft-versus-host disease. Varona, R., Cadenas, V., Lozano, M., et al.[2019]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05993611

Allogeneic CD6 Chimeric Antigen Receptor T Regulatory ... This phase I trial tests the safety, side effects, and best dose of allogeneic CD6 chimeric antigen receptor T regulatory cells (CD6-CAR Tregs) in treating ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05993611?cond=NCT05993611&rank=1

Allogeneic CD6 Chimeric Antigen Receptor T Regulatory Cells ... It identifies the role of the intervention that participants receive. Types of arms include experimental arm, active comparator arm, placebo comparator arm, ...

3. trialx.com trialx.com/clinical-trials/listings/265647/allogeneic-cd6-chimeric-antigen-receptor-t-regulatory-cells-cd6-car-tregs-for-the-treatment-of-patients-with-chronic-graft-versus-host-disease-after-allogeneic-hematopoietic-cell-transplantation/

Allogeneic CD6 Chimeric Antigen Receptor T Regulatory ... This phase I trial tests the safety, side effects, and best dose of allogeneic CD6 chimeric antigen receptor T regulatory cells (CD6-CAR Tregs) in treating ...

4. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/allogeneic-anti-cd6-car-t-regulatory-cells

Clinical Trials Using Allogeneic Anti-CD6 CAR T-regulatory ... Review the clinical trials studying allogeneic anti-cd6 car t-regulatory cells on this list and use the filters to refine the results by age and location.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11070504/

The impact of regulatory T cells on the graft-versus ... Initial studies in animal models suggest that Treg can attenuate GVHD while preserving GVL, but results vary according to tumor type.

6. app.trialscreen.org app.trialscreen.org/trials/phase-1-allogeneic-cd6-chimeric-antigen-receptor-t-regulatory-cells-car-trial-nct05993611

A Phase 1 Study of CD6-CAR Tregs in Chronic Graft vs ... Participation in this study may help control and potentially treat chronic graft versus host disease, a common complication after stem cell transplantation, by ...