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

27 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the treatment CD6-CAR Tregs for chronic graft versus host disease?

Research shows that regulatory T cells (Tregs) can help reduce graft-versus-host disease (GVHD) by suppressing harmful immune responses. Additionally, chimeric antigen receptor (CAR) technology has been used successfully in other conditions to redirect T cells to target specific antigens, suggesting potential for effectiveness in this treatment. ^{1 2 3 4 5}

Is CAR T-Cell Therapy for Chronic Graft Versus Host Disease safe for humans?

Regulatory T cells (Tregs), including those modified with chimeric antigen receptors (CARs), have shown a promising safety profile in early clinical trials for treating graft-versus-host disease (GVHD). These treatments have been well tolerated, with no signs of excessive immune suppression, although caution is advised for patients with infections. ^{1 6 7 8 9}

How is the CD6-CAR Tregs treatment different from other treatments for chronic graft-versus-host disease?

The CD6-CAR Tregs treatment is unique because it uses genetically modified regulatory T cells (Tregs) with a chimeric antigen receptor (CAR) to specifically target and suppress immune responses, potentially offering more effective control of chronic graft-versus-host disease compared to traditional Treg therapies. ^{1 3 4 5 8}

What is the purpose of this trial?

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 patients who have chronic graft versus host disease (cGVHD) after an allogeneic hematopoietic cell transplantation (HCT). An allogeneic HCT is an established treatment for benign or malignant blood and marrow conditions where healthy stem cells from a donor are infused into a patient to help the patient's bone marrow make more healthy cells and platelets. GVHD is a systemic disorder that occurs when the graft's immune cells recognize the host as foreign and attack the recipient's body cells. "Graft" refers to transplanted, or donated tissues, and "host" refers to the tissues of the recipient. It is a common complication after allogeneic HCT. The onset of cGVHD is usually within three years of transplantation and has some features of autoimmune diseases. A strategy that minimizes the incidence and severity of cGVHD, without other adverse effects, is needed to improve survival after allogeneic HCT. T regulatory cells are critical for controlling autoimmunity and maintaining immune homeostasis. Patients with active cGVHD have reduced numbers of T regulatory cells compared to patients without GVHD, suggesting that restoration of T regulatory cells in patients with active cGCHD is impaired and insufficient numbers may contribute to cGVHD. Therefore, therapies that augment numbers and function of T regulatory cells may promote tolerance and control of cGVHD. CAR T-cell therapy is a type of treatment in which T cells (a type of immune system cell) are taken from the blood and changed in the laboratory. The gene for a special receptor that binds to a certain protein, CD6, on the patient's cells is added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion. CD6-CAR Tregs combines the CD6-targeted anti-inflammatory response with the immune regulatory properties of T regulatory cells which could generate a more potent and stable T regulatory cell population to promote immune tolerance and long-term disease control in cGVHD.

Research Team

Amandeep Salhotra

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

CCR6 regulates the function of alloreactive and regulatory CD4+ T cells during acute graft-versus-host disease. [2019]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Tissue-specific regulatory T cells: biomarker for acute graft-vs-host disease and survival. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Adoptive transfer of allogeneic regulatory T cells into patients with chronic graft-versus-host disease. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Anti-Interleukin-6 Promotes Allogeneic Bone Marrow Engraftment and Prolonged Graft Survival in an Irradiation-Free Murine Transplant Model. [2019]

5. England 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. [2020]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Regulatory T Cell Therapy of Graft-versus-Host Disease: Advances and Challenges. [2022]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Treatment of graft-versus-host disease with naturally occurring T regulatory cells. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

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

9. United States pubmed.ncbi.nlm.nih.gov

Adoptive transfer of ex vivo expanded regulatory T cells improves immune cell engraftment and therapy-refractory chronic GvHD. [2023]