CAR T-Cells for Blood Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Mayo Clinic

Must not be taking: Systemic corticosteroids, Immunosuppressive therapy

Disqualifiers: Solid organ transplant, Active infection, CNS involvement, HIV, others

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

Compensation: Varies

Number of Visits: 6

Duration: 1 day

27 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial tests safety, side effects and best dose of B-cell activating factor receptor (BAFFR)-based chimeric antigen receptor T-cells, with fludarabine and cyclophosphamide lymphodepletion, for the treatment of patients with B-cell hematologic malignancies that has come back after a period of improvement (relapsed) or that does not respond to treatment (refractory). BAFFR-based chimeric antigen receptor T-cells is a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein on the patient's cancer 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 for treatment of certain cancers. Giving chemotherapy, such as fludarabine and cyclophosphamide, helps ill cancer cells in the body and helps prepare the body to receive the BAFFR based chimeric antigen receptor T-cells. Giving BAFFR based chimeric antigen receptor T-cells with fludarabine and cyclophosphamide for lymphodepletion may work better for the treatment of patients with relapsed or refractory B-cell hematologic malignancies.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, there is a 100-day washout period required for those who have had prior CD19 directed CAR-T cell therapy.

What data supports the effectiveness of the treatment BAFFR-based CAR T-cells for blood cancer?

Research shows that BAFFR-based CAR T-cells can effectively target and kill various B cell cancers, such as mantle cell lymphoma, multiple myeloma, and acute lymphoblastic leukemia, by binding to specific receptors on cancer cells. This treatment also addresses the issue of cancer cells losing certain markers, which can make other treatments less effective, by targeting a different marker (BAFF-R) that remains present in these cancers. ^{1 2 3 4 5}

Is CAR T-cell therapy safe for humans?

CAR T-cell therapy has shown promise in treating blood cancers, but it comes with safety concerns. Patients may experience serious side effects like cytokine release syndrome (a severe immune reaction) and neurotoxicity (nerve damage), which require careful monitoring and management. ^{6 7 8 9 10}

What makes BAFFR-based CAR T-cell treatment unique for blood cancer?

BAFFR-based CAR T-cells are unique because they target three different receptors (BAFF-R, BCMA, and TACI) on B cell cancers, reducing the chance of cancer cells escaping detection. This approach is different from other CAR T-cell therapies that typically target a single receptor, like CD19. ^{1 3 4 11 12}

Research Team

Mohamed Kharfan-Dabaja, MD

Principal Investigator

Mayo Clinic

Eligibility Criteria

This trial is for patients with various B-cell blood cancers that have either returned after treatment or haven't responded to previous treatments. Participants must meet specific health criteria not detailed here.

Inclusion Criteria

Measurable disease

Hematologic parameters within specified ranges

I can take care of myself and am up and about more than half of my waking hours.

Exclusion Criteria

I had a stem cell transplant using my own cells less than 60 days ago.

I have had a stem cell transplant from a donor.

I have had a solid organ transplant.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Leukapheresis

Patients undergo leukapheresis to collect T cells for modification

1 day

1 visit (in-person)

Lymphodepletion

Patients receive cyclophosphamide and fludarabine or bendamustine to prepare the body for CAR T-cell infusion

3-5 days

3-5 visits (in-person)

Treatment

Patients receive BAFFR-based chimeric antigen receptor T-cells infusion

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 15 years

Multiple visits (in-person and virtual) at specified intervals

Treatment Details

Interventions

• BAFFR-based Chimeric Antigen Receptor T-cells
• Cyclophosphamide
• Fludarabine

Trial Overview The trial is testing a new therapy where patient's T-cells are modified in the lab to attack cancer cells, combined with chemotherapy drugs fludarabine and cyclophosphamide to prepare the body for these engineered T-cells.

Participant Groups

Group I: Treatment (BARRF based chimeric antigen receptor T-cells) Experimental Treatment 12 Interventions

Patients undergo leukapheresis. Patients then receive cyclophosphamide IV, over 60 minutes and fludarabine IV over 30 minutes on day -5 to -3 or bendamustine IV over 10 minutes on days -4 and -3. Patients receive BAFFR based chimeric antigen receptor T-cells IV on day 0. Patients undergo echocardiography and MRI at screening, CT scan, PET scan, bone marrow biopsy/aspirate and blood sample collection throughout the study and tumor biopsy at progression.

Who Is Running the Clinical Trial?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

Findings from Research

BAFF CAR-T cells, developed using a non-viral gene delivery method, effectively target and kill various B cell cancers, including mantle cell lymphoma, multiple myeloma, and acute lymphoblastic leukemia, both in laboratory settings and in animal models.

These CAR-T cells bind to three different BAFF receptors, which helps reduce the risk of cancer cells escaping treatment by losing the targeted antigen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A BAFF ligand-based CAR-T cell targeting three receptors and multiple B cell cancers. Wong, DP., Roy, NK., Zhang, K., et al.[2023]

The development of BAFF-R CAR T cells shows promise in treating B cell malignancies, effectively targeting tumors even when CD19 expression is lost, which is a common issue with current therapies.

In preclinical models, BAFF-R CAR T cells successfully eradicated established tumors and demonstrated antitumor activity against relapsed cases of acute lymphoblastic leukemia (ALL) that had lost CD19 expression, suggesting a potential solution to tumor relapse.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T cells targeting BAFF-R can overcome CD19 antigen loss in B cell malignancies. Qin, H., Dong, Z., Wang, X., et al.[2020]

Chimeric antigen receptor (CAR) and T cell receptor (TCR) engineered T cells show promise in treating blood cancers, particularly with CD19-CAR-T cells demonstrating strong clinical responses in B-cell malignancies.

To enhance the effectiveness and safety of these therapies, researchers are exploring new antigens, improved T cell culture methods, and better administration protocols to address issues like treatment failure and toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overcoming key challenges in cancer immunotherapy with engineered T cells. Arcangeli, S., Mestermann, K., Weber, J., et al.[2021]

CAR T-cell therapy, particularly with agents like Tisagenlecleucel (Kymriah®) and axicabtagene ciloleucel (Yescarta®), has shown strong overall response and survival rates in treating B-cell malignancies, including pediatric acute lymphoblastic leukemia and adult diffuse large B-cell lymphoma.

These therapies utilize the patient's own modified T cells to target CD19, a common antigen in B-cell cancers, and the field is rapidly evolving with new agents and indications being developed for broader applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T-Cell Therapy: Update on the State of the Science. Lamprecht, M., Dansereau, C.[2020]

The novel BAFF-R CAR T-cell therapy shows promise in treating B-cell malignancies, particularly in cases where traditional CD19-targeted therapies may fail due to antigen loss, with effective elimination of BAFF-R expressing tumors demonstrated in mouse models.

This therapy has been developed under strict manufacturing standards and has passed necessary FDA testing, paving the way for a Phase 1 clinical trial in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor efficacy of BAFF-R targeting CAR T cells manufactured under clinic-ready conditions. Dong, Z., Cheng, WA., Smith, DL., et al.[2020]

CAR-T cell therapy has shown remarkable efficacy in treating B cell malignancies, including leukemia, lymphoma, and multiple myeloma, with high response rates, but it comes with significant safety concerns.

The most serious side effects of CAR-T therapy are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), which require supportive care and specific treatments like tocilizumab and steroids to manage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-T Cell Therapy: the Efficacy and Toxicity Balance. Chohan, KL., Siegler, EL., Kenderian, SS.[2023]

A total of 3225 adverse event reports were analyzed for two chimeric antigen receptor T-cell therapies, tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel), revealing that cytokine release syndrome (52.2%) and neurotoxicity (27.2%) were the most common toxicities, often occurring within the first 10 days after treatment.

The study identified specific emerging safety signals, such as a higher risk of cardiomyopathies and gastrointestinal perforations associated with axi-cel, and hepatotoxicity and pupil disorders linked to tisa-cel, highlighting the need for ongoing monitoring of these therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Post-Marketing Surveillance of CAR-T-Cell Therapies: Analysis of the FDA Adverse Event Reporting System (FAERS) Database. Fusaroli, M., Isgrò, V., Cutroneo, PM., et al.[2022]

CAR T-cell therapy is an effective treatment for acute lymphocytic leukemia and B-cell lymphoma, but it requires at least 7 days of hospitalization to monitor for serious side effects like cytokine release syndrome and neurotoxicity.

Early identification and treatment of these toxicities by nursing staff can reverse potentially life-threatening complications, highlighting the importance of objective assessment and consensus grading in managing CAR T-cell therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T-Cell Emergencies: Inpatient Administration, Assessment, and Management. Jackson, S., Wheatley, T.[2021]

CAR-T cell therapy has shown remarkable success in treating B-cell malignancies, but researchers are focused on improving its safety and effectiveness due to risks like cytokine release syndrome and off-target effects.

Innovative safety strategies, such as ON- and OFF-switch CARs and multi-antigen-targeting CAR-T cells, are being developed to enhance the persistence and reduce adverse events associated with CAR-T therapy, paving the way for a new generation of treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engineering Next-Generation CAR-T Cells for Better Toxicity Management. Andrea, AE., Chiron, A., Bessoles, S., et al.[2023]

Chimeric antigen receptor (CAR) T-cell therapy has shown promising results in prolonging survival for patients with relapsed or refractory B-cell malignancies, as evidenced by numerous clinical trials targeting CD19 and CD20.

While CAR T-cell therapy is generally safe and well-tolerated, potential safety concerns include insertional mutagenesis, off-target effects, and inflammatory responses, which need to be carefully monitored.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Advances in immunotherapy of hematological malignancies by using chimeric antigen receptor-modified lymphocytes]. Xu, XJ., Zhao, HZ., Tang, YM.[2018]

Adoptive cell therapy using CAR-modified T cells has shown promising results, achieving complete remission in patients with B cell malignancies over the long term.

There are currently around 100 ongoing clinical trials exploring CAR T cell therapies for various blood cancers and solid tumors, highlighting the rapid advancement and interest in this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The growing world of CAR T cell trials: a systematic review. Holzinger, A., Barden, M., Abken, H.[2018]

CAR T cell therapy is an innovative treatment for patients with relapsed and refractory blood cancers, with two FDA-approved formulations now available and expanding into broader oncology practices.

However, about 50% of patients experience neurological toxicities from this treatment, which can lead to serious complications, highlighting the need for careful monitoring and management of these side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurological Complications of CAR T Cell Therapy. Landry, K., Thomas, AA.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

A BAFF ligand-based CAR-T cell targeting three receptors and multiple B cell cancers. [2023]

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

CAR T cells targeting BAFF-R can overcome CD19 antigen loss in B cell malignancies. [2020]

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

Overcoming key challenges in cancer immunotherapy with engineered T cells. [2021]

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

CAR T-Cell Therapy: Update on the State of the Science. [2020]

5. Germany pubmed.ncbi.nlm.nih.gov

Antitumor efficacy of BAFF-R targeting CAR T cells manufactured under clinic-ready conditions. [2020]

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

CAR-T Cell Therapy: the Efficacy and Toxicity Balance. [2023]

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

Post-Marketing Surveillance of CAR-T-Cell Therapies: Analysis of the FDA Adverse Event Reporting System (FAERS) Database. [2022]

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

Chimeric Antigen Receptor T-Cell Emergencies: Inpatient Administration, Assessment, and Management. [2021]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Engineering Next-Generation CAR-T Cells for Better Toxicity Management. [2023]

10. China pubmed.ncbi.nlm.nih.gov

[Advances in immunotherapy of hematological malignancies by using chimeric antigen receptor-modified lymphocytes]. [2018]

11. Germany pubmed.ncbi.nlm.nih.gov

The growing world of CAR T cell trials: a systematic review. [2018]

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

Neurological Complications of CAR T Cell Therapy. [2021]