Metabolically Fit CD19 CAR T-Cell Therapy for Non-Hodgkin's Lymphoma and Chronic B-Cell Leukemia

Overseen By Jasmin Brooks

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Medical University of South Carolina

Disqualifiers: Pregnancy, Active CNS lymphoma, Uncontrolled infections, 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

Duration: 12 months

27 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment, CD19-CD34t metabolically programmed CAR T-cell therapy, for individuals with certain types of non-Hodgkin's lymphoma or chronic lymphocytic leukemia that have returned or resisted standard treatments. The goal is to determine if this therapy can help when other treatments have failed. Participants will receive varying doses to identify the most effective one. Suitable candidates for this trial have these specific cancers and have undergone at least one previous treatment that was ineffective or ceased to work. As a Phase 1 trial, participants will be among the first to receive this new treatment, aiding researchers in understanding its effects in people.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, guidelines about stopping lymphoma-directed therapy before certain procedures are mentioned, so it's best to discuss your specific medications with the trial team.

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

Research shows that a new treatment, CD19-CD34t CAR T-cell therapy, is under study to assess its safety for people. Patients who received similar treatments in the past have generally tolerated them well. However, some experienced side effects such as fever, tiredness, and low blood cell counts. These side effects often occur because the treatment activates the immune system to fight cancer.

Currently, this treatment remains in the testing phase, with scientists closely monitoring for any negative effects. It's important to note that the FDA has not yet approved this therapy, so researchers continue to gather safety information. For those considering joining a trial, these findings can provide insight into safety expectations, but discussing with a healthcare provider is also crucial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about CD19-CD34t metabolically programmed CAR T-cell therapy because it offers a novel approach to treating Non-Hodgkin's Lymphoma and Chronic B-Cell Leukemia. Unlike standard treatments like chemotherapy and monoclonal antibodies, this therapy uses genetically engineered T-cells that are programmed to specifically target and attack cancer cells expressing the CD19 protein. This method not only aims for more precise cancer cell elimination but also has the potential to reduce collateral damage to healthy cells, potentially leading to fewer side effects and improved outcomes. Additionally, the metabolic programming of these CAR T-cells could enhance their longevity and effectiveness within the body, offering new hope for patients with these conditions.

What evidence suggests that this treatment might be an effective treatment for non-Hodgkin's lymphoma and chronic B-cell leukemia?

Research shows that CD19-targeted CAR T-cell therapy has revolutionized the treatment of certain blood cancers, such as non-Hodgkin's lymphoma and chronic lymphocytic leukemia. This treatment modifies a patient's immune cells to attack cancer cells. Studies have found that these therapies can benefit patients whose cancer did not respond to other treatments. In this trial, participants will receive varying doses of a new version of these therapies, called metabolically programmed CAR T-cells. Early results suggest this version might work more effectively and last longer. Although more research is needed, this approach appears promising for treating challenging blood cancers. ^{1 4 6 7 8}

Who Is on the Research Team?

Brian T. Hess

Principal Investigator

Medical University of South Carolina

Are You a Good Fit for This Trial?

Adults with certain types of B-cell lymphomas or leukemia who've had at least two prior treatments can join this trial. They must be over 18, in fair health (ECOG 0-2), and have someone to help care for them after treatment. People with active brain lymphoma, recent heart issues, uncontrolled infections, or those who are pregnant/breastfeeding cannot participate.

Inclusion Criteria

I have hepatitis B, C, or HIV and meet the specific health criteria.

My lymphoma is confirmed to be CD19 positive.

I am able to get out of my bed or chair and move around.

Exclusion Criteria

I have an autoimmune disease and haven't taken immunosuppressants in the last year.

I have not had a stroke or brain bleed in the last 6 months.

I have active cancer in my brain or spinal cord.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive metabolically programmed CD19 CAR T-cell therapy with CD34 selection markers in a dose-escalation and dose-expansion format

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, including evaluations of progression free survival, duration of response, and overall survival

12 months

Long-term Follow-up

Participants are monitored for long-term safety and efficacy, including ICANS and CRS occurrence evaluations

up to 24 months

What Are the Treatments Tested in This Trial?

Interventions

• CD19-CD34t metabolically programmed CAR T-cell therapy

Trial Overview The study is testing a new CAR T-cell therapy that targets CD19 on cancer cells. It's given after chemotherapy drugs Cyclophosphamide and Fludarabine to prepare the body. The trial will start with lower doses of the CAR T-cells and increase them to find the best dose without severe side effects.

How Is the Trial Designed?

Group I: Dose Level 3 Experimental Treatment 3 Interventions

2 x 10\^6 transduced T cells/kg (± 20%)

Group II: Dose Level 2 Experimental Treatment 3 Interventions

1.5 x 10\^6 transduced T cells/kg (± 20%)

Group III: Dose Level 1 Experimental Treatment 3 Interventions

1 x 10\^6 transduced T cells/kg (± 20%)

CD19-CD34t metabolically programmed CAR T-cell therapy is already approved in United States, European Union for the following indications:

Approved in United States as Yescarta (axicabtagene ciloleucel) for:

• Relapsed/refractory large B-cell lymphoma (LBCL)
• Follicular lymphoma (FL)

Approved in United States as Kymriah (tisagenlecleucel) for:

• Relapsed/refractory B-cell precursor acute lymphoblastic leukemia (B-ALL)
• Diffuse large B-cell lymphoma (DLBCL)
• Follicular lymphoma (FL)

Approved in United States as Tecartus (brexucabtagene autoleucel) for:

• Relapsed/refractory mantle cell lymphoma (MCL)

Approved in United States as Breyanzi (lisocabtagene maraleucel) for:

• Relapsed/refractory large B-cell lymphoma (LBCL)
• Follicular lymphoma (FL)

Approved in European Union as Yescarta (axicabtagene ciloleucel) for:

• Relapsed/refractory large B-cell lymphoma (LBCL)
• Follicular lymphoma (FL)

Approved in European Union as Kymriah (tisagenlecleucel) for:

• Relapsed/refractory B-cell precursor acute lymphoblastic leukemia (B-ALL)
• Diffuse large B-cell lymphoma (DLBCL)
• Follicular lymphoma (FL)

Approved in European Union as Tecartus (brexucabtagene autoleucel) for:

• Relapsed/refractory mantle cell lymphoma (MCL)

Approved in European Union as Breyanzi (lisocabtagene maraleucel) for:

• Relapsed/refractory large B-cell lymphoma (LBCL)
• Follicular lymphoma (FL)

Who Is Running the Clinical Trial?

Medical University of South Carolina

Lead Sponsor

Trials

994

Recruited

7,408,000+

Published Research Related to This Trial

The CD22/CD19 dual-targeting CAR-T-cell therapy showed a remarkable overall response rate of 97% and a complete remission rate of 93% in patients with relapsed/refractory acute lymphoblastic leukemia (ALL), based on a meta-analysis of 14 studies involving 405 patients.

For non-Hodgkin lymphoma (NHL), the therapy resulted in an overall response rate of 85% and a complete remission rate of 57%, with manageable side effects such as cytokine release syndrome occurring in 86% of patients, indicating both efficacy and tolerability of this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of CD22 and CD19 dual-targeting chimeric antigen receptor T-cell therapy in patients with relapsed or refractory B-cell malignancies: A meta-analysis. Nguyen, TT., Thanh Nhu, N., Chen, CL., et al.[2023]

Two patients who received CD19-targeted CAR T cell therapy developed lymphoma, highlighting a potential safety concern associated with this treatment.

This case raises important questions about the long-term effects and monitoring of patients undergoing CAR T cell therapy, particularly regarding the risk of secondary malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Unforeseen Development of Lymphoma Derived from piggyBac CAR T Cells. [2021]

CAR-T cell therapy has shown great success in treating blood cancers but faces challenges such as high recurrence rates and limited effectiveness against solid tumors.

Recent strategies focus on enhancing the metabolism of CAR-T cells to improve their adaptability and effectiveness in fighting tumors, both in laboratory settings and in living organisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimization of metabolism to improve efficacy during CAR-T cell manufacturing. Zhang, M., Jin, X., Sun, R., et al.[2022]

CD19-directed CAR T-cell therapy has shown promising results in treating relapsed/refractory B-cell non-Hodgkin lymphoma, with 30-40% of patients achieving durable responses in pivotal phase I/II trials, leading to FDA and EMA approvals for specific therapies.

Despite its effectiveness, the therapy is associated with significant toxicities, such as cytokine release syndrome and neurotoxicity, which can limit its use and present challenges in patient management during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19-directed CAR T-cell therapy in B-cell NHL. Kersten, MJ., Spanjaart, AM., Thieblemont, C.[2021]

A patient with relapsed and refractory B cell acute lymphoblastic leukemia (B-ALL) achieved over 14 months of minimal residual disease-negative remission after receiving CAR-T cell therapy targeting both CD19 and CD22.

This case suggests that dual-targeting CAR-T cell therapy may enhance the durability of remission in B-ALL patients, potentially addressing issues of antigen escape seen with single-target therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Haploidentical CD19/CD22 bispecific CAR-T cells induced MRD-negative remission in a patient with relapsed and refractory adult B-ALL after haploidentical hematopoietic stem cell transplantation. Jia, H., Wang, Z., Wang, Y., et al.[2020]

CAR T cells engineered to target the CD19 antigen have shown significant promise in treating patients with relapsed and refractory B-cell cancers, leading to durable responses even in those who did not receive a stem cell transplant.

While the treatment is effective, it is associated with notable side effects, including cytokine release syndrome and neurological toxicity, which are linked to T cell activation and expansion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Promise of Chimeric Antigen Receptor T-Cell Therapy. Frey, NV., Porter, DL.[2017]

CD19 CAR-T cells with higher mitochondrial function were associated with better treatment responses in patients with acute lymphoblastic leukemia, indicating that mitochondrial health is crucial for their effectiveness.

Switching the culture media from glucose to galactose enhanced mitochondrial activity and improved the efficacy of CAR-T cells in laboratory tests and in mice, suggesting that optimizing cellular metabolism could lead to better cancer treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved CAR-T cell activity associated with increased mitochondrial function primed by galactose. Gross, G., Alkadieri, S., Meir, A., et al.[2023]

In a study of 16 patients with relapsed/refractory aggressive B-cell lymphoma, bispecific CAR T cells targeting both CD19 and CD22 showed a high efficacy, with 87.5% achieving an objective response and 62.5% achieving complete response.

The treatment demonstrated a favorable safety profile, with only one patient experiencing severe cytokine-release syndrome, and no cases of neurotoxicity, suggesting that this dual-targeted approach may be a safe and effective option for lymphoma therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19/CD22 Dual-Targeted CAR T-cell Therapy for Relapsed/Refractory Aggressive B-cell Lymphoma: A Safety and Efficacy Study. Wei, G., Zhang, Y., Zhao, H., et al.[2022]

In a study of 50 patients receiving CD19 CAR-T cell therapy, 36% experienced infectious complications, with a median time to infection of 225 days, indicating that infections can occur well after treatment.

Severe infections were common, with 54.8% leading to significant health issues, including hospitalization and even death in 6% of patients, highlighting the need for ongoing monitoring and improved antimicrobial prophylaxis strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Infectious complications among CD19 CAR-T cell therapy recipients: A single-center experience. Walker, B., Zimmer, AJ., Stohs, EJ., et al.[2023]

CD19-CAR T cell therapy is feasible and safe for treating children and young adults with refractory B-cell malignancies, with a maximum tolerated dose established at 1×10^6 CAR T cells per kg.

The treatment showed potent anti-leukaemic activity, with all toxicities being fully reversible, including severe cases of cytokine release syndrome in 14% of patients, indicating a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lee, DW., Kochenderfer, JN., Stetler-Stevenson, M., et al.[2022]

CAR T-cell therapy has shown great success in treating B-cell cancers, but its effectiveness in solid tumors is still limited due to the challenging tumor environment.

Improving the metabolic fitness of CAR T-cells is crucial for enhancing their ability to reach and attack solid tumors, and recent strategies are being developed to optimize this aspect of CAR T-cell therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Manipulating the Metabolism to Improve the Efficacy of CAR T-Cell Immunotherapy. Pellegrino, M., Del Bufalo, F., De Angelis, B., et al.[2021]

Adoptive therapy using CAR T-cells, specifically targeting CD19, represents a promising new treatment option for patients with high-risk B-cell non-Hodgkin's lymphomas, such as DLBCL and FL, who do not respond to standard therapies.

The review highlights the efficacy and toxicity profiles of CD19-directed CAR T-cell therapy, showing its potential as a viable alternative for patients with poor prognosis, supported by data from both early single-center studies and larger multicenter clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T cell therapy for B-cell lymphomas. Chavez, JC., Locke, FL.[2020]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05702853

NCT05702853 | Metabolically Fit CD19 CAR T-cell ... This is a single-center, nonrandomized, open-label dose-escalation study followed by dose-expansion of CD19- CD34t metabolically programmed CAR T-cell therapy ...

2. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCT05702853

CD19-CD34t Metabolically Programmed CAR T-Cell ... This phase Ib trial tests the safety and effectiveness of CD19-CD34t metabolically programmed chimeric antigen receptor (CAR) T-cell therapy in treating ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7326110/

CAR T-Cell Therapy for B-Cell non-Hodgkin Lymphoma and ... Chimeric antigen receptor-modified (CAR) T cells targeting CD19 have revolutionized the treatment of relapsed or refractory aggressive B-cell lymphomas, ...

4. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/cd19-cd34tagged-metabolically-programmed-car-t-cells

Clinical Trials Using CD19-CD34tagged Metabolically ... CD19-CD34t Metabolically Programmed CAR T-Cell Therapy for the Treatment of ... Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, or Small Lymphocytic Lymphoma.

5. bmccancer.biomedcentral.com bmccancer.biomedcentral.com/articles/10.1186/s12885-024-12651-6

CD19 CAR T cells for B cell malignancies: a systematic review ... CD19-targeted chimeric antigen receptors (CAR) T cells are one of the most remarkable cellular therapies for managing B cell malignancies.

6. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-10201

CD19-CD34t Metabolically Programmed CAR T-Cell ... This phase Ib trial tests the safety and effectiveness of CD19-CD34t metabolically programmed chimeric antigen receptor (CAR) T-cell therapy in treating ...

7. reporter.nih.gov reporter.nih.gov/search/A-CW_pmx6EaTdNPg1apjyw/project-details/11060889

RePORT RePORTER - National Institutes of Health (NIH) | Thus, we hypothesize that ex vivo expansion and programming of CD19-CAR-Ts to metabolically enhanced hybrid T1/17 (Th1/17 and Tc1/17) phenotype will lead to ...

8. journals.lww.com journals.lww.com/hemasphere/fulltext/2023/12000/car_modified_cellular_therapies_in_chronic.8.aspx

CAR-modified Cellular Therapies in Chronic Lymphocytic... As of December 2023, no CAR T-cell product has been approved for the treatment of patients with CLL. A summary of the efficacy and safety results achieved in ...