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

Trial Summary

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.

What data supports the effectiveness of the treatment CD19-CD34t metabolically programmed CAR T-cell therapy for Non-Hodgkin's Lymphoma and Chronic B-Cell Leukemia?

Research shows that CD19 CAR T-cell therapy has been successful in treating B-cell malignancies like non-Hodgkin's lymphoma, with improved outcomes linked to enhanced mitochondrial function in the cells. Additionally, optimizing the metabolism of CAR T-cells can increase their effectiveness, suggesting that metabolically programmed CAR T-cells could be more effective in treating these conditions. ^{1 2 3 4 5}

Is CD19 CAR T-cell therapy safe for humans?

CD19 CAR T-cell therapy can cause side effects like infections and cytokine release syndrome (a severe immune reaction), but it is generally considered safe with ongoing research to improve safety. Some patients have developed lymphoma from the therapy, and efforts are being made to reduce these risks. ^{6 7 8 9 10}

What makes CD19-CD34t metabolically programmed CAR T-cell therapy unique for treating Non-Hodgkin's Lymphoma and Chronic B-Cell Leukemia?

This treatment is unique because it enhances the metabolic fitness of CAR T-cells, improving their ability to function in challenging environments, which may lead to better outcomes compared to standard CAR T-cell therapies that do not focus on metabolic programming. ^{1 2 3 11 12}

What is the purpose of this trial?

This is a single-center, nonrandomized, open-label dose-escalation study followed by dose-expansion of CD19- CD34t metabolically programmed CAR T-cell therapy in adult patients with relapsed or refractory CD19 B-cell non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).

Research Team

Brian T. Hess

Principal Investigator

Medical University of South Carolina

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Manipulating the Metabolism to Improve the Efficacy of CAR T-Cell Immunotherapy. [2021]

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

Improved CAR-T cell activity associated with increased mitochondrial function primed by galactose. [2023]

3. United States 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. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Optimization of metabolism to improve efficacy during CAR-T cell manufacturing. [2022]

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

CD19-directed CAR T-cell therapy in B-cell NHL. [2021]

6. Denmark pubmed.ncbi.nlm.nih.gov

Infectious complications among CD19 CAR-T cell therapy recipients: A single-center experience. [2023]

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

The Promise of Chimeric Antigen Receptor T-Cell Therapy. [2017]

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

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

9. England 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. [2022]

10. United States 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. [2022]

11. Netherlands pubmed.ncbi.nlm.nih.gov

CAR T cell therapy for B-cell lymphomas. [2020]

12. England 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. [2020]