Gene Therapy for Non-Hodgkin's Lymphoma

(NatHaLi-01 Trial)

Recruiting at 10 trial locations

Overseen By Cellectis Central Contact

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Cellectis S.A.

Must not be taking: Immunosuppressants, Prednisone, others

Disqualifiers: CNS lymphoma, Active infection, Cardiovascular, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

80 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing UCART20x22, a treatment using modified immune cells, in patients with B-Cell Non-Hodgkin Lymphoma that has returned or resisted other treatments. The goal is to see how safe it is and how well it works.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop your current medications, but it does mention that certain prior treatments must be stopped within specific time frames before starting the trial. It's best to discuss your current medications with the trial team to get a clear answer.

What data supports the effectiveness of the treatment UCART20x22 for Non-Hodgkin's Lymphoma?

Research shows that CAR T-cell therapies targeting CD20 and CD22 have been effective in treating B-cell lymphomas, with high response rates and some patients achieving complete remission. Dual-targeting CAR T-cells, like those targeting both CD19 and CD22, have shown promising results in achieving remission in aggressive B-cell lymphoma, suggesting potential effectiveness for UCART20x22. ^{1 2 3 4 5}

Is gene therapy for Non-Hodgkin's Lymphoma, like UCART20x22, generally safe in humans?

The safety data for similar CAR T-cell therapies, which target CD19 and CD22, show that severe side effects like cytokine release syndrome (CRS) and neurotoxicity are rare and reversible. These therapies have been tested in patients with aggressive B-cell lymphomas, and while some patients experienced mild to moderate side effects, the treatments were generally considered safe. ^{1 3 5 6 7}

What makes the treatment UCART20x22 unique for non-Hodgkin's lymphoma?

UCART20x22 is a gene therapy treatment that uses genetically modified T cells to target and kill cancer cells in non-Hodgkin's lymphoma. This approach is unique because it involves modifying the patient's immune cells to enhance their ability to fight the cancer, offering a new strategy compared to traditional treatments like chemotherapy. ^{2 8 9 10 11}

Research Team

Jeremy Abramson, MD

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

This trial is for adults with B-Cell Non-Hodgkin Lymphoma that has come back or hasn't responded to treatment. They must have tried at least two prior treatments, including a specific type of cell therapy if available. People can't join if they've had certain other recent treatments, infections, hypersensitivity reactions, uncontrolled diseases, or another cancer within the last 2 years.

Inclusion Criteria

My condition relapsed or didn't respond after 2 prior treatments.

My condition is a type of non-Hodgkin lymphoma as defined by WHO.

I have my own stem cells stored for a treatment if I'm at high risk of long-lasting blood toxicity.

Exclusion Criteria

Prior use of investigational product within specified time frame prior to start of LD regimen

Active acute or chronic graft versus host disease

History of hypersensitivity to alemtuzumab

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Finding

UCART20x22 tested at several dose levels to determine the Maximum Tolerated Dose (MTD) and/or the Recommended Phase 2 Dose (RP2D)

Varies

Dose Expansion

UCART20x22 administered at the RP2D determined during the dose finding part

Varies

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Treatment Details

Interventions

• UCART20x22

Trial Overview The study tests UCART20x22 (a new therapy) in people with relapsed/refractory B-NHL to find out how safe it is and what dose works best. It's an early-stage trial where everyone gets the experimental treatment intravenously and doctors closely monitor their response.

Participant Groups

Group I: Dose finding part Experimental Treatment 2 Interventions

UCART20x22 tested at several dose levels until the Maximum Tolerated Dose (MTD) and/or the Recommended Phase 2 Dose (RP2D) is identified. Dose expansion part: UCART20x22 administered at the RP2D determined during the dose finding part

UCART20x22 is already approved in United States for the following indications:

Approved in United States as UCART20x22 for:

• Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma (r/r B-NHL)

Who Is Running the Clinical Trial?

Cellectis S.A.

Lead Sponsor

Trials

6

Recruited

200+

Findings from Research

CD22-targeting CAR T-cell therapies show high complete response rates, with 68% in acute lymphoblastic leukemia (ALL) and 64% in non-Hodgkin's lymphoma (NHL), indicating their efficacy in treating these malignancies.

The incidence of severe side effects, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), is low, suggesting that these therapies are relatively safe, especially with dual-targeting CAR T-cells not increasing toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A systematic review and meta-analysis of CD22 CAR T-cells alone or in combination with CD19 CAR T-cells. Fergusson, NJ., Adeel, K., Kekre, N., et al.[2023]

In a phase IIa trial involving 11 patients with relapsed or refractory CD20+ B-cell lymphoma, the use of CAR-modified T cells (CART-20) resulted in an impressive overall response rate of 81.8%, with 6 complete remissions and 3 partial remissions, indicating strong efficacy.

The treatment was well-tolerated with no severe toxicity reported, and the median progression-free survival was over 6 months, suggesting that CART-20 is a promising option for patients with difficult-to-treat lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of CD20-directed Chimeric Antigen Receptor-modified T cells in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an early phase IIa trial report. Zhang, WY., Wang, Y., Guo, YL., et al.[2021]

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]

CAR-T cell therapies show promise for treating non-Hodgkin's and B-cell lymphoma, but the efficacy data comes from small clinical trials with only 522 participants, which may not represent the broader patient population.

Patients in CAR-T trials tend to be younger and predominantly male, and they are followed for shorter periods compared to the general population, suggesting that the effectiveness of CAR-T therapies in real-world settings may differ from trial results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differences in lymphoma patients between chimeric antigen receptor T-cell therapy trials and the general population. Apaydin, EA., Richardson, AS., Baxi, S., et al.[2023]

In a study involving 9 patients with refractory/relapsed B cell lymphoma, a novel anti-CD19 CAR T cell therapy showed a high overall response rate of 77.8%, with 55.6% achieving complete remission.

The treatment demonstrated a favorable safety profile, with only 11.1% of patients experiencing severe cytokine release syndrome and neurotoxicity, while some patients maintained complete remission for over 20 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel dominant-negative PD-1 armored anti-CD19 CAR T cell is safe and effective against refractory/relapsed B cell lymphoma. Liu, X., Zhang, Y., Li, K., et al.[2021]

In a study of 42 patients with relapsed or refractory aggressive B cell lymphoma, the combination of high-dose chemotherapy followed by CD19/22 CAR T cell infusion showed a high overall response rate of 90.5%, indicating strong efficacy for this treatment approach.

The safety profile was favorable, with only 2 patients experiencing grade 3 cytokine release syndrome and 21% experiencing any grade of neurotoxicity, all of which were reversible, suggesting that this therapy is manageable for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19/CD22 Chimeric Antigen Receptor T Cell Cocktail Therapy following Autologous Transplantation in Patients with Relapsed/Refractory Aggressive B Cell Lymphomas. Cao, Y., Xiao, Y., Wang, N., et al.[2022]

In a study of 957 patients receiving CAR T-cell therapy for relapsed/refractory large B-cell lymphomas, the overall nonrelapse mortality (NRM) rate was 5.0%, with the majority of deaths occurring later than 28 days post-infusion, primarily due to infections.

Risk factors for increased NRM included diabetes and elevated ferritin levels at the time of lymphodepletion, which can help guide physicians in selecting and managing patients to minimize these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonrelapse mortality after CAR T-cell therapy for large B-cell lymphoma: a LYSA study from the DESCAR-T registry. Lemoine, J., Bachy, E., Cartron, G., et al.[2023]

T lymphocytes modified with the anti-CD20-CD28-CD137-TCRζ fusion gene demonstrated a significant ability to kill B cell lymphoma cells, achieving a killing rate of approximately 32.89%.

In experiments with nude mice, these engineered T cells effectively inhibited the growth of B cell lymphoma, suggesting a promising new strategy for treating this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Construction of Anti-CD20 Single-Chain Antibody-CD28-CD137-TCRζ Recombinant Genetic Modified T Cells and its Treatment Effect on B Cell Lymphoma. Chen, F., Fan, C., Gu, X., et al.[2018]

Gene therapy is emerging as a promising strategy for treating malignant lymphoma, offering new approaches to improve outcomes for patients who do not respond to conventional treatments like stem cell transplantation.

The three main strategies of gene therapy include directly targeting and killing tumor cells, enhancing the immune response against tumors, and increasing drug resistance in healthy blood cells, which could lead to more effective and personalized treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The current status and future applications of gene therapy and immunogene therapy for malignant lymphoma]. Abe, A., Emi, N.[2012]

Gene therapy shows potential as a new treatment for hematological malignancies like lymphoma, but it requires effective gene transfer and expression in host cells.

Current methods for transferring genes into lymphoma cells face unique challenges, necessitating careful selection of techniques to ensure efficient DNA delivery and expression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy of lymphoma. Buttgereit, P., Schmidt-Wolf, IG.[2012]

Gene therapy strategies for treating B cell lymphomas are still in early research stages, but adoptive immunotherapy using donor leucocyte infusion has shown promising clinical results in aggressive cases.

Current research focuses on using the immune system for treatment, including approaches like introducing toxic 'suicide genes' into B cells and enhancing drug resistance in stem cells, highlighting the need for effective gene delivery methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy for B cell lymphomas. Fielding, AK., Russell, SJ.[2012]

References

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

A systematic review and meta-analysis of CD22 CAR T-cells alone or in combination with CD19 CAR T-cells. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Treatment of CD20-directed Chimeric Antigen Receptor-modified T cells in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an early phase IIa trial report. [2021]

3. 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]

4. Italy pubmed.ncbi.nlm.nih.gov

Differences in lymphoma patients between chimeric antigen receptor T-cell therapy trials and the general population. [2023]

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

A novel dominant-negative PD-1 armored anti-CD19 CAR T cell is safe and effective against refractory/relapsed B cell lymphoma. [2021]

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

CD19/CD22 Chimeric Antigen Receptor T Cell Cocktail Therapy following Autologous Transplantation in Patients with Relapsed/Refractory Aggressive B Cell Lymphomas. [2022]

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

Nonrelapse mortality after CAR T-cell therapy for large B-cell lymphoma: a LYSA study from the DESCAR-T registry. [2023]

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

Construction of Anti-CD20 Single-Chain Antibody-CD28-CD137-TCRζ Recombinant Genetic Modified T Cells and its Treatment Effect on B Cell Lymphoma. [2018]

9. Japan pubmed.ncbi.nlm.nih.gov

[The current status and future applications of gene therapy and immunogene therapy for malignant lymphoma]. [2012]

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

Gene therapy of lymphoma. [2012]

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

Gene therapy for B cell lymphomas. [2012]