Gene Therapy for Non-Hodgkin's Lymphoma

(NatHaLi-01 Trial)

Recruiting at 19 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new gene therapy called UCART20x22 for individuals with B-Cell Non-Hodgkin's Lymphoma (B-NHL) that has recurred or resisted treatment. The main goal is to determine the safest and most effective dose. Participants will receive the treatment through an IV (intravenous) to assess its potential in fighting cancer. The trial seeks individuals who have tried at least two other treatments without success and have specific types of B-NHL, excluding those with certain other conditions. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

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.

Is there any evidence suggesting that UCART20x22 is likely to be safe for humans?

Research has shown that UCART20x22 demonstrates promising safety results in early studies. At the initial dose level, treatment with UCART20x22 was safe and well-tolerated. Importantly, no serious side effects were reported that would prevent increasing the dose, nor were there any brain-related side effects. Additionally, cytokine release syndrome, a reaction that can occur with immune treatments, was mild in all patients. These findings suggest that UCART20x22 is safe at lower doses, but further testing is ongoing to confirm this and determine the optimal dose. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

UCART20x22 is unique because it represents a groundbreaking approach to treating Non-Hodgkin's Lymphoma by utilizing gene-edited T-cells. Unlike traditional therapies such as chemotherapy and monoclonal antibodies, UCART20x22 is designed to target cancer cells more precisely by modifying the patient's own immune cells to better recognize and attack the lymphoma cells. This innovative use of gene editing not only enhances the specificity of the immune response but also holds the potential to minimize side effects compared to conventional treatments. Researchers are excited about this treatment because it could provide a more effective and targeted therapy option for patients, potentially improving outcomes and quality of life.

What evidence suggests that UCART20x22 might be an effective treatment for Non-Hodgkin's Lymphoma?

Research has shown that UCART20x22, the investigational treatment in this trial, may effectively treat B-Cell Non-Hodgkin Lymphoma (B-NHL) that has recurred or resisted other treatments. In early studies, UCART20x22 reduced cancer in 86% of patients, with 57% showing no signs of cancer afterward. This suggests it might benefit many with this type of lymphoma. Additionally, UCART20x22 was detected in cancer samples post-treatment, indicating it actively targets cancer cells. These findings suggest that UCART20x22 could be a promising treatment for B-NHL. ^{1 2 3 5 6}

Who Is on the Research Team?

Jeremy Abramson, MD

Principal Investigator

Harvard Medical School - Massachusetts General

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. cellectis.com cellectis.com/uploads/files/UCART20x22_ASH_Poster_final.pdf

A First-In-Human Phase I/IIa Study of UCART20x22, a - Cellectis UCART20x22 was detected in one patient's post-treatment tumor biopsy. ▫ Overall, these data support the preliminary safety and efficacy of UCART20x22 in this R/ ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05607420

NCT05607420 | Study Evaluating UCART20x22 in B-Cell ... The purpose of this study is to evaluate the safety and clinical activity of UCART20x22 and determine the Maximum Tolerated Dose (MTD) and Recommended Phase 2 ...

3. finance.yahoo.com finance.yahoo.com/news/cellectis-present-development-eti-cel-141500760.html

Cellectis to Present a Development Update for eti-cel at ... Preliminary data recently shared for eti-cel (UCART20x22) show an 86% ORR and a 57% CR rate (n=7), underscoring its potential to improve ...

4. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/2110/499367/Preliminary-Results-of-Nathali-01-A-First-in-Human

Preliminary Results of Nathali-01: A First-in-Human Phase I/IIa ... Methods: The primary endpoints are safety, tolerability, and determining the recommended phase 2 dose of UCART20x22. Additional endpoints ...

5. theglobeandmail.com theglobeandmail.com/investing/markets/stocks/CMVLF/pressreleases/34670164/cellectis-sas-promising-study-on-ucart20x22-for-b-cell-non-hodgkin-lymphoma/

Cellectis SA's Promising Study on UCART20x22 for B-Cell ... ... Non-Hodgkin Lymphoma (B-NHL) aims to assess the safety and clinical effectiveness of UCART20x22. This study is significant as it seeks to ...

6. sciencedirect.com sciencedirect.com/science/article/abs/pii/S000649712308713X

Preliminary Results of Nathali-01: A First-in-Human Phase I ... Summary: Treatment with UCART20x22 at DL1 has been safe and well-tolerated, with no UCART20x22 DLTs or ICANS, and CRS was <G3 in all pts. There was 1 DLT of ...