CRISPR CAR-T Cell Therapy for B-Cell Lymphoma

Recruiting at 34 trial locations

Overseen By Socorro Portella, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Caribou Biosciences, Inc.

Must not be taking: Corticosteroids

Disqualifiers: CNS lymphoma, Seizure disorder, 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

72 Participants Needed

Trial Summary

What is the purpose of this trial?

CB010A is a study evaluating safety, emerging efficacy, pharmacokinetics and immunogenicity of CB-010 in adults with relapsed/refractory B cell non-Hodgkin lymphoma after lymphodepletion consisting of cyclophosphamide and fludarabine.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on systemic corticosteroid therapy or have a thyroid disorder not controlled with stable hormone replacement, you may not be eligible to participate.

What data supports the effectiveness of this treatment for B-Cell Lymphoma?

Research shows that CD19-specific CAR T-cell therapy is effective against relapsed or refractory B-cell lymphoma, and allogeneic CAR-T cells, which are derived from healthy donors, offer a promising 'off the shelf' option with standardized quality. Preliminary data from early clinical trials of allogeneic CARs is encouraging, suggesting potential effectiveness in treating lymphoma. ^{1 2 3 4 5}

Is CRISPR CAR-T Cell Therapy for B-Cell Lymphoma safe for humans?

CRISPR CAR-T cell therapy has been tested in several studies for B-cell lymphoma and other conditions, showing a generally safe profile. Common side effects include cytokine release syndrome (a reaction where the immune system releases too many proteins into the blood too quickly), but serious neurotoxicity (nerve damage) was not observed. Some studies noted potential risks related to genome editing, but overall, the therapy was well-tolerated in patients. ^{3 6 7 8 9}

What makes the CRISPR CAR-T Cell Therapy for B-Cell Lymphoma unique compared to other treatments?

This treatment is unique because it uses CRISPR technology to edit genes in T-cells from healthy donors, creating an 'off the shelf' therapy that is immediately available and standardized, unlike traditional CAR-T therapies that are made from a patient's own cells and take longer to produce. ^{2 10 11 12 13}

Eligibility Criteria

Adults over 18 with relapsed/refractory B cell non-Hodgkin lymphoma who've had standard treatments can join. They must be fairly healthy, able to perform daily activities (ECOG status 0 or 1), and have good organ function. Excluded are those needing steroids, with certain neurological or autoimmune diseases, previous anti-CD19 therapy, stem cell transplants, CNS lymphoma/malignancy, primary immunodeficiency, active thyroid disorders (except stable hypothyroidism), and other recent cancers.

Inclusion Criteria

My blood, kidney, liver, heart, and lung functions are all within normal ranges.

My non-Hodgkin lymphoma has returned or didn't respond after standard treatment.

I am fully active or can carry out light work.

Exclusion Criteria

I haven't had any other cancers in the last 2 years, except those fully treated or unlikely to come back.

Unwillingness to follow extended safety monitoring

You have a weakened immune system from a medical condition you were born with.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepletion

Participants undergo lymphodepletion with cyclophosphamide and fludarabine before receiving CB-010

1 week

Dose Escalation

Participants receive CB-010 in a dose-escalation format to determine the optimal dose

28 days

Multiple visits for monitoring

Expansion

Participants receive CB-010 at the determined optimal dose

Up to 12 months

Regular visits for monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• CB-010
• Cyclophosphamide
• Fludarabine

Trial Overview The ANTLER trial is testing CB-010 after a pre-treatment ('lymphodepletion') with fludarabine and cyclophosphamide in adults with advanced B cell non-Hodgkin lymphoma. It aims to assess the safety of this CRISPR-edited CAR-T therapy as well as its potential effectiveness and how the body processes it.

Participant Groups

Group I: Expansion of CB-010 Experimental Treatment 3 Interventions

Patients with relapsed or refractory non-Hodgkin lymphoma will receive CB-010 following lymphodepletion.

Group II: Dose Escalation of CB-010 Experimental Treatment 3 Interventions

Patients with relapsed or refractory non-Hodgkin lymphoma will receive CB-010 following lymphodepletion.

CB-010 is already approved in United States for the following indications:

Approved in United States as CB-010 for:

• Relapsed/Refractory Large B Cell Lymphoma (LBCL)
• Relapsed/Refractory B Cell Non-Hodgkin Lymphoma (B-NHL)

Who Is Running the Clinical Trial?

Caribou Biosciences, Inc.

Lead Sponsor

Trials

5

Recruited

360+

Findings from Research

The novel CD19-PD-1/CD28 chimeric antigen receptor (CAR) T-cell therapy showed improved T-cell proliferation and effectiveness in killing PD-L1+ B-cell lymphoma cells, demonstrating enhanced efficacy compared to standard CD19 CAR T cells.

In a phase Ib study involving 17 adult patients with refractory or relapsed B-cell lymphoma, 58.8% of patients achieved an objective response, with 41.2% reaching complete remission, and the treatment was well-tolerated with no severe side effects reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19-specific CAR T Cells that Express a PD-1/CD28 Chimeric Switch-Receptor are Effective in Patients with PD-L1-positive B-Cell Lymphoma. Liu, H., Lei, W., Zhang, C., et al.[2022]

Allogeneic CAR-T therapies, derived from healthy donors, offer a promising alternative to autologous CAR-Ts by providing ready-to-use products that are standardized and potentially more effective due to their ability to bypass the immunosuppressive tumor environment.

While allogeneic CARs show encouraging preliminary results in early-phase clinical trials, they require genomic editing to prevent complications like graft versus host disease (GvHD), highlighting the need for further research to ensure their safety and feasibility in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic Chimeric Antigen Receptor Therapy in Lymphoma. Khurana, A., Lin, Y.[2022]

In a clinical trial involving 21 adults with relapsed/refractory B cell non-Hodgkin's lymphoma, the virus-free CAR-T cell therapy PD1-19bbz showed promising efficacy, with 18 out of 21 patients achieving complete response and a median progression-free survival of 19.5 months.

The treatment had a manageable safety profile, with no dose-limiting toxicities reported, although some patients experienced low-grade cytokine release syndrome and hematologic toxicities, indicating that PD1-19bbz could be a safer alternative to traditional CAR-T therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of CRISPR-based non-viral PD1 locus specifically integrated anti-CD19 CAR-T cells in patients with relapsed or refractory Non-Hodgkin's lymphoma: a first-in-human phase I study. Hu, Y., Zu, C., Zhang, M., et al.[2023]

In a study involving 3 patients with relapsed/refractory B-cell malignancies, the novel CD19-KIRS2/Dap12-BB CAR-T cells showed significant short-term efficacy, achieving complete remission in one patient with B-cell acute lymphoblastic leukemia and partial remission in two patients with non-Hodgkin's lymphoma.

While the treatment resulted in manageable adverse reactions, including cytokine release syndrome and hematologic issues, the overall survival rates were promising, with patients living 282, 430, and 338 days post-treatment, indicating potential but highlighting the need for further research on long-term efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Novel CD19-KIRS2/Dap12-BB CAR-T Treatment for 3 Patients with Relapsed and Refractory B-Cell Tumors]. Ji, SW., Hua, T., Wang, JJ., et al.[2023]

CAR-T cell therapy demonstrated a high overall response rate of 85.2% in 27 patients with relapsed/refractory B cell non-Hodgkin lymphoma, with a complete response rate of 63.0% after a median follow-up of 32 months.

While adverse reactions like cytokine release syndrome and myelosuppression were common, they were manageable, and patients achieving a complete response had significantly better long-term survival rates compared to those who did not.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term efficacy of CAR-T cell therapy for patients with relapsed/refractory B cell non-Hodgkin lymphoma. Fu, S., Hu, Y., Huang, H.[2022]

In a phase I study involving 10 patients with refractory diffuse large B-cell lymphoma (DLBCL), the anti-CD19 CAR T cell therapy (C-CAR011) demonstrated a 50% overall response rate at 12 weeks, indicating promising efficacy for this treatment.

The therapy showed a favorable safety profile, with 90% of patients experiencing cytokine release syndrome but no severe (grade ⩾ 3) cases or neurotoxicity, suggesting it is a safe option for patients with heavily treated DLBCL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of CBM.CD19 chimeric antigen receptor T cell in the treatment of refractory diffuse large B-cell lymphoma in Chinese patients. Fan, L., Wang, L., Cao, L., et al.[2022]

The study demonstrated that using CRISPR/Cas9 to knock out the TCR gene in ARI-0001 CAR-T cells can effectively disrupt the TCR without significantly altering the T cell phenotype, achieving over 80% efficiency.

While this method shows promise for creating allogeneic CAR-T cells with maintained anti-tumor activity, there are potential safety risks due to possible large deletions in the genome that require careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of universal (TCRKO) ARI-0001 CAR-T cells for the treatment of B-cell lymphoma. Maldonado-Pérez, N., Tristán-Manzano, M., Justicia-Lirio, P., et al.[2022]

The study reports on three patients with relapsed B-cell lymphomas who were treated with autologous T cells modified to express a CD20-targeted chimeric antigen receptor (CAR), showing promising clinical efficacy.

The treatment demonstrated a favorable safety profile, indicating that genetically modified T cells can be a viable option for patients with relapsed B-cell lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CARs and cancers: questions and answers. Brentjens, RJ.[2021]

In a phase 1 clinical trial involving 14 patients with relapsed/refractory acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL), the novel Sleeping Beauty (SB) CD19-specific CAR T-cell therapy demonstrated a strong safety profile, with no serious adverse events directly linked to the treatment and only mild cytokine release syndrome observed.

Efficacy results showed that 38% of patients with ALL achieved complete remission or incomplete count recovery, and 50% of patients with diffuse large B-cell lymphoma (DLBCL) also achieved complete remission, indicating promising antitumor activity of the SB-based CAR constructs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sleeping beauty generated CD19 CAR T-Cell therapy for advanced B-Cell hematological malignancies. Singh, H., Srour, SA., Milton, DR., et al.[2023]

CAR T-cell therapy is becoming a groundbreaking treatment for aggressive non-Hodgkin B-cell lymphoma, showing promise in improving patient outcomes.

The review discusses not only the efficacy of CAR T-cell therapy but also highlights the potential short- and long-term toxicities associated with the treatment, emphasizing the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T-Cell Therapy in Aggressive B-Cell Lymphoma. Hamilton, MP., Miklos, DB.[2023]

CRISPR/Cas9 gene editing technology is a powerful tool that enhances immune cell therapy for treating lymphoid cancers, such as lymphoma and leukemia.

The review discusses both current and future applications of CRISPR/Cas9 in engineering immune cells, while also addressing challenges and optimizations needed for effective use in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Utilization of CRISPR/Cas9 gene editing in cellular therapies for lymphoid malignancies. Mehravar, M., Roshandel, E., Salimi, M., et al.[2021]

CAR-T-cell therapy has shown significant promise in treating relapsed or refractory B-cell malignancies, such as B-cell non-Hodgkin lymphoma and B-cell acute lymphoblastic leukemia, by targeting specific antigens like CD19 and BCMA.

The review highlights both the efficacy and toxicity of CD19- and BCMA-targeted CAR-T-cell therapies, indicating that while these treatments can be effective, they also come with potential side effects that need to be managed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor-T-Cell Therapy for B-Cell Hematological Malignancies: An Update of the Pivotal Clinical Trial Data. Roex, G., Feys, T., Beguin, Y., et al.[2020]

Anti-CD19 CAR T-cell therapy has demonstrated significant clinical activity in treating B-cell non-Hodgkin lymphoma (NHL), with objective response rates ranging from 50-83% for relapsed diffuse large B-cell lymphoma (DLBCL), 83-93% for follicular lymphoma (FL), and 93% for mantle cell lymphoma (MCL).

This therapy represents a promising treatment option for patients with poor-risk refractory B-cell NHLs, highlighting its potential efficacy in difficult-to-treat cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-CD19 chimeric antigen receptor T-cell therapy in B-cell lymphomas: current status and future directions. Chavez, JC., Yassine, F., Sandoval-Sus, J., et al.[2022]

References

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

CD19-specific CAR T Cells that Express a PD-1/CD28 Chimeric Switch-Receptor are Effective in Patients with PD-L1-positive B-Cell Lymphoma. [2022]

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

Allogeneic Chimeric Antigen Receptor Therapy in Lymphoma. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Safety and efficacy of CRISPR-based non-viral PD1 locus specifically integrated anti-CD19 CAR-T cells in patients with relapsed or refractory Non-Hodgkin's lymphoma: a first-in-human phase I study. [2023]

4. China pubmed.ncbi.nlm.nih.gov

[Novel CD19-KIRS2/Dap12-BB CAR-T Treatment for 3 Patients with Relapsed and Refractory B-Cell Tumors]. [2023]

5. China pubmed.ncbi.nlm.nih.gov

Long-term efficacy of CAR-T cell therapy for patients with relapsed/refractory B cell non-Hodgkin lymphoma. [2022]

6. China pubmed.ncbi.nlm.nih.gov

Phase I study of CBM.CD19 chimeric antigen receptor T cell in the treatment of refractory diffuse large B-cell lymphoma in Chinese patients. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy and safety of universal (TCRKO) ARI-0001 CAR-T cells for the treatment of B-cell lymphoma. [2022]

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

CARs and cancers: questions and answers. [2021]

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

Sleeping beauty generated CD19 CAR T-Cell therapy for advanced B-Cell hematological malignancies. [2023]

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

Chimeric Antigen Receptor T-Cell Therapy in Aggressive B-Cell Lymphoma. [2023]

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

Utilization of CRISPR/Cas9 gene editing in cellular therapies for lymphoid malignancies. [2021]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor-T-Cell Therapy for B-Cell Hematological Malignancies: An Update of the Pivotal Clinical Trial Data. [2020]

13. England pubmed.ncbi.nlm.nih.gov

Anti-CD19 chimeric antigen receptor T-cell therapy in B-cell lymphomas: current status and future directions. [2022]