DuoCAR20.19.22-D95 for Non-Hodgkin's Lymphoma

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Kansas Medical Center

Must not be taking: Steroids, Immunosuppressants, Antiproliferatives, Antibodies

Disqualifiers: CLL, CNS involvement, Hepatitis, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 7 days

54 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires stopping certain medications before participation. Steroids must be stopped more than 72 hours before certain procedures, and other immunosuppressive medications must be stopped at least 2 weeks prior. Additionally, some cancer treatments and antibodies have specific stop times before the trial.

What data supports the effectiveness of the treatment DuoCAR20.19.22-D95 for Non-Hodgkin's Lymphoma?

Research shows that similar treatments, like trispecific duoCAR-T cells targeting CD19, CD20, and CD22, have been effective in eliminating B cell tumors in preclinical models by overcoming antigen loss, which is a common cause of treatment failure. This suggests that targeting multiple antigens, as DuoCAR20.19.22-D95 does, could be a promising strategy for treating Non-Hodgkin's Lymphoma. ^{1 2 3 4 5}

What safety data is available for DuoCAR20.19.22-D95 treatment in humans?

The treatment, which targets both CD19 and CD22, has been studied for safety in patients with aggressive B-cell lymphoma. Most patients experienced mild to moderate cytokine release syndrome (a reaction that can cause fever and flu-like symptoms), with only one severe case reported, and no neurotoxicity (nerve damage) was observed. ^{6 7 8 9 10}

How is the treatment DuoCAR20.19.22-D95 different from other treatments for non-Hodgkin's lymphoma?

DuoCAR20.19.22-D95 is unique because it targets three different antigens (CD19, CD20, and CD22) on B-cell tumors, which helps prevent the cancer from escaping treatment by losing one of these targets. This trispecific approach is designed to be more effective than treatments targeting a single antigen, reducing the chance of relapse. ^{1 2 6 11 12}

What is the purpose of this trial?

This multicenter phase 1 trial with "3 + 3" dose escalation design seeks to examine the feasibility and safety of the administration of autologous T cells that have been modified through the introduction of chimeric antigen receptors targeting the B cell surface antigens CD19/20/22 following administration of a chemotherapy lymphodepletion regimen in adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) or Non-Hodgkin's lymphoma (NHL). The overall goals of this study are to estimate maximum tolerated dose (MTD) level, establish the overall safety profile and evaluate initial efficacy of administering duo-CAR-T cell treatment in this patient population.

Research Team

Joseph McGuirk, D.O.

Principal Investigator

University of Kansas Medical Center

Eligibility Criteria

Adults with B-cell malignancies that have come back or didn't respond to treatment can join. They must be fit for chemotherapy and T cell modification therapy. People are excluded if they've had certain treatments recently, have active infections, or other serious health issues.

Inclusion Criteria

My cancer is a type of aggressive B-Cell NHL or ALL.

I am eligible for or have had a leukapheresis procedure.

Ability of participant to understand this study, and participant willingness to sign a written informed consent

Exclusion Criteria

I currently have COVID-19.

I haven't had chemotherapy other than for immune preparation in the last 2 weeks.

I have not had radiation therapy in the last 2 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepletion

Participants receive lymphodepletion chemotherapy with Fludarabine and Cyclophosphamide

6 days

Inpatient

Treatment

Participants receive DuoCAR20.19.22-D95 CAR T cell infusion

7 days

Inpatient

Dose Escalation and Monitoring

DLT assessments and routine safety monitoring

30 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Long-term Follow-up

Observational follow-up for long-term safety and efficacy

15 years

Treatment Details

Interventions

• DuoCAR20.19.22-D95

Trial Overview The trial tests a new therapy called DuoCAR20.19.22-D95 on patients who've relapsed from B-cell lymphoma or leukemia. It involves modifying the patient's own T cells after chemo to see how well it works and what dose is safe.

Participant Groups

Group I: Phase 1 (Dose Escalation) Experimental Treatment 3 Interventions

Lymphodepletion: Fludarabine: Days -6 to -3 (4 days total) Cyclophosphamide: Days -4 and -3 (2 days total) Investigational Treatment: DuoCAR20.19.22-D95 will be infused on day # 0 Patients will receive lymphodepletion chemotherapy and receive the CAR T cell infusion on day 0 (or up to day +14 in extenuating clinical conditions). Patients will be hospitalized inpatient period of at least 7 days from the day of the CAR T infusion.

Who Is Running the Clinical Trial?

University of Kansas Medical Center

Lead Sponsor

Trials

527

Recruited

181,000+

Findings from Research

CD19CAR T cells have shown promising results in treating aggressive B-lineage cancers, but their effectiveness can be limited by the loss of the targeted CD19 antigen, leading to treatment failure.

The newly developed adapter CAR T cell technology (AdCAR) allows for multitargeting of different antigens, such as CD20 and CD22, which can enhance the anti-cancer activity and potentially overcome issues related to antigen loss in lymphoma treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adapter CAR T Cell Therapy for the Treatment of B-Lineage Lymphomas. Atar, D., Mast, AS., Scheuermann, S., et al.[2022]

The study developed trispecific duoCAR-T cells that target three different B cell leukemia antigens (CD19, CD20, and CD22) to overcome the problem of antigen loss in patients with leukemia and lymphoma, showing promise in preventing relapse.

In mouse models, these duoCAR-T cells effectively rejected tumors composed of various B cell lymphoma variants, while traditional monoCAR-T cells targeting only one antigen failed to prevent tumor progression, highlighting the efficacy of multispecific targeting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trispecific CD19-CD20-CD22-targeting duoCAR-T cells eliminate antigen-heterogeneous B cell tumors in preclinical models. Schneider, D., Xiong, Y., Wu, D., et al.[2021]

In a study of 16 patients with relapsed, refractory B-cell malignancies treated with LV20.19 CAR-T therapy, the two-year progression-free survival (PFS) was 44% and overall survival (OS) was 69%, indicating promising long-term outcomes.

Factors such as lower in vivo CAR-T expansion and high metabolic tumor volume were linked to late relapse and poorer early treatment response, suggesting that these could be important predictors for patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term outcomes and predictors of early response, late relapse, and survival for patients treated with bispecific LV20.19 CAR T-cells. Zurko, JC., Fenske, TS., Johnson, BD., 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 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]

Dual-targeting CAR-T cell therapy shows promising efficacy in treating B cell malignancies, with a 77% overall response rate and 52% complete response rate in patients with B cell non-Hodgkin lymphoma (B-NHL), and a 92% complete response rate in patients with B cell acute lymphoblastic leukemia (B-ALL).

The therapy has a manageable safety profile, with grade ≥3 cytokine release syndrome occurring in 14% of B-NHL patients and 11% of B-ALL patients, indicating that while there are risks, the benefits may outweigh them for many patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Dual-Targeting Chimeric Antigen Receptor-T Therapy for Relapsed or Refractory B Cell Lymphoid Malignancies: A Systematic Review and Meta-Analysis. Yu, M., Zhang, Q., Kong, F., et al.[2023]

In a study of 182 patients with relapsed/refractory large B-cell lymphoma, novel CAR T-cell therapies showed varying efficacy and safety compared to the FDA-approved Yescarta, with some constructs like tandem CD19.CD20.4-1BBζ demonstrating favorable outcomes.

While some experimental CARs had improved safety profiles, they did not consistently outperform Yescarta in terms of progression-free survival, indicating that further research is needed to establish the best treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Innovative Experimental Chimeric Antigen Receptor (CAR) T-cells versus Axicabtagene ciloleucel (Yescarta) for the Treatment of Relapsed/Refractory Large B-Cell Lymphoma (LBCL): Matching Adjusted Indirect Comparisons (MAICs) and Systematic Review. Weinstein, B., Muresan, B., Solano, S., et al.[2022]

Chimeric antigen receptor (CAR)-T cell therapy, specifically targeting CD19, has shown promising results in treating non-Hodgkin lymphomas (NHLs) resistant to standard therapies, leading to FDA and EMA approvals for tisagenlecleucel and axicabtagene ciloleucel.

While CAR-T cell therapy can cause significant adverse events like cytokine release syndrome and neurological toxicity, these effects are manageable with proper medical support, highlighting the importance of trained teams in administering this novel treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-T Cell Therapy in Diffuse Large B Cell Lymphoma: Hype and Hope. Hopfinger, G., Jäger, U., Worel, N.[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. Switzerland pubmed.ncbi.nlm.nih.gov

Adapter CAR T Cell Therapy for the Treatment of B-Lineage Lymphomas. [2022]

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

Trispecific CD19-CD20-CD22-targeting duoCAR-T cells eliminate antigen-heterogeneous B cell tumors in preclinical models. [2021]

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

Long-term outcomes and predictors of early response, late relapse, and survival for patients treated with bispecific LV20.19 CAR T-cells. [2023]

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

Tandem transplantation in lymphoma. [2006]

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

Maintenance and consolidation strategies in non-Hodgkin's lymphoma: A review of the data. [2021]

6. 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]

7. 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]

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

Efficacy and Safety of Dual-Targeting Chimeric Antigen Receptor-T Therapy for Relapsed or Refractory B Cell Lymphoid Malignancies: A Systematic Review and Meta-Analysis. [2023]

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

Efficacy and Safety of Innovative Experimental Chimeric Antigen Receptor (CAR) T-cells versus Axicabtagene ciloleucel (Yescarta) for the Treatment of Relapsed/Refractory Large B-Cell Lymphoma (LBCL): Matching Adjusted Indirect Comparisons (MAICs) and Systematic Review. [2022]

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

CAR-T Cell Therapy in Diffuse Large B Cell Lymphoma: Hype and Hope. [2020]

11. England pubmed.ncbi.nlm.nih.gov

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

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

How I treat double-hit lymphoma. [2022]