CAR T Cell Therapy for Non-Hodgkin's Lymphoma

Overseen By Connie Brecl

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Colorado, Denver

Must not be taking: Antimicrobials, Anticoagulants, Immunosuppressants, others

Disqualifiers: CNS disease, Other malignancies, Cardiac disease, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

68 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called CD19x22 CAR T cells, a type of immunotherapy, for individuals with certain types of non-Hodgkin's lymphoma that have not responded to other treatments. The main goal is to determine the safety and effectiveness of this treatment for these patients. It suits those with aggressive B-cell non-Hodgkin's lymphoma, such as diffuse large B-cell lymphoma or mantle cell lymphoma, who have tried at least two other treatments without success. Participants should not have active disease in the brain and must have measurable disease that can be tracked during the study. 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.

Will I have to stop taking my current medications?

The trial requires that at least 14 days or 5 half-lives must have passed since any prior systemic therapy before starting the trial, except for certain immune therapies which require 5 half-lives. Additionally, at least 7 days must have passed since any prior steroid use, except for specific cases like physiological replacement doses or topical/inhaled steroids.

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

Research has shown that CD19x22 CAR T cells, designed to target specific proteins on cancer cells, have been studied for their safety in treating blood cancers. A review of several studies found this approach effective and generally well-tolerated in people with B-cell cancers. While some side effects were observed, they were mostly manageable.

This treatment is quite advanced. The current trial is in its early stages, focusing on safety in people. So far, evidence suggests that the side effects are tolerable, but this trial will help confirm its safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for Non-Hodgkin's Lymphoma, like chemotherapy and monoclonal antibodies, aim to kill cancer cells but can also affect healthy cells. CD19x22 CAR T Cell Therapy is unique because it uses a patient's own immune cells, which are genetically modified to specifically target and destroy cancer cells expressing the CD19 and CD22 proteins. This targeted approach not only promises to be more effective in eliminating cancer cells but also minimizes damage to healthy cells, potentially leading to fewer side effects. Researchers are excited about this therapy because it represents a personalized treatment option that could offer better outcomes for patients who have not responded well to traditional therapies.

What evidence suggests that CD19x22 CAR T Cells might be an effective treatment for Non-Hodgkin's Lymphoma?

Research shows that CD19x22 CAR T cells, the treatment under study in this trial, hold promise for treating B-cell Non-Hodgkin Lymphoma (B-NHL). Studies have found that targeting both CD19 and CD22 proteins on cancer cells effectively fights the disease. This approach is beneficial when cancer cells lose one of these proteins and become resistant to treatment. The treatment has also shown effectiveness in other B-cell cancers, with manageable side effects according to research reviews. This suggests that CD19x22 CAR T cells could benefit patients whose B-NHL has returned or not responded to other treatments. ^{1 2 3 5 6}

Who Is on the Research Team?

Manali Kamdar, MD, PhD

Principal Investigator

University of Colorado, Denver

Are You a Good Fit for This Trial?

Adolescents and adults with relapsed/refractory B-cell Non-Hodgkin Lymphoma who have tried at least two therapies, including an anthracycline and anti-CD20 monoclonal antibody. Participants must be over 16 years old, in good physical condition (ECOG score of 0 or 1), with no active central nervous system disease, adequate organ function, not pregnant or breastfeeding, willing to use birth control, and able to give informed consent.

Inclusion Criteria

I do not have any brain-related symptoms or signs of disease on my brain MRI.

I am 16 years or older, but the first three participants must be 18 or older.

I have had a stem cell transplant from a donor.

Exclusion Criteria

I have signs or symptoms of brain disease, confirmed by an MRI.

I have been cancer-free for at least 3 years, except for non-melanoma skin cancer or carcinoma in situ.

I have a blood clot that isn't controlled with steady medication.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepleting Chemotherapy

Participants receive lymphodepleting chemotherapy prior to CAR T cell infusion

1 week

Treatment

Infusion of CD19x22 CAR T cells to determine safety and tolerability

12 months

Regular monitoring visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

What Are the Treatments Tested in This Trial?

Interventions

• CD19x22 CAR T Cells

Trial Overview

The trial is testing the safety and tolerability of a new therapy using CD19x22 CAR T cells for those with aggressive forms of B-cell Non-Hodgkin Lymphoma that haven't responded well to other treatments. The first phase will find the highest dose patients can tolerate without severe side effects; the second phase will assess how effective this treatment is.

How Is the Trial Designed?

Group I: Cohort 3: Relapsed and/or Refractory Primary CNS Lymphoma OR secondary CNS Lymphoma Experimental Treatment 1 Intervention

Lymphodepleting chemotherapy followed by CD19x22 CAR T Infusion starting at dose level 2

Group II: Cohort 2 Relapsed/Refractory Mantle Cell Lymphoma Experimental Treatment 1 Intervention

Lymphodepleting chemotherapy followed by CD19x22 CART Infusion starting at dose level 2.

Group III: Cohort 1 Relapsed/Refractory Non-CNS B-Cell Non Hodgkin Lymphoma Experimental Treatment 1 Intervention

Lymphodepleting chemotherapy followed by infusion of CD19x22 CAR T Cells starting at dose level 1.

Who Is Running the Clinical Trial?

University of Colorado, Denver

Lead Sponsor

Trials

1,842

Recruited

3,028,000+

Published Research Related to This Trial

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]

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]

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]

The novel bicistronic CAR T-cell therapy targeting both CD19 and CD20 showed equivalent tumor-killing abilities to traditional monospecific CAR T cells, but with enhanced persistence and cytokine production when stimulated by both antigens.

In a mouse model of CD19/CD20 double-positive tumors, the bicistronic CAR T cells were more effective at eradicating tumors and improving survival compared to monospecific CD19 CAR T cells, suggesting a promising approach for treating relapsed or refractory B cell malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined 4-1BB and ICOS co-stimulation improves anti-tumor efficacy and persistence of dual anti-CD19/CD20 chimeric antigen receptor T cells. Wang, Y., Zhong, K., Ke, J., et al.[2021]

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 phase I clinical trial involving 38 patients with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) and large B cell lymphoma (LBCL), a bispecific CAR targeting CD19 and CD22 showed promising results, with 100% response rate in B-ALL and 62% in LBCL, indicating its potential efficacy against CD19/lo disease.

The study found that relapses in patients were often due to loss of CD19 expression, highlighting the challenge of antigen loss in CAR T cell therapy and suggesting that cytokine production levels could be a key indicator of CAR T cell effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial. Spiegel, JY., Patel, S., Muffly, L., et al.[2023]

BiCAR-T cells, which target both CD19 and CD22, demonstrated significant anti-tumor effects in both laboratory and animal models, suggesting enhanced efficacy compared to single-target CAR-T therapies.

This dual targeting approach may help prevent relapse in B-cell acute lymphoblastic leukemia (B-ALL) by reducing the risk of immune escape due to loss of the targeted antigens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engineering Novel CD19/CD22 Dual-Target CAR-T Cells for Improved Anti-Tumor Activity. Zeng, W., Zhang, Q., Zhu, Y., et al.[2022]

Anti-CD19 CAR T-cell therapy has shown remarkable efficacy in treating relapsed or refractory aggressive B-cell lymphomas, leading to durable remissions in patients who previously had no effective treatment options.

Three CAR T-cell therapies (axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel) are approved for use, each differing in their design, manufacturing processes, and safety profiles, highlighting the need for personalized approaches in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-CD19 CAR T-Cell Therapy for B-Cell Non-Hodgkin Lymphoma. Abramson, JS.[2021]

CD79b is widely expressed on tumor cells in various types of B-cell lymphomas, making it a promising target for CAR T-cell therapy.

Anti-CD79b CAR T-cells demonstrated high specificity and effectiveness in treating B-cell lymphomas, suggesting that targeting CD79b could improve outcomes for patients who do not respond to existing therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting CD79b for Chimeric Antigen Receptor T-Cell Therapy of B-Cell Lymphomas. Ding, S., Mao, X., Cao, Y., et al.[2021]

In a pilot study of 89 patients with refractory/relapsed B-cell malignancies, sequential infusion of CAR19/22 T cells showed a remarkable 96% minimal residual disease-negative response rate in patients with acute lymphoblastic leukemia, indicating high efficacy.

The treatment was found to be safe, with manageable side effects; high-grade cytokine release syndrome occurred in 22.4% of patients, but was reversible in all but one case, suggesting a favorable safety profile for this dual-targeting approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of CAR19/22 T-cell cocktail therapy in patients with refractory/relapsed B-cell malignancies. Wang, N., Hu, X., Cao, W., et al.[2021]

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CAR T cells with dual targeting of CD19 and CD22 in adult ...

Disease progression associated with loss of cell surface CD19 has been reported in 30–95% of relapses after CAR19 therapy in B-ALL, through a ...

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