What side effects are associated with this type of intervention?

Common treatments for Acute Lymphoblastic Leukemia (ALL), particularly CAR T-cell therapies targeting CD19, CD20, and CD22, are associated with several significant side effects. These include cytokine release syndrome (CRS), which can cause fever, hypotension, and altered mental status, and neurotoxicity, which may present as confusion, seizures, or encephalopathy. Other side effects include cytopenias (low blood cell counts), increased risk of infections due to immunosuppression, and potential organ toxicities.

What prior FDA approvals exist?

The FDA has approved several CAR T-cell therapies for the treatment of Acute Lymphoblastic Leukemia (ALL). Notably, Tisagenlecleucel (Kymriah) was the first CAR T-cell therapy approved for pediatric and young adult patients with relapsed or refractory B-cell ALL, targeting the CD19 protein on cancer cells. Another approved therapy is Brexucabtagene autoleucel (Tecartus), which also targets CD19 and is used for relapsed or refractory mantle cell lymphoma, but has shown promise in ALL as well. These therapies involve genetically modifying a patient's T-cells to express a chimeric antigen receptor (CAR) that specifically targets and kills cancer cells expressing CD19. While there are ongoing studies for CAR T-cells targeting multiple antigens like CD19, CD20, and CD22, the current FDA approvals primarily focus on CD19-directed therapies.

What other types of research exist?

Promising novel alternatives to Anti-CD19/CD20/CD22 CAR T-cells for Acute Lymphoblastic Leukemia (ALL) patients include: 1) Bispecific T-cell Engagers (BiTEs) like blinatumomab, which target CD3 on T-cells and CD19 on B-cells, facilitating immune-mediated killing of cancer cells. 2) NOTCH pathway inhibitors, specifically gamma-secretase inhibitors, which target the NOTCH1 receptor frequently activated in T-cell ALL. 3) JAK/STAT pathway inhibitors, which can overcome glucocorticoid resistance in a subset of T-cell ALL. These therapies offer different mechanisms of action and have shown potential in clinical settings.

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CAR T-cell Therapy

CAR T-cell Therapy for Lymphoma and Leukemia

Q: What is the mechanism of action of this treatment?

The most common treatments for Acute Lymphoblastic Leukemia (ALL) include chemotherapy, targeted therapy, and immunotherapy. Among these, CAR T-cell therapy, such as anti-CD19/CD20/CD22 CAR T-cells, is particularly noteworthy. This treatment involves genetically engineering a patient's own T-cells to express chimeric antigen receptors (CARs) that specifically target CD19, CD20, and CD22 proteins on the surface of leukemia cells. Once infused back into the patient, these CAR T-cells can recognize, bind to, and kill the cancer cells. This targeted approach is significant for ALL patients as it offers a personalized treatment option that can lead to remission, especially in cases where the disease is refractory or has relapsed after conventional therapies.

Phase 1

Recruiting

Led By Sumithira Vasu, MD

Research Sponsored by Sumithira Vasu

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Subjects with refractory high-grade B-cell lymphoma relapsing within 12 months of autologous stem cell transplant

Patients with CD19 and/or CD20 and/or CD22 positive lymphoid malignancy, who received blinatumomab or inotuzumab, aged >= 18 years, with ECOG performance status =< 2, adequate organ function, and ability to understand and sign informed consent

Must not have

Evidence of myelodysplasia, positive hepatitis B core antibody or surface antigen, clinically relevant CNS pathology, autoimmune disease with recent immunosuppressive medication requirement, or live vaccines given within 28 days prior to lymphodepleting chemotherapy

Active central nervous system or meningeal involvement by lymphoma or leukemia, active malignancy other than specified exceptions

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 15 years

Awards & highlights

No Placebo-Only Group

Summary

This trial tests the safety and best dose of a new treatment using modified immune cells (CAR T-cells) for patients with certain recurring or hard-to-treat lymphoid cancers. The treatment involves giving patients a brief period of chemotherapy followed by an infusion of these specially designed cells to target and kill cancer cells. Anti-CD19 CAR T-cells currently represent transformational therapy for relapsed/refractory aggressive B-cell lymphomas where durable remissions can be induced in patients with previously incurable chemotherapy-refractory disease.

Who is the study for?

Adults with certain relapsed or refractory lymphoid cancers, including non-Hodgkin lymphoma and various types of leukemia. Participants must have tried at least two prior therapies, have a minimum level of white blood cells, good heart and lung function, and agree to use highly effective contraception. Excluded are those with recent transplants, active infections or other malignancies that could affect the trial's safety.

What is being tested?

The trial is testing genetically engineered CAR T-cells targeting CD19/CD20/CD22 on cancer cells following chemotherapy (cyclophosphamide and fludarabine). It aims to determine the safest dose for infusion of these modified T-cells in patients whose cancers haven't responded well to previous treatments.

What are the potential side effects?

Potential side effects include immune system reactions leading to inflammation in different body parts, symptoms related to infusion such as fever or chills, fatigue, possible organ dysfunction due to targeted cell destruction by CAR T-cells, and increased risk of infection from pre-infusion chemotherapy.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

Select...

My high-grade B-cell lymphoma came back within a year after my stem cell transplant.

Select...

I am 18 or older with a specific type of blood cancer, have received certain treatments, can move around, and understand the consent form.

Select...

I have CLL and have been treated with at least 2 therapies including a BTK inhibitor and venetoclax.

Select...

I have acute B-lymphoblastic leukemia that has not responded to at least 2 treatments or I cannot undergo a stem cell transplant.

Select...

I have lymphoma or leukemia that has not improved after at least two treatments.

Select...

I agree to not have unprotected sex or donate sperm.

Select...

I have B-prolymphocytic leukemia that didn't respond to 1-2 treatments and can't have a stem cell transplant.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

Select...

I don't have myelodysplasia, hepatitis B, significant brain issues, recent autoimmune treatment, or recent live vaccines.

Select...

I do not have active brain or spinal cord cancer.

Select...

I had a stem cell transplant using my own cells less than 6 weeks ago.

Select...

I haven't had a stem cell transplant or live vaccines recently.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 15 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 15 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 15 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Secondary study objectives

Complete response rate

Incidence of adverse events

Overall response rate

+2 more

Other study objectives

Correlation between CD19/20/22 expression on disease response

Correlation between cytokine serum concentrations and disease response

Presence of measurable CAR-T cells

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

2Treatment groups

Experimental Treatment

Group I: Cohort B (lymphodepletion, anti-CD19/CD20/CD22 CAR-T cells)Experimental Treatment3 Interventions

LYMPHODEPLETIVE REGIMEN: Patients receive cyclophosphamide IV over 60 minutes on day -6 and fludarabine IV over 30 minutes on days -5 to -3 in the absence of disease progression or unacceptable toxicity. CAR T-CELL THERAPY: Patients receive anti-CD19/CD20/CD22 CAR-T cells IV over 5-30 minutes on day 0 and 7.

Group II: Cohort A (lymphodepletion; anti-CD19/CD20/CD22 CAR-T cells)Experimental Treatment3 Interventions

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Cyclophosphamide

2010

Completed Phase 4

~2310

Fludarabine Phosphate

1997

Completed Phase 3

~2390

0 / 11Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for Acute Lymphoblastic Leukemia (ALL) include chemotherapy, targeted therapy, and immunotherapy. Among these, CAR T-cell therapy, such as anti-CD19/CD20/CD22 CAR T-cells, is particularly noteworthy. This treatment involves genetically engineering a patient's own T-cells to express chimeric antigen receptors (CARs) that specifically target CD19, CD20, and CD22 proteins on the surface of leukemia cells. Once infused back into the patient, these CAR T-cells can recognize, bind to, and kill the cancer cells. This targeted approach is significant for ALL patients as it offers a personalized treatment option that can lead to remission, especially in cases where the disease is refractory or has relapsed after conventional therapies.