What side effects are associated with this type of intervention?

Chimeric Antigen Receptor (CAR) T-cell therapies targeting CD19, such as those being studied in the huCART19-IL18 trial, are associated with several significant side effects. The most common include cytokine release syndrome (CRS), which can cause fever, hypotension, and respiratory distress, and neurotoxicity, which can lead to confusion, seizures, and encephalopathy. Other potential side effects include infections due to immunosuppression, cytopenias (low blood cell counts), and organ toxicities. These side effects necessitate careful monitoring and management in clinical settings.

What prior FDA approvals exist?

The FDA has approved several CAR-T cell therapies for the treatment of Non-Hodgkin's Lymphoma, particularly those targeting CD19. Notable approvals include axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah), both of which are used for certain types of relapsed or refractory large B-cell lymphoma. These therapies involve modifying a patient's T cells to express a receptor that targets the CD19 antigen on B cells, similar to the huCART19-IL18 cells being studied. Additionally, brexucabtagene autoleucel (Tecartus) has been approved for mantle cell lymphoma, another subtype of NHL. These treatments have shown significant efficacy but are also associated with serious side effects, such as cytokine release syndrome and neurotoxicity.

What other types of research exist?

Promising novel alternatives to huCART19-IL18 cells for Non-Hodgkin's Lymphoma patients include: 1) Bispecific T-cell engagers (BiTEs) such as blinatumomab, which direct T-cells to target CD19+ cells. 2) Antibody-drug conjugates (ADCs) like polatuzumab vedotin, which deliver cytotoxic agents directly to cancer cells. 3) Next-generation CAR-T cell therapies targeting other antigens such as CD20 or CD22. 4) Immune checkpoint inhibitors, which enhance the body's immune response against cancer cells. These therapies have shown promising results in clinical trials and may offer effective treatment options for NHL patients.

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CAR T-cell Therapy

CAR T-cell Therapy for Blood Cancer

Phase 1

Recruiting

Led By Jakub Svoboda, MD

Research Sponsored by University of Pennsylvania

Eligibility Criteria Checklist

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

Must have

--- Patients must have either failed or be ineligible for standard of care Tecartus™ (brexucabtagene autoleucel) or other investigational CAR T cell product; and

--- Relapsed/refractory disease after allogeneic SCT.

Must not have

Active acute or chronic GVHD requiring systemic therapy.

Active autoimmune disease requiring systemic immunosuppressive treatment equivalent to ≥ 10mg of prednisone. Patients with autoimmune neurologic diseases (such as MS) will be excluded.

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 12 months

Awards & highlights

No Placebo-Only Group

Summary

This trial aims to find the safest dose of specially modified immune cells for patients with certain types of cancers that have a specific marker. These cancers include Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, and Acute Lymphoblastic Leukemia. The modified cells are designed to seek out and destroy cancer cells with this marker.

Who is the study for?

Adults with CD19+ cancers like various leukemias and lymphomas, who have active disease despite previous treatments. They must be over 18, in fairly good health (ECOG 0 or 1), with decent organ function and no severe heart issues. Active infections or autoimmune diseases are deal-breakers, as is recent use of certain immune drugs.

What is being tested?

The trial is testing the safety of a new cell therapy called huCART19-IL18 for blood cancers that have a marker called CD19. The goal is to find the highest dose people can take without serious side effects.

What are the potential side effects?

Potential side effects aren't specified here but generally may include flu-like symptoms, fatigue, allergic reactions to the infusion, and possibly more serious immune system-related complications.

Eligibility Criteria

Inclusion Criteria

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

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I cannot use or have not responded to standard CAR T cell therapy.

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My condition worsened or didn't improve after a stem cell transplant.

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I don't have active graft-versus-host disease and don't need immunosuppressants.

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My chronic lymphocytic leukemia has recently relapsed.

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My condition did not improve after initial treatment or I've had at least one treatment.

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My CLL has transformed into a more aggressive form.

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I don't have active graft-versus-host disease and don't need immunosuppressants.

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I am fully active or can carry out light work.

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My condition did not improve after 2 treatments and I can't have stem cell or CAR T cell therapy.

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My condition worsened after 2 treatments, including a BTK inhibitor.

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My condition worsened or didn't improve after a stem cell transplant.

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I have minor or no breathing issues and my oxygen level is above 92% without assistance.

Select...

a. Your creatinine level is less than or equal to 1.6 mg/dl. b. Your ALT/AST levels are less than or equal to 3 times the upper limit of normal range. c. Your direct bilirubin level is less than or equal to 2.0 mg/dl, except if you have Gilbert's syndrome, where it can be up to 3.0 mg/dl. d. You have good lung function with minimal difficulty breathing and pulse oxygen levels above 92% on room air. e. Your left ventricle ejection fraction (LVEF) is at least 40%, confirmed by ECHO/MUGA.

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My condition did not improve after two different treatments.

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I have been diagnosed with a specific type of aggressive B-cell lymphoma.

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My condition worsened or didn't improve after a stem cell transplant using my own cells.

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My condition worsened or didn't improve after a stem cell transplant.

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My cancer cells test positive for CD19.

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My cancer is active, showing signs in blood, bone marrow, or measurable disease.

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My condition relapsed after a stem cell transplant from a donor.

Exclusion Criteria

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

Select...

I am receiving treatment for ongoing GVHD.

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I am on strong medication for an autoimmune disease, but I don't have MS.

Select...

I do not have active hepatitis B or C, or any uncontrolled infection.

Select...

I have severe heart problems that limit my daily activities.

Select...

I haven't taken immune checkpoint inhibitors in the last 4 months.

Select...

I have previously received huCART19 therapy.

Select...

I rely on steroids or immunosuppressant drugs.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 12 months

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~12 months

This trial's timeline: 3 weeks for screening, Varies for treatment, and 12 months for reporting.

Treatment Details

Study Objectives

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

Secondary study objectives

Best Overall Response (BOR)

Characterize low level disease and B cell assessment in response to huCART19-IL18 cells

Event Free Survival (EFS)

+2 more

Awards & Highlights

No Placebo-Only Group

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

Trial Design

17Treatment groups

Experimental Treatment

Group I: NHL Dose Level 5 (DL5)Experimental Treatment1 Intervention

3x10\^8 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push

Group II: NHL Dose Level 4 (DL4)Experimental Treatment1 Intervention

7x10\^7 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push

Group III: NHL Dose Level 3 (DL3)Experimental Treatment1 Intervention

3x10\^7 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push

Group IV: NHL Dose Level 2 (DL2)Experimental Treatment1 Intervention

7x10\^6 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push

Group V: NHL Dose Level 1b (DL1b)Experimental Treatment1 Intervention

3x10\^6 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push

Group VI: NHL Dose Level 1a (DL1a)Experimental Treatment1 Intervention

3x10\^6 huCART19-IL18 cells administered as a single intravenous (IV) infusion or slow IV push

Group VII: NHL Dose Level -1 (DL-1)Experimental Treatment1 Intervention

7x10\^5 huCART19-IL18 cells administered as a single intravenous (IV) infusion or slow IV push; This dose level will only be explored if at least one DLT is observed at Dose Level 1a.

Group VIII: CLL Dose Level 5 (DL5)Experimental Treatment1 Intervention

3x10\^8 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push

Group IX: CLL Dose Level 4 (DL4)Experimental Treatment1 Intervention

7x10\^7 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push

Group X: CLL Dose Level 3 (DL3)Experimental Treatment1 Intervention

3x10\^7 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push

Group XI: CLL Dose Level 2 (DL2)Experimental Treatment1 Intervention

7x10\^6 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push

Group XII: CLL Dose Level 1b (DL1b)Experimental Treatment1 Intervention

3x10\^6 huCART19-IL18 cells administered as a single intravenous (IV) infusion or slow IV push; This dose level will only be explored if at least one DLT is observed at Dose Level 2.

Group XIII: ALL Dose Level 5 (DL5)Experimental Treatment1 Intervention

3x10\^8 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push

Group XIV: ALL Dose Level 4 (DL4)Experimental Treatment1 Intervention

7x10\^7 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push

Group XV: ALL Dose Level 3 (DL3)Experimental Treatment1 Intervention

3x10\^7 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push

Group XVI: ALL Dose Level 2 (DL2)Experimental Treatment1 Intervention

7x10\^6 huCART19-IL18 cells following lymphodepleting chemotherapy administered as a single intravenous (IV) infusion or slow IV push

Group XVII: ALL Dose Level 1b (DL1b)Experimental Treatment1 Intervention

3x10\^6 huCART19-IL18 cells administered as a single intravenous (IV) infusion or slow IV push; This dose level will only be explored if at least one DLT is observed at Dose Level 2.

0 / 27Eligibility 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 Non-Hodgkin's Lymphoma (NHL) include chemotherapy, immunotherapy, and targeted therapies. Chemotherapy uses cytotoxic drugs to kill rapidly dividing cancer cells. Immunotherapy, such as monoclonal antibodies (e.g., rituximab), targets specific proteins on cancer cells to mark them for destruction by the immune system. Targeted therapies, like kinase inhibitors, block specific molecules involved in cancer cell growth and survival. CAR T-cell therapy, particularly those targeting CD19, involves modifying a patient's T cells to express a receptor that recognizes and binds to CD19 on B cells, leading to the destruction of these cancerous cells. The addition of IL-18 in huCART19-IL18 cells aims to enhance the immune response, potentially improving the efficacy of the treatment. These mechanisms are crucial for NHL patients as they offer targeted approaches to eliminate cancer cells while sparing normal cells, potentially leading to better outcomes and fewer side effects.