TMhuCART19-IL18 for Non-Hodgkin's Lymphoma

Overseen By Jakub Svoboda, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Pennsylvania

Must not be taking: Steroids, Immunosuppressants

Disqualifiers: Active infections, Cardiovascular disability, CNS disease, others

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

Compensation: Varies

Number of Visits: Unknown

24 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called TmCD19-IL18 CAR T cells, a type of immunotherapy, for individuals with certain types of Non-Hodgkin's Lymphoma, a cancer affecting the immune system. The main goal is to find a safe dose and assess its effectiveness in treating these cancers. The trial includes different groups, each receiving a different dose to determine the optimal one. It seeks participants with specific types of lymphoma that have recurred or not responded to other treatments, particularly those who have tried at least two previous therapies. 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 innovative therapy.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you depend on systemic steroids or immunosuppressant medications, so you may need to adjust those if applicable.

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

Research has shown that TmCD19-IL18 CAR T cells have been tested for safety in patients with relapsed or hard-to-treat non-Hodgkin lymphoma. Earlier studies found the treatment to have an acceptable safety profile, meaning the side effects were manageable for patients who had already tried many other treatments. The treatment's safety is similar to other CAR T-cell therapies, which involve modifying a patient's own immune cells to better fight cancer. These studies suggest that TmCD19-IL18 may be safe and tolerable for patients. However, since the current trial is in the early stages, researchers are closely monitoring safety and determining the best dose. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for Non-Hodgkin's Lymphoma, which typically involve chemotherapy, radiation, or monoclonal antibodies, TmCD19-IL18 offers a new approach by using genetically engineered CAR T cells. These cells are designed to specifically target and destroy cancer cells expressing the CD19 protein. Additionally, the inclusion of IL-18 in the treatment is significant because it can boost the immune response, potentially enhancing the effectiveness of the CAR T cells. Researchers are excited about this treatment because it could lead to more precise and potent attacks on cancer cells while minimizing harm to healthy cells.

What evidence suggests that TmCD19-IL18 CAR T cells might be an effective treatment for Non-Hodgkin's Lymphoma?

Research has shown that TmCD19-IL18 CAR T cells could effectively treat CD19+ non-Hodgkin's lymphoma (NHL). In a study with 21 patients who had this cancer, many responded well to the treatment. Specifically, early results indicated that the treatment's average effectiveness lasted about 9.6 months, offering hope for patients with limited options. The treatment was generally safe, though some patients experienced mild to moderate cytokine release syndrome, a common side effect of this therapy. This trial will evaluate different dose levels of TmCD19-IL18 CAR T cells to determine the most effective and safe dosage for those with difficult-to-treat NHL. ^{1 2 3 4 5}

Who Is on the Research Team?

Jakub Svoboda, MD

Principal Investigator

University of Pennsylvania

Are You a Good Fit for This Trial?

This trial is for individuals with CD19+ cancers, such as Non-Hodgkin's Lymphoma. Participants must have proper kidney and liver function, no active graft-versus-host disease or need for immunosuppression post-transplant, stable breathing capacity, and evidence of active cancer within the last 12 weeks. They should not be on dialysis or have severe heart issues.

Inclusion Criteria

Signed informed consent form

My organs are functioning well and I have signs of active disease.

Documentation of CD19 expression on malignant cells by flow cytometry/IHC at the Hospital of the University of Pennsylvania

Exclusion Criteria

I rely on steroids or medications that suppress my immune system.

Pregnant or nursing patients

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

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose-Finding

Participants receive TmCD19-IL18 CAR T cells at various dose levels to determine the maximum tolerated dose (MTD)

28 days per dose level

Multiple visits for dose administration and monitoring

Dose Expansion

Participants receive the established MTD to further evaluate safety and manufacturing feasibility

28 days per cycle

Multiple visits for dose administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

15 years

What Are the Treatments Tested in This Trial?

Interventions

• TmCD19-IL18

Trial Overview The study tests TmCD19-IL18 CAR T cells to find a safe dose level and assess its safety, tolerability, manufacturing feasibility, pharmacokinetics (how the drug moves through the body), and initial effectiveness in treating CD19+ cancers using a two-phase approach: Dose-Finding followed by Dose Expansion.

How Is the Trial Designed?

Group I: NHL Dose Level 3 Experimental Treatment 1 Intervention

6x10\^7 TmCD19-IL18 cells administered as a single intravenous (IV) infusion

Group II: NHL Dose Level 2 Experimental Treatment 1 Intervention

2x10\^7 TmCD19-IL18 cells administered as a single intravenous (IV) infusion

Group III: NHL Dose Level 1a Experimental Treatment 1 Intervention

5x10\^6 TmCD19-IL18 CAR T cells

Group IV: NHL Dose Level 1 Experimental Treatment 1 Intervention

7x10\^6 TmCD19-IL18 cells administered as a single intravenous (IV) infusion

Group V: NHL Dose Level -1 Experimental Treatment 1 Intervention

2x10\^6 TmCD19-IL18 cells administered as a single intravenous (IV) infusion

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

Kite, A Gilead Company

Industry Sponsor

Trials

45

Recruited

4,300+

Published Research Related to This Trial

Adoptive cellular therapy using CAR-modified T cells targeting CD19 has shown significant clinical efficacy in treating relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) in both children and adults, with some patients also benefiting from treatment for chronic lymphocytic leukemia (CLL) and B-cell non-Hodgkin lymphoma (B-NHL).

Current research is expanding the use of CAR T-cell therapies to other cancers, including multiple myeloma and solid tumors, while also addressing challenges such as severe cytokine release syndrome and neurologic toxicities associated with the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review: Current clinical applications of chimeric antigen receptor (CAR) modified T cells. Geyer, MB., Brentjens, RJ.[2022]

In a clinical trial involving 22 patients with advanced-stage lymphoma, CAR-19 T cells preceded by low-dose chemotherapy resulted in a 73% overall remission rate, with 55% achieving complete remissions.

High serum levels of interleukin-15 (IL-15) were linked to better outcomes, indicating that this cytokine may enhance the effectiveness of CAR-19 T cell therapy in treating relapsed lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lymphoma Remissions Caused by Anti-CD19 Chimeric Antigen Receptor T Cells Are Associated With High Serum Interleukin-15 Levels. Kochenderfer, JN., Somerville, RPT., Lu, T., et al.[2021]

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]

A systematic analysis of CAR T-cell therapy adverse events revealed 5,112 reports of hematotoxicity, highlighting significant under-reporting of severe conditions like hemophagocytic lymphohistiocytosis (HLH) and disseminated intravascular coagulation (DIC), which have high mortality rates of 69.9% and 59.6%, respectively.

The study identified 23 hematologic adverse events that were significantly over-reported compared to the general database, emphasizing the need for increased awareness and monitoring of these rare but potentially fatal toxicities in CAR T therapy patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hemophagocytic lymphohistiocytosis and disseminated intravascular coagulation are underestimated, but fatal adverse events in chimeric antigen receptor T-cell therapy. Song, Z., Tu, D., Tang, G., et al.[2023]

CD19-directed CAR T-cell therapy has significantly transformed the treatment approach for aggressive B-cell non-Hodgkin lymphoma, offering new hope for patients.

There are currently three commercially available CAR T-cell therapies targeting CD19, indicating a growing acceptance and application of this innovative immunotherapy in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T-Cell Therapy for Relapsed/Refractory Aggressive Large B-Cell Lymphoma. Gideon, J.[2023]

Three CAR-T cell therapies (Yescarta®, Kymriah®, and Breyanzi®) have been approved for treating relapsed or refractory diffuse large B cell lymphomas (DLBCL), significantly improving patient outcomes where conventional treatments fail.

Recent updates and real-life data suggest that CAR-T therapies may be effective earlier in treatment and could be extended to other types of B lymphomas, with new CAR-T cell strategies being explored for Hodgkin's and T-cell lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[CAR-T cells in lymphomas: Current and evolving role]. Messéant, O., Houot, R.[2021]

In a phase I clinical trial involving 20 patients with B-cell lymphoma, 55% achieved complete remission using the new anti-CD19 CAR T-cell therapy Hu19-CD828Z, demonstrating its effectiveness against lymphoma.

Hu19-CD828Z therapy resulted in significantly lower rates of severe neurologic toxicity (5%) compared to the previously tested FMC63-28Z therapy (50%), likely due to reduced cytokine release associated with the Hu19-CD828Z CAR design.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and feasibility of anti-CD19 CAR T cells with fully human binding domains in patients with B-cell lymphoma. Brudno, JN., Lam, N., Vanasse, D., et al.[2021]

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]

CAR-T cell therapy targeting the CD19 antigen has significantly changed treatment for patients with relapsed or refractory B cell non-Hodgkin lymphoma, with two FDA-approved products available: axicabtagene ciloleucel and tisagenlecleucel.

The review highlights the clinical outcomes and toxicity profiles of these CAR-T therapies, indicating their effectiveness across major B cell NHL subtypes, while also discussing new CAR-T constructs currently being researched.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor modified T cell therapy in B cell non-Hodgkin lymphomas. Levin, A., Shah, NN.[2021]

In a review of 646 adverse event reports for the CAR T-cell therapy tisagenlecleucel from August 2017 to August 2019, the most common adverse event was cytokine release syndrome (CRS), reported in 51.1% of cases, with a serious outcome in over 95% of reports.

Despite the high reporting rate of adverse events (81.0%), most deaths (64%) were due to the progression of the underlying disease rather than the therapy itself, indicating that no new safety concerns were identified post-marketing, and the rates of CRS and neurotoxicity were lower than those observed in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events reported to the U.S. Food and Drug Administration Adverse Event Reporting System for tisagenlecleucel. Dores, GM., Jason, C., Niu, MT., et al.[2021]

In a study of 957 patients receiving CAR T-cell therapy for relapsed/refractory large B-cell lymphomas, the overall nonrelapse mortality (NRM) rate was 5.0%, with the majority of deaths occurring later than 28 days post-infusion, primarily due to infections.

Risk factors for increased NRM included diabetes and elevated ferritin levels at the time of lymphodepletion, which can help guide physicians in selecting and managing patients to minimize these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonrelapse mortality after CAR T-cell therapy for large B-cell lymphoma: a LYSA study from the DESCAR-T registry. Lemoine, J., Bachy, E., Cartron, G., et al.[2023]

A patient with primary mediastinal large B-cell lymphoma achieved a complete metabolic response after receiving pembrolizumab following relapse 3.5 months post-CD19-directed CAR T-cell therapy, indicating the potential efficacy of immune checkpoint inhibitors in this setting.

Despite achieving remission, treatment with pembrolizumab was stopped after six cycles due to pneumonitis, highlighting the importance of monitoring for side effects while using immune checkpoint inhibitors after CAR T-cell therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab-induced Remission After Failure of Axicabtagene Ciloleucel: Case Report and Literature Review. Dimou, M., Bitsani, A., Bethge, W., et al.[2022]

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]

Citations

1. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-10266

Genetically Engineered Cells (TmCD19-IL18 CAR T ... TmCD19-IL18 CAR T cells may be safe, tolerable and/or effective in treating patients with CD19+ relapsed or refractory non-Hodgkin lymphoma. Eligibility ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.7004

Safety and efficacy of armored huCART19-IL18 in patients ... Results: As of January 20, 2024, 21 pts with CD19+ NHL were infused with huCART19-IL18. Characteristics include median age 64 yrs (47-74), 76% ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05989204

NCT05989204 | TmCD19-IL18 in CD19+ Cancers This is a Phase I, open-label dose finding study to assess the safety and feasibility, pharmacokinetics, and preliminary efficacy of TmCD19-IL18 CAR T cells ...

4. esmo.org esmo.org/oncology-news/hucart19-il18-shows-promising-efficacy-at-low-cell-doses-in-patients-with-lymphoma-after-the-failure-of-previous-anti-cd19-car-t-cell-therapy

huCART19-IL18 Shows Promising Efficacy at Low Cell ... With a median follow-up of 17.5 months (range, 3 to 34), the median duration of response was 9.6 months (90% CI 5.5 to not reached). Some ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40334157/

Enhanced CAR T-Cell Therapy for Lymphoma after Previous ... Results: A total of 21 patients received huCART19-IL18. Cytokine release syndrome occurred in 62% of the patients (47% with grade 1 or 2), and ...