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

Trial Summary

What is the purpose of this trial?

This is a Phase I, open-label dose finding study to assess the safety, tolerability, manufacturing feasibility, pharmacokinetics, and preliminary efficacy of TmCD19-IL18 CAR T cells in patients with CD19+ cancers. This study will take place in two parts: a Dose-Finding Phase to determine the maximum tolerate dose (MTD), followed by a Dose Expansion Phase. In the Dose-Finding Phase, dose levels will be evaluated using a 3+3 dose escalation design to determine the MTD (as defined below). Cumulative safety experience and manufacturing feasibility data from the Dose-Finding Phase will then be used to identify the dose level that can be progressed into the Dose Expansion Phase.

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.

What data supports the effectiveness of the treatment TmCD19-IL18 CAR T cells for Non-Hodgkin's Lymphoma?

Research shows that CAR T-cell therapy targeting CD19 has been effective in treating aggressive B-cell non-Hodgkin lymphoma, with high remission rates observed in patients. Additionally, high levels of a protein called interleukin-15 (IL-15) in the blood are linked to better outcomes with this type of treatment. ^{1 2 3 4 5}

What is known about the safety of CAR T-cell therapies like TMhuCART19-IL18 for humans?

CAR T-cell therapies, including those targeting CD19, have been associated with side effects such as cytokine release syndrome (a severe immune reaction) and neurological toxicity, which can be serious but are generally manageable with proper medical care. Other potential risks include hemophagocytic lymphohistiocytosis (a severe inflammatory condition) and disseminated intravascular coagulation (a blood clotting disorder), which are rare but can be fatal. These therapies have been studied in various conditions, and while they show promise, they require careful monitoring for these adverse events. ^{6 7 8 9 10}

What makes the TMhuCART19-IL18 treatment unique for non-Hodgkin's lymphoma?

The TMhuCART19-IL18 treatment is unique because it combines CAR T-cell therapy targeting CD19 with interleukin-18 (IL-18), which may enhance the immune response against lymphoma cells, offering a novel approach compared to existing CAR T-cell therapies that do not include IL-18. ^{1 2 11 12 13}

Research Team

Jakub Svoboda, MD

Principal Investigator

University of Pennsylvania

Eligibility Criteria

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

I have severe heart problems that limit my daily activities.

Pregnant or nursing patients

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

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

Lymphoma Remissions Caused by Anti-CD19 Chimeric Antigen Receptor T Cells Are Associated With High Serum Interleukin-15 Levels. [2021]

2. England pubmed.ncbi.nlm.nih.gov

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

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

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

4. Greece pubmed.ncbi.nlm.nih.gov

Pembrolizumab-induced Remission After Failure of Axicabtagene Ciloleucel: Case Report and Literature Review. [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

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

7. Italy pubmed.ncbi.nlm.nih.gov

Hemophagocytic lymphohistiocytosis and disseminated intravascular coagulation are underestimated, but fatal adverse events in chimeric antigen receptor T-cell therapy. [2023]

8. United States 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. [2021]

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

Adverse events reported to the U.S. Food and Drug Administration Adverse Event Reporting System for tisagenlecleucel. [2021]

10. United States 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. [2023]

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

Chimeric antigen receptor modified T cell therapy in B cell non-Hodgkin lymphomas. [2021]

12. England pubmed.ncbi.nlm.nih.gov

Review: Current clinical applications of chimeric antigen receptor (CAR) modified T cells. [2022]

13. France pubmed.ncbi.nlm.nih.gov

[CAR-T cells in lymphomas: Current and evolving role]. [2021]