Human-Domain CAR T Therapy for Leukemia and Lymphoma

Recruiting at 1 trial location

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Seattle Children's Hospital

Must not be taking: Immunosuppressants, Virotherapy

Disqualifiers: Active malignancy, CNS pathology, Severe infection, others

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

Compensation: Varies

Number of Visits: Unknown

16 Participants Needed

Trial Summary

What is the purpose of this trial?

Patients with relapsed or refractory leukemia or lymphoma are often refractory to further chemotherapy. In this study, the investigators will attempt to use T cells obtained directly from the patient, which can be genetically engineered to express a fully human chimeric antigen receptor (CAR). The CAR used in this study can recognize CD19, a protein expressed on the surface of leukemia and lymphoma cells. The fully human CAR used in this study may help protect against rejection of the CAR T cells, which in turn could lead to lasting protection against return of the leukemia or lymphoma. The phase 1 part of this study will determine the safety of these CAR T cells, and the phase 2 part of the study will determine how effective this CAR T cell therapy is. Both patients who have never had prior CAR T cell therapy and those who have had prior CAR T cell therapy may be eligible to participate in this study.

Will I have to stop taking my current medications?

The trial requires that participants stop certain medications before joining. You need to be at least 7 days past your last chemotherapy, biologic therapy, and corticosteroid therapy, 3 days past Tyrosine Kinase Inhibitor use, and 1 day past hydroxyurea. If you're on maintenance chemotherapy or intrathecal chemotherapy, you may continue those.

What data supports the effectiveness of the treatment SCRI-huCAR19v1, SCRI-huCAR19v2 for leukemia and lymphoma?

Research shows that CAR-T cells with humanized components, like those in SCRI-huCAR19v1 and SCRI-huCAR19v2, have been effective in killing leukemia cells and improving survival in animal models. Additionally, similar CAR-T therapies targeting CD19 have shown success in treating various blood cancers, suggesting potential effectiveness for these treatments. ^{1 2 3 4 5}

What safety data exists for Human-Domain CAR T Therapy for Leukemia and Lymphoma?

CAR T cell therapy can cause serious side effects like cytokine release syndrome (a severe immune reaction) and neurotoxicity (nerve damage), with varying risks depending on the type of cancer and patient age. Studies show that using certain designs of CAR T cells can reduce these risks, and treatments like corticosteroids can help manage side effects. Overall, while effective, CAR T therapy requires careful monitoring for these potential adverse effects. ^{6 7 8 9 10}

What makes the Human-Domain CAR T Therapy for Leukemia and Lymphoma unique?

This treatment uses humanized components in CAR-T cells, which are designed to target and kill cancer cells more effectively while reducing side effects like neurotoxicity. It represents an advancement over traditional CAR-T therapies by potentially offering safer and more effective options for patients with leukemia and lymphoma. ^{1 2 3 11 12}

Research Team

Colleen Annesley, MD

Principal Investigator

Seattle Children's Hospital

Eligibility Criteria

This trial is for young individuals (1-30 years old) with CD19+ leukemia or lymphoma that hasn't responded to other treatments. They must be able to undergo apheresis, have a life expectancy of at least 8 weeks, and use effective contraception. Those with severe infections, primary immunodeficiency, active malignancies besides the study's focus, symptomatic CNS issues uncontrolled by enrollment, or active GVHD are excluded.

Inclusion Criteria

I took hydroxyurea more than 1 day ago.

It has been over 30 days since my last CAR T cell treatment.

My organs are working well.

Exclusion Criteria

I am currently being treated for or have symptoms of GVHD.

I am currently fighting a severe infection.

I have a primary immunodeficiency syndrome.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Treatment

Determine the safety of CD19-specific CAR T cells

4 weeks

Phase 2 Treatment

Determine the effectiveness of CD19-specific CAR T cell therapy

9 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• SCRI-huCAR19v1
• SCRI-huCAR19v2

Trial Overview The trial tests two versions of SCRI-huCAR19 CAR T cells designed to target CD19 on cancer cells. It aims to see if these genetically engineered T cells from patients can treat leukemia/lymphoma without being rejected by the body. The first phase checks safety; the second phase assesses effectiveness.

Participant Groups

Group I: SCRI-huCAR19v2 Experimental Treatment 1 Intervention

Patients will receive SCRI-huCAR19v2 in either Phase 1 or Phase II

Group II: SCRI-huCAR19v1 - [CLOSED] Experimental Treatment 1 Intervention

Patients will receive SCRI-huCAR19v1 in either Phase 1 or Phase II. As of 02/13/2020 this study cohort is permanently closed.

Who Is Running the Clinical Trial?

Seattle Children's Hospital

Lead Sponsor

Trials

319

Recruited

5,232,000+

Findings from Research

CAR T-cell therapy has shown durable remission in B-cell leukemia and lymphoma, highlighting its potential effectiveness for treating other types of cancers.

Recent advancements in CAR design and clinical application strategies aim to enhance T-cell proliferation and efficacy while minimizing toxicity, making this therapy more accessible to patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T-Cells: New Approaches to Improve Their Efficacy and Reduce Toxicity. Maus, MV., Powell, DJ.[2018]

Chimeric antigen receptor (CAR) therapy, particularly targeting CD19, has shown significant efficacy in treating patients with chemorefractory B cell malignancies, leading to its potential regulatory approval as a cell-based immunotherapy.

While CAR therapy is effective, it is associated with toxicities such as cytokine release syndrome, neurotoxicity, and B cell aplasia, which require careful management in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biology and clinical application of CAR T cells for B cell malignancies. Davila, ML., Sadelain, M.[2023]

In a review of 35 studies involving 1412 patients with acute lymphocytic leukemia (ALL) and lymphoma treated with CD19 CAR-T cell therapy, severe cytokine release syndrome (sCRS) occurred in 18.5% of patients, highlighting a significant side effect of this treatment.

The incidence of sCRS was notably higher in patients under 18 years old (28.6%) compared to those over 18 (16.1%), suggesting that age may influence the risk of this adverse effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The incidence of cytokine release syndrome and neurotoxicity of CD19 chimeric antigen receptor-T cell therapy in the patient with acute lymphoblastic leukemia and lymphoma. Cao, JX., Wang, H., Gao, WJ., et al.[2020]

Chimeric antigen receptor (CAR) T cell therapy targeting CD19 and CD20 has shown a promising overall response rate of 61% in treating B-cell hematologic malignancies, with a complete response rate of 42% and partial response rate of 19% across 16 studies involving 195 patients.

However, the therapy is associated with significant adverse events, including cytokine release syndrome and neurotoxicity (both at 33%), and B-cell aplasia in 54% of patients, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-CD 19 and anti-CD 20 CAR-modified T cells for B-cell malignancies: a systematic review and meta-analysis. Riaz, IB., Zahid, U., Kamal, MU., et al.[2023]

Engineered T cell therapies, like CAR T cells and TCR T cell therapies, have shown remarkable efficacy in treating certain blood cancers, highlighting their potential as a powerful tool in cancer immunotherapy.

However, these therapies also pose unique safety challenges, such as cytokine release syndrome and neurotoxicity, which require careful nonclinical safety assessments to ensure patient safety during development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonclinical safety assessment of engineered T cell therapies. Lebrec, H., Maier, CC., Maki, K., et al.[2022]

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 study involving 1,926 subjects from 17 clinical trials, patients with acute lymphocytic leukemia (ALL) were found to have a higher risk of severe cytokine release syndrome (sCRS) and severe neurological toxicities (sNTX) compared to those with non-Hodgkin's lymphoma (NHL) or multiple myeloma (MM).

The use of CAR T cells produced with gammaretrovirus vectors containing CD28 sequences was linked to increased rates of sNTX, while administering cytokine-directed therapies and corticosteroids at lower toxicity grades was associated with reduced rates of sCRS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cross-study safety analysis of risk factors in CAR T cell clinical trials: An FDA database pilot project. Foster, M., Negash, Y., Eberhardt, L., et al.[2022]

CAR-T therapy has shown promising results in treating leukemia and lymphoma, offering potentially curative options for patients who previously had limited treatment choices, as highlighted in studies presented at the 61st annual meeting of the American Society of Hematology.

Recent advancements in CAR-T constructs aim to enhance treatment efficacy and durability while also improving strategies to manage toxicity, indicating a focus on both effectiveness and patient safety in the evolving field of cellular immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updates in Chimeric Antigen Receptor T-Cell (CAR-T) Therapy for Lymphoma and Leukemia from the Annual Meeting of American Society of Hematology 2019. Bukhari, A., Siglin, J., Lutfi, F., et al.[2020]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

The novel anti-CD19 chimeric antigen receptors with humanized scFv (single-chain variable fragment) trigger leukemia cell killing. [2017]

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

Human Binding Domains Reduce Neurotoxicity of Anti-CD19 CAR-T Cells. [2020]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Broadening the horizon: potential applications of CAR-T cells beyond current indications. [2023]

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

Chimeric Antigen Receptor T-Cells: New Approaches to Improve Their Efficacy and Reduce Toxicity. [2018]

5. Japan pubmed.ncbi.nlm.nih.gov

Biology and clinical application of CAR T cells for B cell malignancies. [2023]

6. England pubmed.ncbi.nlm.nih.gov

The incidence of cytokine release syndrome and neurotoxicity of CD19 chimeric antigen receptor-T cell therapy in the patient with acute lymphoblastic leukemia and lymphoma. [2020]

7. England pubmed.ncbi.nlm.nih.gov

Anti-CD 19 and anti-CD 20 CAR-modified T cells for B-cell malignancies: a systematic review and meta-analysis. [2023]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Nonclinical safety assessment of engineered T cell therapies. [2022]

9. 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]

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

Cross-study safety analysis of risk factors in CAR T cell clinical trials: An FDA database pilot project. [2022]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Updates in Chimeric Antigen Receptor T-Cell (CAR-T) Therapy for Lymphoma and Leukemia from the Annual Meeting of American Society of Hematology 2019. [2020]

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

Constant attack on T cell lymphomas. [2018]