CAR T-Cell Therapy for Leukemia

Recruiting at 1 trial location

Overseen By Melissa S Varghese, B.A.

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Stephan Grupp MD PhD

Must not be taking: Systemic steroids, Immunosuppressants

Disqualifiers: Hepatitis B, Hepatitis C, HIV, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

89 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will determine the safety and efficacy of moving to a second-generation manufacturing process using the CliniMACS Prodigy platform to manufacture huCART19 cells for patients with B cell Acute Lymphoblastic Leukemia (B-ALL).

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but you cannot use systemic steroids or immunosuppressants at the time of cell infusion or collection. Some steroids are allowed at other times, and inhaled steroids or physiologic replacement hydrocortisone are permitted.

What data supports the effectiveness of the treatment Autologous Humanized CD19-Directed Chimeric Antigen Receptor T-Cells (huCART19) for leukemia?

Research shows that similar CD19-targeted chimeric antigen receptor (CAR) T-cell therapies have been effective in treating certain types of leukemia, such as acute lymphoblastic leukemia (ALL), with some patients achieving complete remission. Additionally, targeting both CD19 and CD22 antigens in younger patients with ALL has shown promising results, with manageable side effects and complete responses in some cases. ^{1 2 3 4 5}

Is CAR T-Cell Therapy for Leukemia safe for humans?

CAR T-Cell Therapy, including versions targeting CD19, has shown some safety concerns, with common side effects like cytokine release syndrome (a severe immune reaction) and neurological issues. However, these side effects are often manageable, and newer versions of the therapy are being developed to reduce these risks. ^{4 6 7 8 9}

What makes the CAR T-Cell Therapy for Leukemia treatment unique?

This treatment uses a patient's own T-cells, which are modified to target and destroy leukemia cells by recognizing a specific protein called CD19 on their surface. It offers a novel approach for patients who do not respond to traditional chemotherapy, with high success rates in achieving remission. ^{6 10 11 12 13}

Research Team

Allison Barz Leahy, MD

Principal Investigator

Children's Hospital of Philadelphia

Stephan Grupp, MD,PhD

Principal Investigator

Children's Hospital of Philadelphia

Eligibility Criteria

This trial is for children and young adults aged 0-29 with B-cell Acute Lymphoblastic Leukemia (B-ALL) who have either relapsed or didn't respond well to previous treatments. Participants must have CD19+ ALL, adequate organ function, and a performance score of at least 50. They should not be pregnant, nursing, or have active infections like hepatitis B/C or HIV.

Inclusion Criteria

My brain-related disease is responding to treatment.

I had a poor response to previous B cell therapy.

Signed Informed Consent

Exclusion Criteria

I currently have an infection that is not under control.

My brain condition is getting worse despite treatment, or I have brain lesions that could make treatment risky.

I am HIV positive.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Phase 1 dose escalation using a '3+3' design to establish the recommended phase 2 dose of huCART19 cells

Varies

Dose Expansion

Phase 2b dose expansion where subjects receive the highest safe dose of huCART19 cells

Varies

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Treatment Details

Interventions

• Autologous Humanized CD19-Directed Chimeric Antigen Receptor T-Cells (huCART19)

Trial Overview The study tests the safety and effectiveness of huCART19 T cells made using a new method called CliniMACS Prodigy platform in patients with B-ALL. It aims to see if this second-generation process can improve treatment outcomes for these patients.

Participant Groups

Group I: Dose Expansion Arms Experimental Treatment 1 Intervention

If at least one dose level of the dose escalation phase is determined to be safe, the phase 2b dose expansion phase of the trial will be opened to enrollment. Subjects will receive the highest dose of huCART19 cells that were determined to be safe in the dose escalation part of the trial. 2 cohorts are planned: * Cohort A (relapsed/refractory, CAR T cell naïve) * Cohort B (prior treatment with CD19-directed CAR T cells)

Group II: Dose Escalation Arm Experimental Treatment 1 Intervention

The phase 1 dose escalation portion of the trial will use a standard "3+3" design to establish the recommended phase 2 dose of huCART19 cells in patients with subjects with prior treatment with CD19-directed CAR T cells. Two dose escalations of huCART19 are planned for the dose escalation phase.

Autologous Humanized CD19-Directed Chimeric Antigen Receptor T-Cells (huCART19) is already approved in United States for the following indications:

Approved in United States as huCART19 for:

• B-cell Acute Lymphoblastic Leukemia (B-ALL)

Who Is Running the Clinical Trial?

Stephan Grupp MD PhD

Lead Sponsor

Trials

5

Recruited

370+

Children's Hospital of Philadelphia

Collaborator

Trials

749

Recruited

11,400,000+

Findings from Research

Chimeric antigen receptor-modified T cells targeting CD19 showed significant clinical activity in two children with relapsed acute lymphoblastic leukemia (ALL), leading to complete remission in one patient for 11 months after treatment.

While the treatment was effective, both patients experienced severe adverse events, including cytokine-release syndrome and B-cell aplasia, highlighting the need for careful monitoring and potential additional targeting strategies due to the emergence of CD19-negative tumor cells in one patient.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. Grupp, SA., Kalos, M., Barrett, D., et al.[2023]

CD4 is identified as a promising target for CAR-T cell therapy in treating acute myeloid leukemia (AML), as it is expressed in certain AML subtypes but not on normal hematopoietic stem cells, allowing for targeted treatment.

CD4 redirected CAR-T cells effectively eliminated CD4-expressing AML cells in laboratory settings and demonstrated strong anti-leukemic effects in a mouse model, suggesting potential for clinical application in refractory AML cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical Targeting of Human Acute Myeloid Leukemia Using CD4-specific Chimeric Antigen Receptor (CAR) T Cells and NK Cells. Salman, H., Pinz, KG., Wada, M., et al.[2020]

Chimeric antigen receptor (CAR) T cells targeting both CD123 and CD33, in addition to CLL-1, showed improved anti-tumor activity against acute myeloid leukemia (AML) cells, especially when the target cells expressed low levels of these antigens.

The study demonstrated that dual targeting led to enhanced T cell activation and better tumor control in vivo, resulting in improved survival rates in animal models without any antigen escape in residual tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combinatorial antigen targeting strategies for acute leukemia: application in myeloid malignancy. Atilla, PA., McKenna, MK., Watanabe, N., et al.[2023]

In a phase I trial involving 12 younger patients with relapsed or refractory B-cell acute lymphoblastic leukemia, the use of chimeric antigen receptor T cells targeting CD19 and CD22 showed manageable toxicity levels.

Out of the 12 patients, 5 achieved complete responses, indicating promising efficacy of this treatment approach in this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting CD19-CD22 Aids Younger Patients with ALL. [2021]

The study found that Tn/mem-derived CD19-CAR T cells were safe and effective in treating adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL), with 87% of participants achieving complete remission or partial remission.

Among the 46 participants treated, those with Philadelphia-like ALL and extramedullary disease showed high response rates, and undergoing allogeneic hematopoietic cell transplantation after treatment significantly improved relapse-free survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Favorable Activity and Safety Profile of Memory-Enriched CD19-Targeted Chimeric Antigen Receptor T-Cell Therapy in Adults with High-Risk Relapsed/Refractory ALL. Aldoss, I., Khaled, SK., Wang, X., et al.[2023]

CAR T cell therapy, specifically targeting the CD19 antigen, has shown high response rates in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL), indicating its potential as a new treatment option.

Despite its effectiveness, CAR T cell therapy is associated with severe toxicities like cytokine release syndrome and neurotoxicity, which pose challenges for its widespread use and highlight the need for ongoing improvements in the technology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor Therapy in Acute Lymphoblastic Leukemia Clinical Practice. Luskin, MR., DeAngelo, DJ.[2018]

Chimeric-antigen-receptor T cells (CAR-T) targeting CD19 are associated with several adverse drug reactions (ADRs), with the most common being cytokine release syndrome (CRS), neurological disorders, and hematological disorders, as identified in a study analyzing 1783 safety reports.

While CAR-T therapy can lead to severe ADRs, particularly in the week following administration, the overall fatality rate from these reactions is relatively low at 5.5%, though serious conditions like hemophagocytic-lymphohistiocytosis and infections require careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor T-cells safety: A pharmacovigilance and meta-analysis study. Dolladille, C., Ederhy, S., Ezine, E., et al.[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]

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]

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]

CAR T cell therapy targeting CD19 has shown remarkable efficacy, achieving complete remission in up to 90% of patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), compared to a 30% response rate with traditional chemotherapy.

The therapy involves genetically modifying T cells to express a chimeric antigen receptor, allowing them to effectively target and eliminate cancer cells, although it is important to note that there are unique toxicities associated with this treatment that require careful management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19-Targeted CAR T cells as novel cancer immunotherapy for relapsed or refractory B-cell acute lymphoblastic leukemia. Davila, ML., Brentjens, RJ.[2023]

CAR T cell therapy has shown effectiveness in treating various hematological malignancies, including B lymphoblastic leukemia and lymphoma, with advancements in CD19, BCMA, and CD7 CAR-T cells.

Research is ongoing to improve CAR T cell therapies by developing multi-target and universal CAR-T cells, as well as iPSC-derived CAR cells, aiming for enhanced efficacy and reduced side effects in treating myeloid malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progress on CAR-T cell therapy for hematological malignancies. Hu, K., Huang, Y., Hu, Y., et al.[2022]

In a pilot clinical trial involving 9 patients with relapsed or chemotherapy-refractory B-cell acute lymphocytic leukemia (B-ALL), genetically modified T cells targeting the CD19 antigen showed a 56% overall survival rate at 18 weeks.

The study demonstrated that donor-derived anti-CD19 CAR T cells can lead to significant regression of both hematopoietic and extramedullary B-ALL, although some patients experienced grade 2-3 graft-versus-host disease (GVHD) after treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerance and efficacy of autologous or donor-derived T cells expressing CD19 chimeric antigen receptors in adult B-ALL with extramedullary leukemia. Dai, H., Zhang, W., Li, X., et al.[2021]

References

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

Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. [2023]

2. Australia pubmed.ncbi.nlm.nih.gov

Preclinical Targeting of Human Acute Myeloid Leukemia Using CD4-specific Chimeric Antigen Receptor (CAR) T Cells and NK Cells. [2020]

3. England pubmed.ncbi.nlm.nih.gov

Combinatorial antigen targeting strategies for acute leukemia: application in myeloid malignancy. [2023]

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

Targeting CD19-CD22 Aids Younger Patients with ALL. [2021]

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

Favorable Activity and Safety Profile of Memory-Enriched CD19-Targeted Chimeric Antigen Receptor T-Cell Therapy in Adults with High-Risk Relapsed/Refractory ALL. [2023]

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

Chimeric Antigen Receptor Therapy in Acute Lymphoblastic Leukemia Clinical Practice. [2018]

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

Chimeric antigen receptor T-cells safety: A pharmacovigilance and meta-analysis study. [2021]

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. 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]

10. Japan pubmed.ncbi.nlm.nih.gov

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

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

CD19-Targeted CAR T cells as novel cancer immunotherapy for relapsed or refractory B-cell acute lymphoblastic leukemia. [2023]

12. China pubmed.ncbi.nlm.nih.gov

Progress on CAR-T cell therapy for hematological malignancies. [2022]

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

Tolerance and efficacy of autologous or donor-derived T cells expressing CD19 chimeric antigen receptors in adult B-ALL with extramedullary leukemia. [2021]