CAR T-Cell Therapy for Leukemia

Overseen By Aimee C. Talleur, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: St. Jude Children's Research Hospital

Must not be taking: Systemic steroids, Intrathecal chemotherapy

Disqualifiers: HIV, CNS-3 disease, uncontrolled infection, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

60 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol suggests that you may need to stop certain medications. Specifically, you should not be on systemic steroids exceeding a certain dose or any systemic therapy that might interfere with the CAR T-cell product within 14 days before the infusion. Additionally, intrathecal chemotherapy should not be taken within 7 days prior to the infusion.

What data supports the effectiveness of the treatment CD19-CAR T-cells for leukemia?

Research shows that CD19-CAR T-cell therapy can lead to complete remission in patients with certain types of leukemia, such as B-cell acute lymphoblastic leukemia (B-ALL). However, while initial remission rates are high, maintaining long-term remission can be challenging, with some patients experiencing relapse. ^{1 2 3 4 5}

Is CAR T-cell therapy generally safe for humans?

CAR T-cell therapy, including CD19-specific CAR T-cells, has shown promise in treating certain blood cancers, but it can cause serious side effects like cytokine release syndrome (a severe immune reaction) and neurotoxicity (nerve damage). These side effects are significant but can often be managed with medical care. Cardiovascular issues like irregular heartbeats and low blood pressure have also been reported, but more research is needed to fully understand these risks. ^{6 7 8 9 10}

How is the CAR T-Cell Therapy for Leukemia treatment different from other treatments?

This treatment uses donor-derived memory T-cells that are engineered to target CD19, which is different from traditional autologous CAR T-cell therapies that use the patient's own cells. This approach can be beneficial for patients who cannot produce their own CAR T-cells due to T-cell dysfunction. ^{5 11 12 13 14}

What is the purpose of this trial?

This is a Phase I clinical study evaluating the safety and maximum tolerated dose of a novel CAR T-cell product: allogeneic memory (CD45RA- negative) T-cells expressing a CD19-specific CAR 41BBz (CD19-CAR.CD45RA- negative T-cells) for the treatment of patients ≤ 21 years old with relapsed and/ or refractory CD19-positive leukemia. Primary Objective To determine the maximum tolerated dose (MTD) and characterize the safety profile and dose-limiting toxicities (DLTs) of treatment with allogeneic CD19-CAR.CD45RA-negative T-cells in pediatric, adolescent and young adult patients ≤ 21 years of age, with relapsed and/or refractory CD19-positive leukemia. Secondary Objectives * To evaluate the anti-leukemic activity of allogeneic CD19-CAR.CD45RA-negative T-cells. * To determine rates and severity of graft-versus-host-disease (GVHD) after treatment with allogeneic CD19-CAR.CD45RA-negative T-cells. Exploratory Objectives * To study the expansion, persistence and phenotype of allogeneic CD19-CAR.CD45RA-negative T-cells. * To characterize the cytokine profile in the peripheral blood and CSF after treatment with allogeneic CD19-CAR.CD45RA-negative T-cells. * To assess whether allogeneic CD19-CAR.CD45RA-negative T-cells acquire functional versus exhaustion-associated epigenetic programs. * To determine immune reconstitution post treatment, and the clonal structure and endogenous repertoire of allogeneic CD19-CAR.CD45RA-negative T-cells and relate inferred specificity to CAR response profiles. * To characterize incidence and mechanisms of relapse post-therapy with allogeneic CD19-CAR.CD45RA-negative T-cells.

Research Team

Aimee C. Talleur, MD

Principal Investigator

St. Jude Children's Research Hospital

Stephen Gottschalk, MD

Principal Investigator

St. Jude Children's Research Hospital

Eligibility Criteria

This trial is for young patients (≤ 21 years old) with relapsed or refractory CD19-positive leukemia who haven't responded to previous treatments and are not suitable for autologous CD19-CAR T-cell therapy. They should have a matched family member donor, good heart, kidney, liver function, no severe infections or significant arrhythmias, and must agree to birth control if sexually active.

Inclusion Criteria

I can do most activities but may need help.

EKG without evidence of clinically significant arrhythmia

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

Exclusion Criteria

Not applicable.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive allogeneic CD19-CAR.CD45RA-negative T-cells with dose escalation to determine the maximum tolerated dose

4 weeks

Weekly visits for dose escalation and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of dose-limiting toxicities

4 weeks

Bi-weekly visits for safety monitoring

Exploratory Analysis

Study of T-cell expansion, persistence, phenotype, and cytokine profile in peripheral blood and CSF

Ongoing

Treatment Details

Interventions

• CD19-CAR(Mem) T-cells

Trial Overview The study tests the safety and maximum tolerated dose of allogeneic memory T-cells expressing a CD19-specific CAR in children and young adults with leukemia. It aims to find out how well these cells work against leukemia without causing graft-versus-host disease.

Participant Groups

Group I: Group B Experimental Treatment 6 Interventions

Participants in group B have not received a prior stem cell transplant from their CAR T-cell donor.

Group II: Group A Experimental Treatment 6 Interventions

Participants in group A have received a prior stem cell transplant from their CAR T-cell donor.

CD19-CAR(Mem) T-cells is already approved in United States, European Union for the following indications:

Approved in United States as CD19-CAR T-cells for:

• Relapsed/Refractory CD19-positive leukemia

Approved in European Union as CD19-CAR T-cells for:

• Relapsed/Refractory CD19-positive leukemia

Who Is Running the Clinical Trial?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Recruited

5,326,000+

Findings from Research

In a phase 1 trial involving 6 patients with relapsed/refractory B-ALL, bispecific CAR T cell therapy targeting both CD19 and CD22 achieved a complete remission (CR) rate of 100%, demonstrating its potent anti-leukemic activity.

The therapy was found to be safe, with no neurotoxicity reported, although one patient experienced a relapse with CD19-negative leukemia, highlighting the challenge of antigen escape in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bispecific CAR-T cells targeting both CD19 and CD22 for therapy of adults with relapsed or refractory B cell acute lymphoblastic leukemia. Dai, H., Wu, Z., Jia, H., et al.[2021]

A new strategy has been developed to create virus-specific T cells from donor blood that can be genetically modified to target leukemia cells, specifically those expressing the CD19 marker, which could help prevent or treat leukemia relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT).

The modified T cells showed similar activation and effectiveness in killing leukemia cells when stimulated through either the chimeric antigen receptor (CAR) or their natural T cell receptor (TCR), indicating that this approach could provide a robust method for targeted leukemia therapy while minimizing the risk of graft-versus-host disease (GVHD).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Generation of CD19-chimeric antigen receptor modified CD8+ T cells derived from virus-specific central memory T cells. Terakura, S., Yamamoto, TN., Gardner, RA., et al.[2023]

In a study involving 7 patients with B-cell acute lymphoblastic leukemia (B-ALL), all participants achieved complete remission in the bone marrow after receiving CD19 CAR-T cell therapy, demonstrating the treatment's efficacy.

However, within a month of treatment, 2 patients developed acute myeloid leukemia (AML) related to their original B-ALL, highlighting a potential risk of immune escape and the need for careful monitoring in patients undergoing this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. Gardner, R., Wu, D., Cherian, S., et al.[2022]

CD19-specific CAR T-cell therapy shows high initial remission rates (over 80%) in pediatric patients with relapsed or refractory B-ALL, but only 40% to 50% achieve durable remission.

The review discusses the potential benefits of consolidative hematopoietic cell transplantation for patients who achieve a complete response after CAR T-cell therapy, as well as strategies to enhance the effectiveness and longevity of CAR T cells in preventing relapse.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preventing relapse after CD19 CAR T-cell therapy for pediatric ALL: the role of transplant and enhanced CAR T cells. Talleur, AC., Naik, S., Gottschalk, S.[2023]

Allogeneic donor CAR19 T cells show potential as an effective treatment for refractory CD19+ acute lymphoblastic leukemia (ALL) in a mouse model, addressing challenges with autologous CAR T cell production due to patient T-cell dysfunction.

This study suggests that using CAR19 T cells from healthy donors could be a viable alternative for patients who struggle to produce their own functional T cells, potentially improving treatment outcomes for ALL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic CAR19 cells clear ALL. Neeson, P.[2021]

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]

CAR-T-cell therapy has shown significant promise in treating relapsed or refractory B-cell malignancies, such as B-cell non-Hodgkin lymphoma and B-cell acute lymphoblastic leukemia, by targeting specific antigens like CD19 and BCMA.

The review highlights both the efficacy and toxicity of CD19- and BCMA-targeted CAR-T-cell therapies, indicating that while these treatments can be effective, they also come with potential side effects that need to be managed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor-T-Cell Therapy for B-Cell Hematological Malignancies: An Update of the Pivotal Clinical Trial Data. Roex, G., Feys, T., Beguin, Y., et al.[2020]

CAR T-cell therapy, particularly targeting CD19, has shown high complete response rates in patients with relapsed or refractory B-cell malignancies, offering hope for those with limited treatment options.

While CAR T-cell therapy can lead to significant toxicities such as cytokine release syndrome, these can be effectively managed, and sustained B-cell aplasia may indicate long-term disease control in responding patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T-Cell Therapy for the Community Oncologist. Maus, MV., Levine, BL.[2021]

CAR-T cell therapy targeting CD19 has shown remarkable success in treating refractory/relapsed acute lymphoblastic leukemia (ALL), achieving complete remission rates as high as 90% in both children and adults.

While CAR-T therapy is promising for hematologic cancers, challenges remain for its application in solid tumors due to immunosuppressive environments, and there are significant risks of severe toxicities like cytokine release syndrome (CRS) and neurotoxicity that require careful management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor modified T-cells for cancer treatment. Han, X., Wang, Y., Han, WD.[2020]

CD19-specific CAR T cell therapies are effective for treating difficult-to-treat blood cancers, but they can cause significant cardiovascular toxicity, including issues like tachycardia, arrhythmias, and left ventricular dysfunction.

There is a need for more research to better understand these cardiovascular risks and to develop a cardiac surveillance protocol for patients undergoing CAR T cell therapy, ensuring safer treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T Cell Therapy-Related Cardiovascular Outcomes and Management: Systemic Disease or Direct Cardiotoxicity? Ghosh, AK., Chen, DH., Guha, A., et al.[2021]

The study successfully developed a clinical-grade manufacturing process for allogeneic CD19-CAR T cells using donor memory T cells, which expanded significantly (34.2-fold) and showed effective CAR expression (45.5%).

These engineered CD19-CAR T cells demonstrated the ability to recognize and kill CD19-positive cancer cells in laboratory tests and exhibited strong antitumor activity in a model of acute lymphoblastic leukemia (ALL), indicating their potential as a viable treatment option for patients who cannot use autologous CAR T cell therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of a cGMP-compliant process to manufacture donor-derived, CD45RA-depleted memory CD19-CAR T cells. Kim-Hoehamer, YI., Riberdy, JM., Zheng, F., et al.[2023]

The study introduces an innovative oncolytic vaccinia virus that creates truncated CD19 expression in solid tumors, enhancing the targeting ability of CD19-specific CAR-T cell therapies.

In both immunodeficient and immunocompetent mouse models, this approach effectively eradicates solid tumors, suggesting a promising strategy to improve CAR-T cell therapy outcomes in treating hematopoietic malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination Therapy for Solid Tumors: Taking a Classic CAR on New Adventures. Dagher, O., King, TR., Wellhausen, N., et al.[2021]

Adoptive T cell immunotherapy, particularly using tumor infiltrating lymphocytes (TILs), has shown the ability to induce significant cancer regression in metastatic melanoma, highlighting its potential effectiveness in cancer treatment.

The development of anti-CD19 CAR-T cells has marked a significant advancement in treating refractory B lymphocyte leukemia, but challenges remain in creating a standardized method for generating effective anti-leukemia T cells for all patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Approaches for generation of anti-leukemia specific T cells. Jin, Z., Xu, L., Li, Y.[2020]

Allogeneic stem cell transplantation (alloSCT) is a powerful treatment for leukemia, leveraging the body's immune system to target and eliminate cancer cells, but it carries risks like graft-versus-host disease (GvHD).

Recent advancements in T-cell engineering and the identification of specific leukemia antigens have led to promising clinical trials, particularly with anti-CD19 CAR T-cells, showing significant potential in treating various types of leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive T-cell therapy for Leukemia. Garber, HR., Mirza, A., Mittendorf, EA., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Bispecific CAR-T cells targeting both CD19 and CD22 for therapy of adults with relapsed or refractory B cell acute lymphoblastic leukemia. [2021]

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

Generation of CD19-chimeric antigen receptor modified CD8+ T cells derived from virus-specific central memory T cells. [2023]

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

Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. [2022]

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

Preventing relapse after CD19 CAR T-cell therapy for pediatric ALL: the role of transplant and enhanced CAR T cells. [2023]

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

Allogeneic CAR19 cells clear ALL. [2021]

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

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

7. Switzerland pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor-T-Cell Therapy for B-Cell Hematological Malignancies: An Update of the Pivotal Clinical Trial Data. [2020]

8. England pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T-Cell Therapy for the Community Oncologist. [2021]

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

Chimeric antigen receptor modified T-cells for cancer treatment. [2020]

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

CAR T Cell Therapy-Related Cardiovascular Outcomes and Management: Systemic Disease or Direct Cardiotoxicity? [2021]

11. England pubmed.ncbi.nlm.nih.gov

Development of a cGMP-compliant process to manufacture donor-derived, CD45RA-depleted memory CD19-CAR T cells. [2023]

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

Combination Therapy for Solid Tumors: Taking a Classic CAR on New Adventures. [2021]

13. China pubmed.ncbi.nlm.nih.gov

Approaches for generation of anti-leukemia specific T cells. [2020]

14. Denmark pubmed.ncbi.nlm.nih.gov

Adoptive T-cell therapy for Leukemia. [2023]