Cellular Immunotherapy for Acute Lymphoblastic Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: Investigational agents, Corticosteroids

Disqualifiers: Uncontrolled illness, Active infection, Active malignancy, others

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

Compensation: Varies

Number of Visits: 24

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose and assess the side effects of a new cellular immunotherapy for high-risk acute lymphoblastic leukemia (ALL), a type of blood cancer. The treatment involves inserting a modified gene into white blood cells to enhance the immune system's ability to target and destroy cancer cells. It evaluates two types of T-cells, specifically CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T-lymphocytes and CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes, to identify which is more effective. Individuals with ALL who have experienced a relapse or have minimal residual disease (tiny amounts of cancer remaining after treatment) may be suitable candidates for this trial. As a Phase 1 trial, this research focuses on understanding how the treatment functions in people, offering participants the opportunity to be among the first to receive this innovative therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop all current medications, but it does mention that you need to be off immunosuppressant medications for at least 2 weeks before a certain procedure, with some exceptions for steroids and tyrosine kinase inhibitors. It's best to discuss your specific medications with the study team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that a specific type of modified T-cells, called CD19CAR T-cells, are safe for patients with certain cancers, even those at high risk. For instance, a study published in "Blood" found that these T-cells were well-tolerated by patients with difficult-to-treat non-Hodgkin lymphoma.

Similarly, another type of CD19CAR T-cells underwent safety testing. Research published in "Leukemia" showed that this T-cell therapy was not only effective but also safe for patients with acute lymphoblastic leukemia, even in complicated cases.

These findings suggest that both types of T-cell treatments have generally been well-tolerated in previous studies. However, since this is an early-phase trial, more data is needed to fully understand the safety of each treatment. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for acute lymphoblastic leukemia because they utilize a cutting-edge approach known as CAR T-cell therapy. Unlike standard treatments like chemotherapy and radiation, which broadly attack cancer cells, these therapies use genetically engineered T-cells to specifically target and destroy cancer cells expressing the CD19 antigen. This targeted action not only promises greater effectiveness but also potentially reduces damage to healthy cells. The treatments also feature distinct T-cell enhancements: one is enriched with a type of T-cell known as Tcm for potentially longer-lasting effects, while the other uses Tn/mem-enriched T-cells, which might offer a different balance of efficacy and safety. This precision and personalization in attacking cancer cells represent a significant advancement over traditional methods.

What evidence suggests that this trial's treatments could be effective for acute lymphoblastic leukemia?

Research has shown that the CD19-targeted CAR T cells used in this trial have been very effective against cancer in patients with relapsed or difficult-to-treat B cell acute lymphoblastic leukemia (ALL). These treatments modify certain white blood cells to find and destroy cancer cells. Studies indicate that many patients experience significant improvements, with some even achieving remission. This trial will compare two types of T cells: CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T-lymphocytes and CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes, to determine which is most effective for patients. Early results are promising, but further research is needed to fully understand their potential. ^{1 6 7 8 9}

Who Is on the Research Team?

Ibrahim Aldoss, MD

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

This trial is for patients with high-risk acute lymphoblastic leukemia who have had a relapse or still have disease after treatment. They must be in good physical condition, not need oxygen support, and have normal organ function. Pregnant women and those with active infections or other cancers are excluded.

Inclusion Criteria

Patients with CNS involvement by leukemia (CNS2 and CNS3) after discussions with the study team

I have a small amount of cancer cells left after my first treatment.

Patients able to understand and sign a written informed consent

Exclusion Criteria

I am not currently on any experimental treatments or undergoing chemotherapy or radiation.

I have a disorder that affects my lymph cells.

I do not have any uncontrolled illnesses or conditions that would limit my participation.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepleting Chemotherapy

Patients receive a lymphodepleting regimen 3-14 days before T-cell infusion

1-2 weeks

T-cell Infusion

Patients receive CD19CAR-CD28-CD3zeta-EGFRt-expressing T cells IV over 15 minutes on day 0

1 day

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 15 years

24 hours post-infusion, weekly for 1 month, monthly for 1 year, then yearly

What Are the Treatments Tested in This Trial?

Interventions

• CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T-lymphocytes
• CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes

Trial Overview The trial tests cellular immunotherapy by modifying white blood cells to fight cancer. It aims to determine the best dose and side effects of this therapy using T-lymphocytes engineered to target leukemia cells.

How Is the Trial Designed?

Group I: Arm I (cellular immunotherapy closed to accrual January 2019) Experimental Treatment 2 Interventions

Patients receive lymphodepleting regimen per treating physician's discretion 3-14 days before the T-cell infusion. Patients receive CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T cells IV over 15 minutes on day 0. Patients who have evidence of disease, whose tumor(s) continue to express the appropriate antigen target may receive an optional second infusion of CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T cells after 28 days.

Group II: Arm II (cellular immunotherapy) Active Control 2 Interventions

Patients receive lymphodepleting regimen per treating physician's discretion 3-14 days before the T-cell infusion. Patients receive CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/nem-enriched T cells IV over 15 minutes on day 0. Patients who have evidence of disease, whose tumor(s) continue to express the appropriate antigen target may receive an optional second infusion of CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/nem-enriched T cells after 28 days.

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

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]

CD19/20/22 CAR T-cells have been developed to effectively target B-lineage acute lymphoblastic leukemia (BL-ALL) that has relapsed with CD19(-) disease, showing efficacy in both laboratory and animal models.

These CAR T-cells maintain their effectiveness against CD19(+) disease while also being able to kill CD19(-) blasts, suggesting they could serve as a new treatment option for patients who do not respond to traditional CD19-targeting therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T-cells that target acute B-lineage leukemia irrespective of CD19 expression. Fousek, K., Watanabe, J., Joseph, SK., et al.[2022]

T-cell acute lymphoblastic leukemia (T-ALL) remains difficult to treat, especially in relapsed or resistant cases, due to limited novel therapeutic options and challenges like shared surface targets between normal and cancerous T-cells.

Recent advancements in immunotherapy, including monoclonal antibodies, bispecific T-cell engagers (BTCEs), and CAR T-cells, show promising results and are progressing through clinical trials, offering hope for improved treatment strategies for T-ALL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The emerging scenario of immunotherapy for T-cell Acute Lymphoblastic Leukemia: advances, challenges and future perspectives. Caracciolo, D., Mancuso, A., Polerà, N., et al.[2023]

CD19 CAR T-cell therapy has shown a high complete remission rate in pediatric acute lymphoblastic leukemia, highlighting its efficacy as a treatment for this type of cancer.

Despite its effectiveness, CD19 CAR T-cell therapy is associated with significant adverse reactions and an increased risk of cancer recurrence, necessitating further research into mechanisms of recurrence and strategies to mitigate these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cluster of differentiation 19 chimeric antigen receptor T-cell therapy in pediatric acute lymphoblastic leukemia. Fu, Z., Zhou, J., Chen, R., et al.[2020]

Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 has become a significant advancement in treating relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), with two such therapies approved by regulatory agencies.

Despite the success of CD19-targeting CAR T-cells, some patients still experience relapses, highlighting the need for ongoing research into resistance mechanisms and potential strategies to overcome them.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T-Cells for the Treatment of B-Cell Acute Lymphoblastic Leukemia. Saleh, K., Pasquier, F., Bigenwald, C., et al.[2023]

Adoptive cellular therapy using CD19 CAR T cells has shown remarkable efficacy in achieving remission in 67-90% of patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), indicating a promising treatment option for this high-risk group.

While CD19 CAR T-cell therapy can lead to significant toxicities such as cytokine release syndrome and neurologic dysfunction, these effects are generally manageable with supportive care, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19-redirected chimeric antigen receptor-modified T cells: a promising immunotherapy for children and adults with B-cell acute lymphoblastic leukemia (ALL). Tasian, SK., Gardner, RA.[2020]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT02146924

Study Details | NCT02146924 | Cellular Immunotherapy in ... This phase I trial studies the side effects and best dose of cellular immunotherapy in treating patients with high-risk acute lymphoblastic leukemia.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4684949/

Efficacy and Toxicity Management of 19-28z CAR T Cell ... We next demonstrated potent antitumor benefit after infusing CD19-targeted 19-28z CAR T cells into five adults with relapsed or refractory B cell acute ...

3. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/cd19car-cd28-cd3zeta-egfrt-expressing-tn-mem-enriched-t-lymphocytes

Clinical Trials Using CD19CAR-CD28-CD3zeta-EGFRt- ... Humanized CD19-Specific CAR T Cells for the Treatment of Patients with Positive Relapsed or Refractory CD19 Positive B-Cell Acute Lymphoblastic Leukemia.

4. researchgate.net researchgate.net/publication/349499787_A_Review_of_Clinical_Outcomes_of_CAR_T-Cell_Therapies_for_B-Acute_Lymphoblastic_Leukemia

A Review of Clinical Outcomes of CAR T-Cell Therapies ... Adoptive T cells engineered to express a chimeric antigen receptor (CAR-T) is emerging as an effective technique for treating these patients.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9395272/

Use of CAR T-cell for acute lymphoblastic leukemia (ALL ... In this review different generations, challenges, and clinical studies related to chimeric antigen receptor (CAR) T-cells for ALL treatment are discussed.

6. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/cd19car-cd28-cd3zeta-egfrt-expressing-tcm-enriched-t-lymphocytes

Clinical Trials Using CD19CAR-CD28-CD3zeta-EGFRt ... Review the clinical trials studying cd19car-cd28-cd3zeta-egfrt-expressing tcm-enriched t-lymphocytes on this list and use the filters to refine the results ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11539471/

Advances in CAR-T therapy for central nervous system tumors This review examined the research progress of chimeric antigen receptor T-cell therapy in gliomas, medulloblastomas, and lymphohematopoietic tumors of the ...

8. ashpublications.org ashpublications.org/blood/article/127/24/2980/35453/Phase-1-studies-of-central-memory-derived-CD19-CAR

Phase 1 studies of central memory–derived CD19 CAR T–cell ... TCM-derived CD19 CAR T–cell therapy is safe for treatment of poor-risk NHL patients undergoing autologous HSCT. Addition of a CD28 ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10544259/

PMC - PubMed Central High efficacy and safety of low-dose CD19-directed CAR-T cell therapy in 51 refractory or relapsed B acute lymphoblastic leukemia patients. Leukemia 2017;31 ...