CAR T Cell Therapy for Acute Lymphoblastic Leukemia

Recruiting in Duarte (>99 mi)

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: Systemic steroids, Immunosuppressants

Disqualifiers: Autoimmune disease, Cardiovascular disability, 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: 1

Duration: 1 day

18 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial tests the safety, side effects, and best dose of autologous anti-CD19 CAR-expressing T lymphocytes (CD19-CAR T cells) in older adults with B-cell acute lymphoblastic leukemia. Chimeric antigen receptor (CAR) T-cell therapy is a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein on the patient's cancer cells is added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of B-cell acute lymphoblastic leukemia.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does exclude those using systemic steroids or chronic immunosuppressants. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment Autologous Anti-CD19 CAR-expressing T Lymphocytes for Acute Lymphoblastic Leukemia?

Research shows that CD19 CAR T-cell therapy can lead to high remission rates in patients with relapsed or refractory acute lymphoblastic leukemia, with one study reporting a 90% remission rate. However, long-term remission is achieved in about 40% to 50% of patients, indicating the treatment's potential but also highlighting the need for further strategies to maintain remission. ^{1 2 3 4 5}

Is CAR T Cell Therapy for Acute Lymphoblastic Leukemia safe for humans?

CAR T Cell Therapy, specifically targeting CD19, has been generally well tolerated in clinical trials for acute lymphoblastic leukemia, with manageable side effects like cytokine release syndrome (a condition where the immune system is overly activated) and neurotoxicity (nervous system side effects). Most side effects have been temporary or manageable with supportive care, and the therapy has shown a favorable safety profile in both children and adults. ^{4 6 7 8 9}

How is the treatment Autologous Anti-CD19 CAR-expressing T Lymphocytes unique for acute lymphoblastic leukemia?

This treatment uses a patient's own T-cells, which are modified to target and kill leukemia cells by recognizing a specific protein called CD19 on their surface. It offers a personalized approach and has shown high initial remission rates, although maintaining long-term remission can be challenging. ^{1 3 4 5 10}

Research Team

Ibrahim Aldoss, MD

Principal Investigator

City of Hope Medical Cancer Center

Eligibility Criteria

Adults aged 55 or older with B-cell acute lymphoblastic leukemia in first remission can join this trial. They must have a good performance status, proper liver and kidney function, and no severe infections like HIV or hepatitis. Women of childbearing age need a negative pregnancy test and agree to use birth control.

Inclusion Criteria

Total bilirubin =< 1.5 X upper limit of normal (ULN) (unless has Gilbert's disease)

My cancer is in its first full remission.

Agreement to allow the use of archival tissue from diagnostic tumor biopsies. Exceptions may be granted with Study Principal Investigator (PI) approval

Exclusion Criteria

I tested negative for active hepatitis B.

History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent(s)

My brain or spinal cord cancer hasn't responded to specific treatments but is now in remission.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Leukapheresis and Pre-treatment

Patients undergo T cell leukapheresis and receive fludarabine and cyclophosphamide intravenously

1-2 weeks

Multiple visits for leukapheresis and chemotherapy administration

Treatment

Patients receive CD19-CAR T cell infusion intravenously

1 day

1 visit (in-person) for infusion

Follow-up

Participants are monitored for safety, effectiveness, and adverse events after treatment

28 days

Regular visits for monitoring adverse events and response

Long-term Follow-up

Participants are monitored for event-free survival, overall survival, and relapse

Up to 15 years

Treatment Details

Interventions

• Autologous Anti-CD19 CAR-expressing T Lymphocytes

Trial Overview The trial is testing the safety and optimal dose of modified T cells (CD19-CAR T cells) that are designed to target leukemia cells in older adults. It involves taking the patient's own immune cells, modifying them in a lab, growing large numbers, and infusing them back into the patient.

Participant Groups

Group I: Treatment (CD19-CAR T cells) Experimental Treatment 7 Interventions

Patients undergo T cell leukapheresis, receive fludarabine and cyclophosphamide IV, and then receive CD19-CAR T cell infusion IV on study.

Autologous Anti-CD19 CAR-expressing T Lymphocytes is already approved in United States, European Union for the following indications:

Approved in United States as Tisagenlecleucel (Kymriah) for:

• B-cell acute lymphoblastic leukemia (ALL)
• Large B-cell lymphoma (LBCL)

Approved in European Union as Tisagenlecleucel (Kymriah) for:

• B-cell acute lymphoblastic leukemia (ALL)
• Diffuse large B-cell lymphoma (DLBCL)

Approved in United States as Axicabtagene ciloleucel (Yescarta) for:

• Large B-cell lymphoma (LBCL)
• Follicular lymphoma (FL)

Approved in European Union as Axicabtagene ciloleucel (Yescarta) for:

• Diffuse large B-cell lymphoma (DLBCL)
• Follicular lymphoma (FL)

Approved in United States as Lisocabtagene maraleucel (Breyanzi) for:

• Large B-cell lymphoma (LBCL)
• Follicular lymphoma (FL)

Approved in European Union as Lisocabtagene maraleucel (Breyanzi) for:

• Diffuse large B-cell lymphoma (DLBCL)
• Follicular lymphoma (FL)

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+

Findings from Research

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]

In a study involving nine patients with relapsed B-cell acute lymphoblastic leukemia (B-ALL) and low donor chimerism after allogeneic stem cell transplant, autologous anti-CD19 CAR T cell therapy successfully restored complete donor chimerism in vitro after 12 days of culture.

The therapy showed strong cytotoxic effects against leukemia cells, with most patients experiencing mild cytokine release syndrome as the main adverse event, and two out of three treated patients achieving complete response without acute graft-versus-host disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low Level Donor Chimerism of CD19 CAR-T Cells Returned to Complete Donor Chimerism in Patients with Relapse After Allo-Hematopoietic Stem Cell Transplant. Li, Q., Mu, J., Yuan, J., et al.[2022]

A 71-year-old woman with relapsed and refractory acute lymphoblastic leukemia (ALL) achieved undetectable minimal residual disease after receiving haplo-identical donor-derived CD19 CAR-T cells combined with mobilized peripheral blood stem cells, indicating potential efficacy in treating elderly patients.

While the treatment led to full donor cell engraftment, it also caused transient cytokine release and mild fever, along with reversible increases in liver enzymes, highlighting the need for caution regarding complications from donor cell infusions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Co-infusion of haplo-identical CD19-chimeric antigen receptor T cells and stem cells achieved full donor engraftment in refractory acute lymphoblastic leukemia. Cai, B., Guo, M., Wang, Y., et al.[2018]

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]

In a phase 1b/2 study involving 21 patients with relapsed and refractory acute lymphoblastic leukemia (R/R ALL), autologous CD19 CAR T cell therapy achieved a remarkable remission rate of 90%, including successful treatment of extramedullary leukemic sites.

While 16 patients experienced cytokine release syndrome and 11 had neurotoxicity, there were no toxic deaths, indicating that the treatment is relatively safe despite these side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Locally produced CD19 CAR T cells leading to clinical remissions in medullary and extramedullary relapsed acute lymphoblastic leukemia. Jacoby, E., Bielorai, B., Avigdor, A., et al.[2019]

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]

The novel second-generation CD19 CAR T-cell therapy, AUTO1, showed a tolerable safety profile with no cases of severe cytokine release syndrome and manageable neurotoxicity in a study of 20 adult patients with relapsed or refractory B-ALL.

AUTO1 achieved a high remission rate, with 85% of patients reaching minimal residual disease-negative complete response at one month, and demonstrated excellent persistence of CAR T-cells, indicating its potential as an effective treatment option for this challenging condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durable Responses and Low Toxicity After Fast Off-Rate CD19 Chimeric Antigen Receptor-T Therapy in Adults With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia. Roddie, C., Dias, J., O'Reilly, MA., et al.[2023]

In a phase 1 trial involving 15 pediatric and young adult patients with relapsed or refractory B-ALL, the dual-targeting CAR T-cell therapy AUTO3 demonstrated a favorable safety profile with no severe toxicities reported and an impressive remission rate of 86% one month post-treatment.

Despite the high initial remission rate, the one-year overall survival rate was 60% and event-free survival rate was 32%, indicating that improvements in the persistence of AUTO3 CAR T-cells are necessary to enhance long-term outcomes and prevent relapses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase 1 trial. Cordoba, S., Onuoha, S., Thomas, S., et al.[2022]

In a phase 1 study involving 12 pediatric patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), the autologous CD19-CAR T-cell therapy was well tolerated, with low rates of cytokine release syndrome (6 patients) and neurotoxicity (3 patients).

75% of the patients achieved a minimal residual disease-negative complete response in the bone marrow, although higher disease burden before treatment was linked to more side effects and lower response rates, emphasizing the importance of pre-infusion disease status on treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preferential expansion of CD8+ CD19-CAR T cells postinfusion and the role of disease burden on outcome in pediatric B-ALL. Talleur, AC., Qudeimat, A., Métais, JY., et al.[2022]

The study found that high levels of leukemia blast contamination in the starting material did not negatively impact the manufacturing of CAR T-cells or their ability to expand, suggesting that CAR T-cell therapy can be safely produced even from contaminated samples.

Using a specific CAR design with a short linker (CAR.CD19 SL) enhances the ability of CAR T-cells to target and kill CD19+ leukemia cells, providing a potential safety advantage in preventing leukemic relapse.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Strategy to prevent epitope masking in CAR.CD19+ B-cell leukemia blasts. Quintarelli, C., Guercio, M., Manni, S., et al.[2022]

References

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

CAR T-cells that target acute B-lineage leukemia irrespective of CD19 expression. [2022]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Low Level Donor Chimerism of CD19 CAR-T Cells Returned to Complete Donor Chimerism in Patients with Relapse After Allo-Hematopoietic Stem Cell Transplant. [2022]

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

Co-infusion of haplo-identical CD19-chimeric antigen receptor T cells and stem cells achieved full donor engraftment in refractory acute lymphoblastic leukemia. [2018]

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

Locally produced CD19 CAR T cells leading to clinical remissions in medullary and extramedullary relapsed acute lymphoblastic leukemia. [2019]

6. England 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). [2020]

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

Durable Responses and Low Toxicity After Fast Off-Rate CD19 Chimeric Antigen Receptor-T Therapy in Adults With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia. [2023]

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

CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase 1 trial. [2022]

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

Preferential expansion of CD8+ CD19-CAR T cells postinfusion and the role of disease burden on outcome in pediatric B-ALL. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Strategy to prevent epitope masking in CAR.CD19+ B-cell leukemia blasts. [2022]