CAR T-Cell Therapy for Acute Lymphoblastic Leukemia

Overseen By NCI Pediatric Leukemia, Lymphoma Transpl

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Antidepressants, Antineoplastics, others

Disqualifiers: CNS disease, Hyperleukocytosis, Pregnancy, 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: 9

Duration: 1 day

126 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Acute lymphoblastic leukemia (ALL) is the most common cancer in children. About 90% of children and young adults who are treated for ALL can now be cured. But if the disease comes back, the survival rate drops to less than 50%. Better treatments are needed for ALL relapses. Objective: To test chimeric antigen receptor (CAR) therapy. CARs are genetically modified cells created from each patient s own blood cells. his trial will use a new type of CAR T-cell that is targeting both CD19 and CD22 at the same time. CD19 and CD22 are proteins found on the surface of most types of ALL. Eligibility: People aged 3 to 39 with ALL or related B-cell lymphoma that has not been cured by standard therapy. Design: Participants will be screened. This will include: Physical exam Blood and urine tests Tests of their lung and heart function Imaging scans Bone marrow biopsy. A large needle will be inserted into the body to draw some tissues from the interior of a bone. Lumbar puncture. A needle will be inserted into the lower back to draw fluid from the area around the spinal cord. Participants will undergo apheresis. Their blood will circulate through a machine that separates blood into different parts. The portion containing T cells will be collected; the remaining cells and fluids will be returned to the body. The T cells will be changed in a laboratory to make them better at fighting cancer cells. Participants will receive chemotherapy starting 4 or 5 days before the CAR treatment. Participants will be admitted to the hospital. Their own modified T cells will be returned to their body. Participants will visit the clinic 2 times a week for 28 days after treatment. Follow-up will continue for 15 years....

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop all current medications, but there are specific 'washout' periods (time without taking certain medications) for some treatments. For example, you need to stop systemic chemotherapy and certain other therapies at least 2 weeks before starting the trial, with longer periods for specific drugs like clofarabine. However, some medications like intrathecal chemotherapy and certain maintenance therapies may not require a washout period.

What data supports the effectiveness of the treatment CD19/CD22 Bicistronic Chimeric Antigen Receptor (CAR) T Cells, CD19/CD22 CAR T Cells, AUTO3 for Acute Lymphoblastic Leukemia?

Research shows that the AUTO3 treatment, which targets both CD19 and CD22, had an 86% remission rate in patients with B-cell acute lymphoblastic leukemia one month after treatment. This dual targeting approach may help prevent relapse by addressing the loss of the targeted antigen, a common issue with single-target therapies. ^{1 2 3 4 5}

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

In a study with pediatric and young adult patients using AUTO3 (a type of CAR T-Cell therapy targeting CD19 and CD22), the treatment showed a favorable safety profile with no severe side effects like cytokine release syndrome or neurotoxicity reported. ^{1 6 7 8 9}

What makes the CD19/CD22 CAR T-Cell treatment unique for acute lymphoblastic leukemia?

This treatment is unique because it targets two proteins, CD19 and CD22, on cancer cells, which helps prevent the cancer from escaping treatment by losing one of these proteins. This dual targeting approach aims to improve the effectiveness and reduce the chance of relapse compared to treatments that target only one protein. ^{1 2 3 5 6}

Research Team

Nirali N. Shah

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

This trial is for children and young adults aged 3 to 35 with B-cell malignancies like ALL or lymphoma that's come back or didn't respond to treatment. They must have tried at least one standard chemo and one additional therapy, may have had a stem cell transplant, and can't be pregnant or breastfeeding. Participants need decent heart and lung function, no severe infections (HIV/HBV/HCV), no other cancers unless cured over two years ago, and must agree to birth control measures.

Inclusion Criteria

My cancer did not respond to initial chemotherapy and a follow-up treatment.

My tests show some remaining cancer cells or active cancer.

My cancer is a type of blood cancer like ALL, CML in ALL phase, or high-grade lymphoma.

Exclusion Criteria

Participants with positive serum or urine beta-HCG pregnancy test performed at screening

I have active brain lymphoma or symptoms of it.

I meet the required waiting period after my last cancer treatment before joining this trial.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Multiple visits for physical exam, blood and urine tests, imaging scans, bone marrow biopsy, and lumbar puncture

Apheresis

Participants undergo apheresis to collect T cells for modification

1 day

1 visit (in-person)

Chemotherapy

Participants receive chemotherapy 4 or 5 days before CAR T-cell treatment

4-5 days

Inpatient stay

Treatment

Participants receive CD19/CD22-CAR T-cell infusion

1 day

Inpatient stay

Initial Follow-up

Participants visit the clinic 2 times a week for 28 days after treatment

4 weeks

8 visits (in-person)

Long-term Follow-up

Participants are monitored for safety and effectiveness, with follow-up continuing for 15 years

15 years

Regular visits as per protocol

Treatment Details

Interventions

• CD19/CD22 Bicistronic Chimeric Antigen Receptor (CAR) T Cells

Trial Overview The study tests a new CAR T-cell therapy targeting both CD19/CD22 proteins on cancer cells. It involves modifying the patient's own T cells in the lab after chemotherapy preparation. Patients will receive their modified T cells back into their body in hospital settings followed by regular clinic visits for monitoring over an extended period of up to 15 years.

Participant Groups

Group I: 4/Phase II Dose Expansion- with high disease burden Experimental Treatment 3 Interventions

CD19/CD22-CAR-transduced T cells at MTD/or highest dose administered with LD regimen #2

Group II: 3/Phase II Dose Expansion- with low disease burden Experimental Treatment 3 Interventions

CD19/CD22-CAR-transduced T cells at MTD/or highest dose administered with LD

Group III: 2b/Phase 1 Dose Escalation - high disease burden Experimental Treatment 3 Interventions

CD19/CD22-CAR-transduced T cells

Group IV: 2/Phase I Dose Escalation- with intensified LD - CLOSED Experimental Treatment 3 Interventions

CD19/CD22-CAR-transduced T cells + standard LD

Group V: 1b/Phase 1 Dose Escalation - low disease burden Experimental Treatment 3 Interventions

CD19/CD22-CAR-transduced T cells

Group VI: 1/Phase I Dose Escalation-with standard LD - CLOSED Experimental Treatment 3 Interventions

CD19/CD22-CAR-transduced T cells at escalating dose + standard LD

CD19/CD22 Bicistronic Chimeric Antigen Receptor (CAR) T Cells is already approved in United States, European Union for the following indications:

Approved in United States as CD19/CD22 CAR T Cells for:

• Recurrent or refractory CD19/CD22-expressing B cell malignancies

Approved in European Union as AUTO3 for:

• Relapsed/refractory large B-cell lymphoma

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

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]

BiCAR-T cells, which target both CD19 and CD22, demonstrated significant anti-tumor effects in both laboratory and animal models, suggesting enhanced efficacy compared to single-target CAR-T therapies.

This dual targeting approach may help prevent relapse in B-cell acute lymphoblastic leukemia (B-ALL) by reducing the risk of immune escape due to loss of the targeted antigens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engineering Novel CD19/CD22 Dual-Target CAR-T Cells for Improved Anti-Tumor Activity. Zeng, W., Zhang, Q., Zhu, Y., et al.[2022]

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 58 children and young adults with relapsed or refractory B-cell malignancies, CD22-targeted CAR T cells achieved a complete remission rate of 70%, demonstrating significant efficacy as an alternative treatment for patients who did not respond to CD19-targeted therapies.

The treatment was generally safe, with most side effects being mild to moderate, although cytokine release syndrome occurred in 86.2% of participants, indicating the need for careful monitoring and potential toxicity management strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD4/CD8 T-Cell Selection Affects Chimeric Antigen Receptor (CAR) T-Cell Potency and Toxicity: Updated Results From a Phase I Anti-CD22 CAR T-Cell Trial. Shah, NN., Highfill, SL., Shalabi, H., et al.[2021]

A patient with relapsed and refractory B cell acute lymphoblastic leukemia (B-ALL) achieved over 14 months of minimal residual disease-negative remission after receiving CAR-T cell therapy targeting both CD19 and CD22.

This case suggests that dual-targeting CAR-T cell therapy may enhance the durability of remission in B-ALL patients, potentially addressing issues of antigen escape seen with single-target therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Haploidentical CD19/CD22 bispecific CAR-T cells induced MRD-negative remission in a patient with relapsed and refractory adult B-ALL after haploidentical hematopoietic stem cell transplantation. Jia, H., Wang, Z., Wang, Y., et al.[2020]

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]

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]

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]

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. 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]

2. England pubmed.ncbi.nlm.nih.gov

Engineering Novel CD19/CD22 Dual-Target CAR-T Cells for Improved Anti-Tumor Activity. [2022]

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

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

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

CD4/CD8 T-Cell Selection Affects Chimeric Antigen Receptor (CAR) T-Cell Potency and Toxicity: Updated Results From a Phase I Anti-CD22 CAR T-Cell Trial. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Haploidentical CD19/CD22 bispecific CAR-T cells induced MRD-negative remission in a patient with relapsed and refractory adult B-ALL after haploidentical hematopoietic stem cell transplantation. [2020]

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

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

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

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

8. 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]

9. England pubmed.ncbi.nlm.nih.gov

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