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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for acute lymphoblastic leukemia (ALL) using CAR T-cell therapy. CAR T-cells are specially modified cells derived from a patient's own blood to target cancer cells more effectively. The trial tests CD19/CD22 Bicistronic Chimeric Antigen Receptor (CAR) T Cells, which target two proteins, CD19 and CD22, commonly found on ALL cells. Suitable candidates for this trial are individuals aged 3 to 39 with ALL or related B-cell lymphoma that hasn't responded to standard treatments. As a Phase 1/Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group.

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.

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

Research has shown that CD19/CD22 dual-targeting CAR T-cell therapy holds promise and maintains a good safety record for treating B-cell cancers, a type of blood cancer. Studies have found this therapy effective while keeping side effects manageable. For instance, a meta-analysis, which combines results from multiple studies, demonstrated that this dual-targeting approach works well with tolerable side effects.

Another study carefully examined the safety of targeting both CD19 and CD22 proteins, finding it safe and practical. While side effects exist, they generally fall within an acceptable range for this advanced treatment. Discussing specific risks and benefits with the medical team conducting the trial remains crucial. Overall, available data suggests this therapy is fairly well-tolerated in individuals with relapsed B-cell acute lymphoblastic leukemia (ALL). ^{1 2 3 4 5}

Why are researchers excited about this study treatment for ALL?

Most treatments for Acute Lymphoblastic Leukemia (ALL), like chemotherapy and bone marrow transplants, work by targeting rapidly dividing cells throughout the body. But CD19/CD22 Bicistronic Chimeric Antigen Receptor (CAR) T-Cell therapy works differently, harnessing the power of the patient's own immune system. Researchers are excited because this therapy genetically modifies T cells to specifically target and destroy cancer cells expressing CD19 and CD22, potentially offering a more precise and personalized treatment. This approach not only aims to improve effectiveness but also reduce the side effects typically associated with broader treatments.

What evidence suggests that this CAR T-cell therapy could be an effective treatment for acute lymphoblastic leukemia?

Research shows that a new treatment called CAR T-cell therapy, specifically using CD19/CD22 Bicistronic Chimeric Antigen Receptor (CAR) T Cells, may help treat relapsed acute lymphoblastic leukemia (ALL). This trial will evaluate the effectiveness of these CAR T-cells in different patient groups, including those with high and low disease burdens. Studies have found that this approach can greatly improve long-term survival for patients whose cancer returned after a stem cell transplant. CAR T-cells targeting CD19 alone have already achieved great success in difficult cases of B-cell ALL. By also targeting CD22, this treatment might better control the disease's progression. Previous patients treated with these CAR T-cells showed promising results, suggesting this method could offer new hope for those with relapsed ALL. ^{2 3 5 6 7}

Who Is on the Research Team?

Nirali N. Shah

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Group VII: A/Pre-treatment Active Control 1 Intervention

All participants enrolled on the study prior to treatment initiation.

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12050930/

Five-year outcome of CD19 followed by CD22 chimeric ... Our study revealed that, in post-HCT relapsed B-ALL patients, the combination of CD19 and CD22 CAR T-cell therapy significantly improved long-term survival.

2. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/5877/527643/Long-Term-Outcomes-and-Adverse-Events-of-CAR-T-19

Long-Term Outcomes and Adverse Events of CAR T-19 Cell ... Discussion: CAR T-cell therapy, particularly anti-CD19, shows substantial efficacy in achieving MRD-CR in r/r B-ALL patients. The combination of ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12049870/

CD22 CAR-T cells secreting CD19 T-cell engagers for ... CD22 CAR-T cells secreting CD19 T-cell engagers for improved control of B-cell acute lymphoblastic leukemia progression

4. thelancet.com thelancet.com/journals/ebiom/article/PIIS2352-3964(25)00316-0/fulltext

Tandem CD19/CD22 CAR T-cells as potential therapy for ... Chimeric antigen receptor (CAR) T-cells targeting CD19 have shown impressive outcomes in refractory/relapsed B-cell acute lymphoblastic ...

5. ehoonline.biomedcentral.com ehoonline.biomedcentral.com/articles/10.1186/s40164-024-00593-5

Prominent efficacy and good safety of sequential CD19 ... This study aimed to evaluate the efficacy and safety of sequential CD19 and CD22 CAR-T cell therapy in adult patients with R/R B-ALL between ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10557829/

Effectiveness and safety of CD22 and CD19 dual‐targeting ... Our meta‐analysis demonstrated that the CD22/CD19 dual‐targeting CAR‐T‐cell strategy has high efficiency with tolerable adverse effects in B‐cell malignancies.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT03448393

NCT03448393 | CD19/CD22 Chimeric Antigen Receptor ... This trial will test whether simultaneous targeting of CD19 and CD22 using a novel bivalent CD19/22-CAR is safe and feasible. Objectives: -Assess the safety of ...