CAR T-Cell Therapy for Leukemia and Lymphoma

Overseen By Haneen Shalabi, D.O.

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Antineoplastics, Immunosuppressants

Disqualifiers: Pregnancy, HIV, Hepatitis B, others

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

Compensation: Varies

Number of Visits: 3

Duration: 1 day

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment for certain blood cancers, including B-cell leukemia and lymphoma, using CAR T-cell therapy. The process involves modifying a person's immune cells in the lab to enhance their ability to attack cancer cells. The trial aims to assess the safety of this therapy and determine its effectiveness in reducing cancer. It may suit children and young adults, ages 3 to 39, whose cancer hasn't improved with standard treatments and whose cancer cells display specific markers (CD19 and CD22 proteins). As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have had systemic chemotherapy, anti-neoplastic investigational agents, or antibody-based therapies within 2 weeks prior to apheresis, with some exceptions. It's best to discuss your specific medications with the trial team.

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

In a previous study, researchers found that CD19/CD22 CAR T-cell therapy effectively treated B-cell cancers, with generally manageable side effects. Another study focused on patients with large B-cell lymphoma and showed that targeting both CD19 and CD22 proteins benefited those unresponsive to earlier treatments.

Additionally, data from Spain on 10 patients demonstrated that this treatment is safe and effective when used as a last resort. Doctors used the therapy for patients with no other options, and it proved safe in that context.

Overall, these studies suggest the treatment is well-tolerated with manageable side effects. However, since this trial is in its early phase, the main goal is to ensure safety and determine the best dose. This step is crucial to confirm the treatment's safety before testing it in larger groups. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard leukemia and lymphoma treatments that typically involve chemotherapy and radiation, CAR T-Cell therapy introduces a groundbreaking approach by using genetically modified T-cells. These modified T-cells are engineered to target and destroy cancer cells more precisely, specifically honing in on CD19 and CD22 markers present on malignant cells. This targeted mechanism not only enhances the precision of the treatment but also shows promise in reducing the side effects commonly associated with traditional therapies. Researchers are particularly excited because CAR T-Cell therapy offers a potential new avenue for patients who have not responded well to existing treatments.

What evidence suggests that CD19/CD22 CAR T-Cell Therapy might be an effective treatment for B-cell cancer?

This trial will evaluate CAR T-cell therapy targeting both CD19 and CD22 proteins for treating B-cell cancers like leukemia and lymphoma. Participants will receive this therapy, which has shown promise in previous studies. Research suggests that targeting these two proteins increases the likelihood of attacking cancer cells and preventing recurrence. One study found that patients who received this treatment lived longer. Another analysis showed that the therapy was effective and had manageable side effects. This treatment uses the body's own immune cells, modified to better locate and combat cancer cells. ^{1 2 4 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 3-39 with specific B-cell cancers that haven't been cured by standard treatments. Participants must have CD19 protein on their cancer cells, be in good health otherwise, able to perform daily activities, and not pregnant or breastfeeding. They should also agree to use birth control during the study.

Inclusion Criteria

My B cell ALL or lymphoma has not responded to at least two treatments.

I have no other curative treatment options and cannot undergo or have chosen not to undergo a stem cell transplant.

I am between 3 and 39 years old.

Exclusion Criteria

My condition is rapidly worsening, which may prevent me from completing the treatment.

I have had previous treatments for my condition.

I have previously undergone CAR therapy or similar treatments.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Leukapheresis

Participants undergo leukapheresis to collect lymphocytes for modification

1 day

1 visit (in-person)

Conditioning Regimen

Participants receive a lymphodepleting preparative regimen of fludarabine and cyclophosphamide

5 days

Inpatient stay

Treatment

Infusion of CD19/CD22-CAR T-cells

1 day

Inpatient stay

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Frequent follow-up visits for 1 year, then 5 visits over the next 4 years

Long-term Follow-up

Participants answer questions and have blood tests annually

15 years

What Are the Treatments Tested in This Trial?

Interventions

• CD19/CD22 CAR T-Cells
• Cyclophosphamide
• Fludarabine

Trial Overview The trial tests a new therapy using the patient's own T cells modified with CD19/CD22-CAR genes to fight B-cell leukemia and lymphoma. It involves taking blood or bone marrow samples, giving chemotherapy drugs Cyclophosphamide and Fludarabine, then infusing the engineered CAR T-cells back into patients.

How Is the Trial Designed?

Group I: Dose Expansion Experimental Treatment 12 Interventions

Cluster of differentiation 19 (CD19)/cluster of differentiation 22 (CD22)-chimeric antigen receptor (CAR)-transduced T cells at maximum tolerated dose (MTD) or highest dose administered.

Group II: Dose Escalation Experimental Treatment 12 Interventions

Cluster of differentiation 19 (CD19)/cluster of differentiation 22 (CD22)-chimeric antigen receptor (CAR)-transduced T cells at escalating doses.

CD19/CD22 CAR T-Cells is already approved in United States, European Union for the following indications:

Approved in United States as CD19/CD22 CAR T-Cell Therapy for:

• Recurrent or Refractory CD19/CD22-expressing B Cell Malignancies

Approved in European Union as CD19/CD22 CAR T-Cell Therapy for:

• Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia
• 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

The CD22/CD19 dual-targeting CAR-T-cell therapy showed a remarkable overall response rate of 97% and a complete remission rate of 93% in patients with relapsed/refractory acute lymphoblastic leukemia (ALL), based on a meta-analysis of 14 studies involving 405 patients.

For non-Hodgkin lymphoma (NHL), the therapy resulted in an overall response rate of 85% and a complete remission rate of 57%, with manageable side effects such as cytokine release syndrome occurring in 86% of patients, indicating both efficacy and tolerability of this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of CD22 and CD19 dual-targeting chimeric antigen receptor T-cell therapy in patients with relapsed or refractory B-cell malignancies: A meta-analysis. Nguyen, TT., Thanh Nhu, N., Chen, CL., et al.[2023]

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]

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 phase II clinical trial involving 33 patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), CD19/CD22 dual-targeted CAR-T therapy showed a high overall response rate of 90.9% and a complete remission rate of 63.6% after a median follow-up of 10.9 months.

The therapy was found to be safe, with no severe grade 4 cytokine release syndrome (CRS) and only mild, transient toxicities observed, indicating that CAR-T therapy can be a potent and manageable treatment option for R/R DLBCL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decitabine-primed tandem CD19/CD22 CAR-T therapy in relapsed/refractory diffuse large B-cell lymphoma patients. Qu, C., Zou, R., Wang, P., et al.[2022]

In a clinical trial involving 32 adults with relapsed B cell non-Hodgkin's lymphoma, CD19 CAR-T cells showed significantly improved efficacy when administered after cyclophosphamide and fludarabine (Cy/Flu) lymphodepletion, achieving a 50% complete remission rate and a 72% overall response rate.

The study identified that the Cy/Flu regimen enhanced CAR-T cell expansion and persistence while minimizing immune responses that could limit efficacy, although it also resulted in severe cytokine release syndrome and neurotoxicity in a notable percentage of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy of non-Hodgkin's lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Turtle, CJ., Hanafi, LA., Berger, C., et al.[2022]

The combination therapy of fludarabine, cyclophosphamide, and rituximab (FCR) achieved a high complete remission (CR) rate of 70% in 224 previously untreated patients with chronic lymphocytic leukemia (CLL), indicating its efficacy as an initial treatment.

Despite the high response rate, the treatment was associated with significant side effects, including grade 3 to 4 neutropenia in 52% of treatment courses and a notable incidence of infections, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. Keating, MJ., O'Brien, S., Albitar, M., et al.[2021]

In a study of 26 patients with relapsed/refractory B-cell acute lymphoblastic leukemia receiving CD19 CAR T-cell therapy, higher cumulative exposure to fludarabine (≥14 mg*h/L) was linked to significantly better leukemia-free survival (12.9 months) compared to lower exposure (<14 mg*h/L, 1.8 months).

Patients with lower fludarabine exposure also experienced a higher rate of CD19-positive relapse (100% vs. 27.4%) and shorter duration of B-cell aplasia, indicating that optimizing fludarabine dosing could improve outcomes in CAR T-cell therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine exposure predicts outcome after CD19 CAR T-cell therapy in children and young adults with acute leukemia. Dekker, L., Calkoen, FG., Jiang, Y., et al.[2022]

In a case study of a patient with relapsed/refractory B-cell acute lymphoblastic leukemia, lymphodepletion using clofarabine and cyclophosphamide before CAR-T-cell therapy led to successful remission, demonstrating clofarabine's potential as an alternative to fludarabine.

Clofarabine did not impair the effectiveness of the CAR-T cells, as evidenced by the patient's cytokine release syndrome and the absence of minimal residual disease, indicating a successful treatment outcome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clofarabine for Lymphodepletion Before CAR-T-Cell Infusion: A Brief Case Report. Foti, A., Stein, D., Seidel, D., et al.[2023]

In a study of 12 patients with cutaneous T-cell lymphoma, the combination of fludarabine and cyclophosphamide showed clinical benefits, particularly in patients with Sézary syndrome, where five out of eight patients responded positively to treatment.

Despite some patients experiencing significant responses, including one complete response, the treatment was associated with severe bone marrow suppression, indicating that it should be used cautiously and primarily for palliative care in refractory cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A trial of fludarabine and cyclophosphamide combination chemotherapy in the treatment of advanced refractory primary cutaneous T-cell lymphoma. Scarisbrick, JJ., Child, FJ., Clift, A., et al.[2019]

CAR T-cells are engineered T-cells that target the CD19 antigen, showing promising initial results in treating various B-cell malignancies, including acute lymphocytic leukaemia and chronic lymphocytic leukaemia.

While the treatment shows potential, there are significant differences in patient responses and notable side effects that require careful management, highlighting the need for personalized approaches in therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T-cells fighting B-cell lymphoproliferative malignancies: the emerging field of CD19 CAR T-cell therapy. Heijink, DM., Kater, AP., Hazenberg, MD., et al.[2017]

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]

In a study of 16 patients with relapsed/refractory aggressive B-cell lymphoma, bispecific CAR T cells targeting both CD19 and CD22 showed a high efficacy, with 87.5% achieving an objective response and 62.5% achieving complete response.

The treatment demonstrated a favorable safety profile, with only one patient experiencing severe cytokine-release syndrome, and no cases of neurotoxicity, suggesting that this dual-targeted approach may be a safe and effective option for lymphoma therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19/CD22 Dual-Targeted CAR T-cell Therapy for Relapsed/Refractory Aggressive B-cell Lymphoma: A Safety and Efficacy Study. Wei, G., Zhang, Y., Zhao, H., et al.[2022]

Citations

1. 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.

2. nature.com nature.com/articles/s41591-021-01436-0

CAR T cells with dual targeting of CD19 and CD22 in adult ... To prevent relapse with CD19− or CD19lo disease, we tested a bispecific CAR targeting CD19 and/or CD22 (CD19-22.BB.z-CAR) in a phase I clinical ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03233854

NCT03233854 | CD19/CD22 Chimeric Antigen Receptor ... A CAR is a genetically-engineered receptor made so that immune cells (T cells) can attack cancer cells by recognizing and responding to the CD19/CD22 proteins.

4. haematologica.org haematologica.org/article/view/11872

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.

5. sciencedirect.com sciencedirect.com/science/article/pii/S2352396425003160

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 leukaemia (r/r B-ALL); ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03233854

NCT03233854 | CD19/CD22 Chimeric Antigen Receptor ... A CAR is a genetically-engineered receptor made so that immune cells (T cells) can attack cancer cells by recognizing and responding to the CD19/CD22 proteins.

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40753722/

Tandem CD19/CD22 CAR T-cells as potential therapy for ... Methods: We report Spanish clinical data on the safety and efficacy of tandem anti-CD19/CD22 CAR T-cells administered on a compassionate use ...