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

44 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: B-cell leukemias and lymphomas are cancers that are often difficult to treat. The primary objective of this study is to determine the ability to take a patient's own cells (T lymphocytes) and grow them in the laboratory with the CD19/CD22-CAR receptor gene through a process called 'lentiviral transduction (also considered gene therapy) and growing them to large numbers to use as a treatment for hematologic cancers in children and young adults.. Researchers want to see if giving modified CD19/CD22-CAR T cells to people with these cancers can attack cancer cells. In addition, the safety of giving these gene modified cells to humans will be tested at different cell doses. Additional objectives are to determine if this therapy can cause regression of B cell cancers and to measure if the gene modified cells survive in patients blood. Objective: To study the safety and effects of giving CD19/CD22-CAR T cells to children and young adults with B-cell cancer. Eligibility: People ages 3-39 with certain cancers that have not been cured by standard therapy. Their cancer tissue must express the CD19 protein. Design: A sample of participants blood or bone marrow will be sent to NIH and tested for leukemia. Participants will be screened with: Medical history Physical exam Urine and blood tests (including for HIV) Heart and eye tests Neurologic assessment and symptom checklist. Scans, bone marrow biopsy, and/or spinal tap Some participants will have lung tests. Participants will repeat these tests throughout the study and follow-up. Participants will have leukapheresis. Blood will be drawn from a plastic tube (IV) or needle in one arm then go through a machine that removes lymphocytes. The remaining blood will be returned to the participant s other arm. Participants will stay in the hospital about 2 weeks. There they will get: Two chemotherapy drugs by IV Their changed cells by IV Standard drugs for side effects Participants will have frequent follow-up visits for 1 year, then 5 visits for the next 4 years. Then they will answer questions and have blood tests every year for 15 years. ...

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.

What data supports the idea that CAR T-Cell Therapy for Leukemia and Lymphoma is an effective treatment?

The available research shows that CAR T-Cell Therapy, specifically targeting CD19 and CD22, is effective for treating leukemia and lymphoma. One study found that using both CD19 and CD22 targets helps overcome issues that occur when only one target is used, like the cancer coming back. Another study highlighted that using fludarabine and cyclophosphamide before the CAR T-Cell Therapy improved outcomes for patients with a type of leukemia. This combination helped patients live longer without the cancer returning. Additionally, a case report showed that even when using an alternative drug, clofarabine, before the therapy, the treatment was still effective, leading to remission in a patient with leukemia. These findings suggest that CAR T-Cell Therapy is a promising treatment option for these cancers. ^{1 2 3 4 5}

What safety data is available for CAR T-Cell Therapy targeting CD19/CD22 in leukemia and lymphoma?

Safety data for CD19/CD22 CAR T-Cell Therapy indicates that severe cytokine release syndrome (CRS) and neurotoxicity are potential risks. In one study, severe CRS was observed in 13% of patients, and grade ≥3 neurotoxicity in 28%. Another study reported severe grade 4 CRS in 1 patient, with no neurotoxicity observed. A third study found no severe grade 4 CRS, with grade 3 CRS in 7 patients and mild neurotoxic effects in 3 patients. Overall, toxicities were transient and reversible, with no CAR-T-related mortality reported. The addition of fludarabine to the lymphodepletion regimen improved outcomes and minimized immune responses that could limit CAR-T cell expansion and efficacy. ^{1 3 6 7 8}

Is the treatment CD19/CD22 CAR T-Cells, Cyclophosphamide, Fludarabine a promising treatment for leukemia and lymphoma?

Yes, the CD19/CD22 CAR T-Cell treatment is promising for leukemia and lymphoma. It targets two proteins on cancer cells, which helps prevent the cancer from escaping treatment. Studies show it can be effective in patients who have not responded to other treatments. ^{1 9 10 11 12}

Research Team

Nirali N. Shah

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

Group I: Dose expansion Experimental Treatment 3 Interventions

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

Group II: Dose escalation Experimental Treatment 3 Interventions

CD19/CD22-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+

Findings from Research

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]

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 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 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]

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 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]

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]

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]

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]

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]

References

1. United States 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. [2023]

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

Clofarabine for Lymphodepletion Before CAR-T-Cell Infusion: A Brief Case Report. [2023]

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

Fludarabine exposure predicts outcome after CD19 CAR T-cell therapy in children and young adults with acute leukemia. [2022]

4. England pubmed.ncbi.nlm.nih.gov

A trial of fludarabine and cyclophosphamide combination chemotherapy in the treatment of advanced refractory primary cutaneous T-cell lymphoma. [2019]

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

Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. [2021]

6. United States 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. [2022]

7. United States 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. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Decitabine-primed tandem CD19/CD22 CAR-T therapy in relapsed/refractory diffuse large B-cell lymphoma patients. [2022]

9. Netherlands pubmed.ncbi.nlm.nih.gov

T-cells fighting B-cell lymphoproliferative malignancies: the emerging field of CD19 CAR T-cell therapy. [2017]

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

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

11. 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]

12. England pubmed.ncbi.nlm.nih.gov

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