CAR T-cell Therapy for Leukemia

Overseen By James N Kochenderfer, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Checkpoint inhibitors, Anticoagulants

Disqualifiers: HIV, Pregnancy, Active infections, others

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

Compensation: Varies

Number of Visits: 7

58 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: About 23,000 people die from B-cell cancers in the US each year. These cancers, often called leukemia or lymphoma, affect a type of white blood cell called B cells. These cancers are difficult to treat, and the therapies used can have bad side effects. Researchers want to try a new type of treatment. This new treatment uses a patient s own immune cells (T cells) that are modified to carry genes (chimeric antigen receptor, or CAR T cells) to kill cancer cells. Objective: To test a treatment using CAR T cells in people with B-cell cancers. Eligibility: People aged 18 to 75 years with a B-cell cancer that has not been controlled with standard therapies. Design: Participants will be screened. They will have: Blood and urine tests. A needle will be inserted to draw a sample of tissue from inside the hip bone. For some patients, a needle will be inserted into their lower back to get a sample of the fluid around their spinal cord. A tumor biopsy might be needed. Imaging scans. Tests of their heart function. Participants will undergo apheresis: Blood will be drawn from a needle in an arm. The blood will pass through a machine that separates out the T cells. The remaining blood will be returned to the body through a second needle. Participants will receive 2 chemotherapy drugs once a day for 3 days. Participants will be admitted to the hospital for at least 9 days. Their T cells, now modified, will be infused back into their bloodstream through a tube placed in a large vein. Follow-up visits will continue for 5 years, but patients will need to stay in touch with the CAR treatment team for 15 year.

Will I have to stop taking my current medications?

The trial requires that you stop taking any systemic corticosteroids greater than 5 mg/day at least 14 days before starting the trial. Additionally, you must not have received any anti-CD20 or anti-CD19 antibody products in the past 60 days before the CAR T-cell infusion. If you are on systemic anticoagulant therapy, you may need to stop, except for aspirin.

What data supports the effectiveness of the treatment Anti-CD19 and Anti-CD20 Bicistronic Chimeric Antigen Receptor T Cells for leukemia?

Research shows that targeting two antigens at once, like CD19 and CD22, can improve the effectiveness of CAR T-cell therapy by reducing the chance of the cancer escaping treatment. This approach has shown promising results in lab studies and animal models, suggesting it might help in treating leukemia more effectively. ^{1 2 3 4 5}

Is CAR T-cell therapy generally safe for humans?

CAR T-cell therapy, including treatments targeting CD19 and CD20, has shown some safety concerns. Common side effects include cytokine release syndrome (a severe immune reaction), neurotoxicity (nerve damage), and B-cell aplasia (loss of B cells, which are part of the immune system). Other potential risks involve effects on the heart, lungs, and other organs, and long-term safety is still being studied. ^{6 7 8 9 10}

How is the CAR T-cell therapy for leukemia with Anti-CD19 and Anti-CD20 unique?

This treatment is unique because it uses genetically engineered T cells to target two proteins, CD19 and CD20, on leukemia cells, potentially reducing the risk of the cancer escaping treatment by losing one of these targets. This dual-target approach aims to improve the effectiveness and durability of the response compared to therapies targeting a single protein. ^{1 5 11 12 13}

Research Team

James N Kochenderfer, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

Adults aged 18-75 with B-cell cancers uncontrolled by standard therapies can join. They must have tried certain treatments depending on their cancer type, and it's been enough time since those treatments. People with HIV, other active infections or malignancies, severe allergies to trial drugs, or who are pregnant/breastfeeding cannot participate.

Inclusion Criteria

Participants must have measurable malignancy as defined by specific criteria

It has been over 2 weeks since my last systemic treatment before my scheduled cell therapy.

I meet the age, health, and treatment history requirements.

Exclusion Criteria

I currently have an infection that is not under control.

I do not have active hemolytic anemia, HIV, HTLV, Babesia, West Nile virus, T. Cruzi, or a positive RPR test.

I am on blood thinners other than aspirin.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Multiple visits for tests and assessments

Apheresis

Blood is drawn to separate T cells for genetic modification

1 day

1 visit (in-person)

Chemotherapy Conditioning

Participants receive cyclophosphamide and fludarabine for lymphocyte depletion

3 days

3 visits (in-person)

CAR T-cell Infusion

Modified T cells are infused back into the participant

1 day

1 visit (in-person)

Inpatient Monitoring

Participants are monitored for toxicity following T-cell infusion

9 days

Inpatient stay

Outpatient Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Regular visits at 2 weeks, 1, 2, 3, 4, 6, 9, and 12 months

Long-term Follow-up

Participants are monitored for long-term safety and gene therapy effects

15 years

Treatment Details

Interventions

• Anti-CD19 and Anti-CD20 Bicistronic Chimeric Antigen Receptor T Cells

Trial Overview The trial tests a new therapy using the patient's own T cells modified with genes (CAR T cells) targeting CD19/CD20 to fight B-cell cancers. It includes chemotherapy drugs Cyclophosphamide and Fludarabine before infusing the CAR T cells back into the patient.

Participant Groups

Group I: 2/Conditioning chemotherapy plus CAR T-cells expansion phase Experimental Treatment 3 Interventions

MTD dose or Optimal dose of Anti-CD19 and anti-CD20 CAR T- cells/kg + conditioning chemotherapy

Group II: 1/Conditioning chemotherapy plus CAR T-cells dose escalation Experimental Treatment 3 Interventions

Escalating dose of anti-CD19 and anti-CD20 CAR T- cells/kg + conditioning chemotherapy

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

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]

The development of dual-targeting CAR T cells that target both CD19 and BAFF-R shows promise in overcoming treatment failures due to antigen loss in B-cell malignancies, specifically acute lymphoblastic leukemia (ALL).

In preclinical studies, these dual CAR T cells effectively eradicated both CD19- and BAFF-R-negative ALL variants in mice, demonstrating superior efficacy compared to single-target CAR T cells and suggesting potential for durable remissions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19/BAFF-R dual-targeted CAR T cells for the treatment of mixed antigen-negative variants of acute lymphoblastic leukemia. Wang, X., Dong, Z., Awuah, D., et al.[2023]

In a phase 1 trial of 53 adults with relapsed B-cell acute lymphoblastic leukemia, 83% achieved complete remission after receiving CD19-specific CAR T cells, indicating high initial efficacy.

Patients with a low disease burden before treatment experienced significantly longer overall survival (20.1 months) and fewer severe side effects, such as cytokine release syndrome, compared to those with a higher disease burden.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia. Park, JH., Rivière, I., Gonen, M., et al.[2023]

CAR-modified T cell therapy targeting the CD19 antigen has shown remarkable efficacy in treating relapsed/refractory acute lymphoblastic leukemia, achieving complete remission rates as high as 90%.

While this therapy is highly effective, it also leads to significant T-cell proliferation, which can cause cytokine release syndrome, highlighting the need for improved management strategies for this toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor T-cell therapy for ALL. Maude, SL., Shpall, EJ., Grupp, SA.[2020]

CD19+ CAR T-cells have shown high effectiveness against various cancers, but their complete risk profile, including complications, was not fully understood during initial clinical trials.

Emerging evidence from post-approval studies reveals significant complications associated with CD19+ CAR T-cell therapy, such as cytokine release syndrome and neurotoxicity, indicating that these therapies can affect multiple organ systems and may lead to long-term health issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complications after CD19+ CAR T-Cell Therapy. Penack, O., Koenecke, C.[2020]

Chimeric antigen receptor (CAR) T cell therapy targeting CD19 and CD20 has shown a promising overall response rate of 61% in treating B-cell hematologic malignancies, with a complete response rate of 42% and partial response rate of 19% across 16 studies involving 195 patients.

However, the therapy is associated with significant adverse events, including cytokine release syndrome and neurotoxicity (both at 33%), and B-cell aplasia in 54% of patients, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-CD 19 and anti-CD 20 CAR-modified T cells for B-cell malignancies: a systematic review and meta-analysis. Riaz, IB., Zahid, U., Kamal, MU., et al.[2023]

In a study of 35 patients with refractory acute lymphoblastic leukemia (ALL), CAR-T cell therapy demonstrated a high total effective rate of 91.43%, with 68.57% achieving complete response after one month of treatment.

The therapy was associated with significant changes in immune cell populations, including a decrease in regulatory T cells and an increase in natural killer cells, while side effects were generally mild and manageable, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of CAR-T Cell Therapy on Immune Cells and Related Toxic Side Effect Analysis in Patients with Refractory Acute Lymphoblastic Leukemia. Li, L., Gao, J., Sun, Z., et al.[2023]

Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 has become a significant advancement in treating relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), with two such therapies approved by regulatory agencies.

Despite the success of CD19-targeting CAR T-cells, some patients still experience relapses, highlighting the need for ongoing research into resistance mechanisms and potential strategies to overcome them.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T-Cells for the Treatment of B-Cell Acute Lymphoblastic Leukemia. Saleh, K., Pasquier, F., Bigenwald, C., et al.[2023]

Chimeric antigen receptor (CAR) T-cell therapy has shown significant efficacy in treating refractory leukemia, particularly with CD19-targeting CAR-T cells leading to sustained responses in patients with relapsed acute lymphoblastic leukemia.

Recent advancements in CAR-T cell design, including improved intracellular activating domains and viral vector transduction, have enhanced the effectiveness of these therapies and expanded the range of potential leukemic antigens for targeting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-T therapy for leukemia: progress and challenges. Wang, X., Xiao, Q., Wang, Z., et al.[2018]

CAR T cell therapy targeting CD19 has shown remarkable efficacy, achieving complete remission in up to 90% of patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), compared to a 30% response rate with traditional chemotherapy.

The therapy involves genetically modifying T cells to express a chimeric antigen receptor, allowing them to effectively target and eliminate cancer cells, although it is important to note that there are unique toxicities associated with this treatment that require careful management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19-Targeted CAR T cells as novel cancer immunotherapy for relapsed or refractory B-cell acute lymphoblastic leukemia. Davila, ML., Brentjens, RJ.[2023]

CAR T cell therapy targeting CD19 has shown remarkable efficacy, achieving remission rates as high as 90% in relapsed/refractory acute lymphoblastic leukemia (ALL), but lower response rates in chronic lymphocytic leukemia (CLL) highlight the need for ongoing research to improve outcomes.

Long-term follow-up indicates that CAR T cell therapy may provide durable remissions, but the emergence of escape pathways necessitates combinatorial treatment strategies and careful toxicity management to enhance safety and effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T Cell Therapy in Acute Lymphoblastic Leukemia and Potential for Chronic Lymphocytic Leukemia. Singh, N., Frey, NV., Grupp, SA., et al.[2018]

References

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

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

2. 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]

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

CD19/BAFF-R dual-targeted CAR T cells for the treatment of mixed antigen-negative variants of acute lymphoblastic leukemia. [2023]

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

Blinatumomab as salvage therapy in patients with relapsed/refractory B-ALL who have failed/progressed after anti-CD19-CAR T therapy. [2023]

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

Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia. [2023]

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

Chimeric antigen receptor T-cell therapy for ALL. [2020]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Complications after CD19+ CAR T-Cell Therapy. [2020]

8. England pubmed.ncbi.nlm.nih.gov

Anti-CD 19 and anti-CD 20 CAR-modified T cells for B-cell malignancies: a systematic review and meta-analysis. [2023]

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

Effects of CAR-T Cell Therapy on Immune Cells and Related Toxic Side Effect Analysis in Patients with Refractory Acute Lymphoblastic Leukemia. [2023]

10. Switzerland pubmed.ncbi.nlm.nih.gov

CAR T-Cells for the Treatment of B-Cell Acute Lymphoblastic Leukemia. [2023]

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

CAR-T therapy for leukemia: progress and challenges. [2018]

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

CD19-Targeted CAR T cells as novel cancer immunotherapy for relapsed or refractory B-cell acute lymphoblastic leukemia. [2023]

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

CAR T Cell Therapy in Acute Lymphoblastic Leukemia and Potential for Chronic Lymphocytic Leukemia. [2018]