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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment for B-cell cancers, such as leukemia and lymphoma. The treatment modifies the patient's own T cells to attack cancer cells. This specific therapy, known as Anti-CD19 and Anti-CD20 Bicistronic Chimeric Antigen Receptor T Cells, is a type of CAR T-cell therapy. Eligible participants should have a B-cell cancer that hasn't responded well to standard treatments. The trial consists of two stages: testing different doses of the new CAR T-cell therapy and determining the optimal dose for treating these cancers. Participants will undergo several tests and procedures to prepare for and monitor the treatment. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this innovative therapy.

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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that CAR T-cell therapy, which uses specially modified immune cells to fight cancer, holds promise for treating B-cell cancers like leukemia and lymphoma. Studies have found that CAR T cells targeting CD19 can lead to complete remissions, meaning the cancer may temporarily disappear. This suggests the treatment can be highly effective.

Regarding safety, previous research on similar CAR T-cell therapies indicates they are generally well-tolerated, allowing most patients to undergo treatment without severe issues. However, some side effects, such as fever, low blood pressure, and confusion or headache, have been observed. These symptoms are usually temporary and can often be managed with medical care.

The treatment in this study also targets CD20, another marker on cancer cells. This dual targeting might help prevent cancer from returning if one target is lost. Safety data on this dual approach is still being gathered, but it builds on the success of CD19-targeted therapies, which are already approved for some conditions.

Since this trial is in the early phase, it primarily focuses on understanding safety and determining the right dose. Participants are closely monitored to ensure their well-being. For those considering joining, it's important to know that safety is a top priority, and researchers are committed to carefully managing any side effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about CAR T-cell therapy for leukemia because it offers a highly targeted approach by using genetically engineered T-cells to hunt down and destroy cancer cells. Unlike standard chemotherapy and radiation, which can damage healthy cells, this treatment specifically targets the CD19 and CD20 proteins found on leukemia cells, potentially reducing side effects. Additionally, this approach allows for a personalized treatment, as the T-cells are derived from the patient's own body, which could lead to more effective and longer-lasting results.

What evidence suggests that this trial's treatments could be effective for B-cell cancers?

Research has shown that CAR T-cell therapy, which targets proteins CD19 and CD20, holds promise for treating B-cell cancers like leukemia. In this trial, participants will receive either an escalating dose or an optimal dose of Anti-CD19 and Anti-CD20 Bicistronic Chimeric Antigen Receptor T Cells, combined with conditioning chemotherapy. One study found that CAR T cells targeting CD19 led to complete remissions in some patients with leukemia or lymphoma, meaning the cancer disappeared after treatment, at least temporarily. Another study suggested that targeting both CD19 and CD20 might help prevent cancer cells from evading treatment. This dual-target approach aims to improve outcomes and reduce the chances of cancer returning. Early results are encouraging, but it's important to remember this remains an experimental treatment. ^{1 2 3 5 6}

Who Is on the Research Team?

James N Kochenderfer, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

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 have Burkitt lymphoma and have undergone at least one chemotherapy treatment.

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

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]

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]

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]

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 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]

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]

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]

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]

Citations

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Efficacy and safety of CD19 combined with CD22 or CD20 ... This study explored the synergistic anti-tumor effects of CD19 combined with CD22 or CD20 dual-target CAR T-cell therapy in hematologic ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05797233

Study Details | NCT05797233 | Trial of Anti-CD19 and ... Autologous T- cells genetically modified to express CARs targeting the B-cell antigen CD19 have caused complete remissions in patients with leukemia or lymphoma ...

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Long-term outcomes following CAR T cell therapy The data demonstrate that CD19-targeted CAR T cells can induce prolonged remissions in patients with B cell malignancies, often with minimal long-term ...

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A phase 1 study of KITE-363 anti-CD19/CD20 chimeric ... KITE-363 is a bicistronic, autologous CAR T-cell therapy that can potentially prevent CD19 escape through upfront dual targeting of CD19 and CD20.

5. sciencedirect.com sciencedirect.com/science/article/pii/S2329050124000287

Optimization of anti-CD19 CAR T cell production for ... Overall, results from these clinical trials of anti-CD19 CARs for CLL demonstrated significant anti-leukemia activity; however, CR rates and PFSs are lower than ...

6. cell.com cell.com/molecular-therapy-family/oncology/fulltext/S2372-7705(23)00047-5

Development of a bicistronic anti-CD19/CD20 CAR ... To address CD19 loss from lymphoma after anti-CD19 chimeric antigen receptor (CAR) T cell therapy, we designed a bicistronic construct ...