CAR T-Cell Therapy for Blood Cancer

(CARPASCIO Trial)

Recruiting at 1 trial location

Overseen By Carlos Ramos, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Baylor College of Medicine

Must not be taking: Corticosteroids

Disqualifiers: Severe infection, GVHD, Pregnancy, others

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

Compensation: Varies

Number of Visits: 1

Duration: 6 weeks

7 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications, but you cannot be on other investigational antitumor therapy for one month before joining the study. Also, you cannot be taking high doses of corticosteroids for GVHD treatment.

What data supports the effectiveness of the treatment CD19.CAR-CD28Z T Cells for blood cancer?

Research shows that CD19-targeted CAR T-cell therapy has been highly effective in treating certain blood cancers, like B-cell acute lymphoblastic leukemia (B-ALL), by rapidly reducing cancer cells and achieving complete remission in many patients. This treatment has shown promise in patients who did not respond to other treatments, making it a powerful option for those with difficult-to-treat blood cancers. ^{1 2 3 4 5}

Is CAR T-Cell Therapy generally safe for humans?

CAR T-Cell Therapy, including CD19-targeted types, has shown some safety concerns. Common side effects include cytokine release syndrome (a severe immune reaction) and neurotoxicity (nerve damage). Other potential issues include heart problems and prolonged low blood cell counts, but these vary by individual and treatment specifics. ^{6 7 8 9 10}

How is CAR T-Cell Therapy for Blood Cancer different from other treatments?

CAR T-Cell Therapy for Blood Cancer is unique because it uses specially engineered T cells to target and destroy cancer cells by recognizing a specific protein called CD19 on their surface. This approach has shown remarkable success in treating certain blood cancers, especially those that do not respond to traditional chemotherapy. ^{1 2 3 11 12}

What is the purpose of this trial?

Patients have a type of lymph gland cancer called Non-Hodgkin Lymphoma (NHL), acute lymphocytic leukemia (ALL) or chronic lymphocytic leukemia (CLL) (these diseases will be referred to as "lymphoma" or "leukemia"). The lymphoma or leukemia has come back or has not gone away after treatment (including the best treatment known for these cancers). Because there is no standard treatment for this cancer at this time, subjects are asked to volunteer to be in a gene transfer research study using special immune cells. The body has different ways of fighting infection and disease. No one way seems perfect for fighting cancers. This research study combines two different ways of fighting disease, antibodies and T cells, hoping that they will work together. Both antibodies and T cells have been used to treat patients with cancers; they have shown promise, but have not been strong enough to cure most patients. T cells can kill tumor cells but there normally are not enough of them to kill all the tumor cells. Some researchers have taken T cells from a person's blood, grown more of them in the laboratory and then given them back to the person. The antibody used in this study is called anti-CD19. This antibody sticks to cancer cells because of a substance on the outside of these cells called CD19. CD19 antibodies have been used to treat people with lymphoma and leukemia. For this study, the CD19 antibody has been changed so that instead of floating free in the blood it is now joined to the T cells. When an antibody is joined to a T cell in this way it is called a chimeric receptor. The T lymphocytes will also contain CD28, which stimulates T cells and makes them last longer. Treatment with CD19/CD28 chimeric receptor-T cells has had activity against lymphoma and leukemia when the cells are made from the patients affected by these diseases. In this study, investigators are going to see if this treatment works even better when they make these cells from a healthy stem cell donor. If investigators are not able to collect blood from the stem cell donor, they will collect blood from the subject to make the CD19/CD28 chimeric receptor-T cells. These CD19/CD28 chimeric receptor T cells are investigational products not approved by the FDA. The purpose of this study is to find the biggest dose of chimeric T Cells that is safe, to see how long T cells with this chimeric receptor last, to learn what the side effects are, and to see whether this therapy might help people with lymphoma or leukemia after a stem cell transplantation from a donor.

Research Team

Carlos Ramos, MD

Principal Investigator

Baylor College of Medicine

Eligibility Criteria

This trial is for patients with certain blood cancers (NHL, ALL, CLL) that have returned or persisted despite treatment. Participants must be undergoing or have undergone a stem cell transplant and have an identified donor. They should not be on other investigational antitumor therapies, must meet specific health criteria like organ function, and agree to effective birth control use.

Inclusion Criteria

Life expectancy of ≥12 weeks

Bilirubin ≤ 2 times the upper limit of normal

Patients or legal guardians must sign an informed consent

Exclusion Criteria

Pregnant or lactating

History of hypersensitivity reactions to murine protein-containing products

My graft-versus-host disease is more severe than grade II.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-treatment

Participants may receive chemotherapy with cyclophosphamide and fludarabine if their circulating T cell levels are high

1-2 weeks

Treatment

Participants receive an injection of CD19/CD28 chimeric receptor-T cells and are monitored for up to 4 hours post-infusion

6 weeks

1 visit (in-person) for infusion, followed by monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, with potential for additional T cell infusions if beneficial

4-6 weeks

Regular follow-up visits (in-person)

Long-term follow-up

Participants are followed for long-term side effects of gene transfer

Up to 15 years

Treatment Details

Interventions

• CD19.CAR-CD28Z T Cells

Trial Overview The study tests the safety and effectiveness of CD19.CAR-CD28Z T Cells at escalating doses in fighting lymphoma/leukemia post-stem cell transplantation from a donor. It aims to determine the maximum safe dose, how long these modified T cells last in the body, side effects they may cause, and their potential benefits.

Participant Groups

Group I: Subgroup B2 Experimental Treatment 1 Intervention

Patients with other B cell malignancies and with an unrelated or HLA-mismatched donor will receive CD19.CAR-CD28Z T Cells - dose escalation 2

Group II: Subgroup B1 Experimental Treatment 1 Intervention

Patients with other B-cell malignancies and with an HLA-matched related donor will receive CD19.CAR-CD28Z T Cells - dose escalation 1

Group III: Subgroup A2 Experimental Treatment 1 Intervention

Patients with residual or relapsed B-cell ALL and with an unrelated or HLA-mismatched donor will receive CD19.CAR-CD28Z T Cells - dose escalation 2

Group IV: Subgroup A1 Experimental Treatment 1 Intervention

Patients with residual or relapsed B-cell ALL and with an HLA-matched related donor will receive CD19.CAR-CD28Z T Cells - dose escalation 1

Who Is Running the Clinical Trial?

Baylor College of Medicine

Lead Sponsor

Trials

1,044

Recruited

6,031,000+

The Methodist Hospital Research Institute

Collaborator

Trials

299

Recruited

82,500+

Center for Cell and Gene Therapy, Baylor College of Medicine

Collaborator

Trials

114

Recruited

2,900+

Findings from Research

Chimeric antigen receptor (CAR) therapy, particularly targeting CD19, has shown significant efficacy in treating patients with chemorefractory B cell malignancies, leading to its potential regulatory approval as a cell-based immunotherapy.

While CAR therapy is effective, it is associated with toxicities such as cytokine release syndrome, neurotoxicity, and B cell aplasia, which require careful management in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biology and clinical application of CAR T cells for B cell malignancies. Davila, ML., Sadelain, M.[2023]

CD19 is a highly effective target for CAR T-cell therapies, showing significant responses in patients with relapsed B-cell malignancies, particularly chronic lymphocytic leukemia and acute lymphoblastic leukemia.

While treatment with CD19-CAR T cells can lead to severe systemic inflammatory reactions, these are generally reversible with proper medical care, highlighting the importance of monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19-CAR trials. Ramos, CA., Savoldo, B., Dotti, G.[2022]

Chimeric antigen receptor (CAR) and T cell receptor (TCR) engineered T cells show promise in treating blood cancers, particularly with CD19-CAR-T cells demonstrating strong clinical responses in B-cell malignancies.

To enhance the effectiveness and safety of these therapies, researchers are exploring new antigens, improved T cell culture methods, and better administration protocols to address issues like treatment failure and toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overcoming key challenges in cancer immunotherapy with engineered T cells. Arcangeli, S., Mestermann, K., Weber, J., et al.[2021]

In a study involving five adults with relapsed B cell acute lymphoblastic leukemia (B-ALL), treatment with autologous T cells modified to express a CD19-specific CAR (19-28z) led to rapid tumor eradication and complete remissions without minimal residual disease (MRD), indicating strong efficacy of this therapy.

The treatment was generally well tolerated, although patients with higher tumor burdens experienced significant cytokine elevations, which required management with steroids, highlighting the need for monitoring and potential intervention during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Brentjens, RJ., Davila, ML., Riviere, I., et al.[2023]

Adoptive cellular therapy using CAR-modified T cells targeting CD19 has shown significant clinical efficacy in treating relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) in both children and adults, with some patients also benefiting from treatment for chronic lymphocytic leukemia (CLL) and B-cell non-Hodgkin lymphoma (B-NHL).

Current research is expanding the use of CAR T-cell therapies to other cancers, including multiple myeloma and solid tumors, while also addressing challenges such as severe cytokine release syndrome and neurologic toxicities associated with the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review: Current clinical applications of chimeric antigen receptor (CAR) modified T cells. Geyer, MB., Brentjens, RJ.[2022]

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 involving 9 patients with relapsed or refractory B cell non-Hodgkin's lymphoma, both CD28 and 4-1BB targeted CAR-T cells showed similar antitumor efficacy, achieving a complete response rate of 67% within 3 months.

However, the 4-1BB (BBz CAR-T) cells were better tolerated, with only mild adverse events, while the CD28 (28z CAR-T) cells caused severe side effects, leading to the discontinuation of further evaluation for that group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Parallel Comparison of 4-1BB or CD28 Co-stimulated CD19-Targeted CAR-T Cells for B Cell Non-Hodgkin's Lymphoma. Ying, Z., He, T., Wang, X., et al.[2020]

In a review of 60 studies involving 913 participants, CAR-T cell therapy showed a promising complete response rate of 54.4% in patients with CD19+ hematologic malignancies, indicating its efficacy in treating certain blood cancers.

However, safety concerns were significant, with 55.3% of hematologic patients experiencing cytokine release syndrome and 37.2% experiencing neurotoxicity, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risks and Benefits of Chimeric Antigen Receptor T-Cell (CAR-T) Therapy in Cancer: A Systematic Review and Meta-Analysis. Grigor, EJM., Fergusson, D., Kekre, N., et al.[2020]

CD19-specific CAR T cell therapies are effective for treating difficult-to-treat blood cancers, but they can cause significant cardiovascular toxicity, including issues like tachycardia, arrhythmias, and left ventricular dysfunction.

There is a need for more research to better understand these cardiovascular risks and to develop a cardiac surveillance protocol for patients undergoing CAR T cell therapy, ensuring safer treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T Cell Therapy-Related Cardiovascular Outcomes and Management: Systemic Disease or Direct Cardiotoxicity? Ghosh, AK., Chen, DH., Guha, A., et al.[2021]

In a phase 1 clinical trial involving 14 patients with relapsed/refractory acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL), the novel Sleeping Beauty (SB) CD19-specific CAR T-cell therapy demonstrated a strong safety profile, with no serious adverse events directly linked to the treatment and only mild cytokine release syndrome observed.

Efficacy results showed that 38% of patients with ALL achieved complete remission or incomplete count recovery, and 50% of patients with diffuse large B-cell lymphoma (DLBCL) also achieved complete remission, indicating promising antitumor activity of the SB-based CAR constructs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sleeping beauty generated CD19 CAR T-Cell therapy for advanced B-Cell hematological malignancies. Singh, H., Srour, SA., Milton, DR., et al.[2023]

CD19-targeted CAR T cell therapy has shown remarkable efficacy, achieving complete remission in 70-90% of patients with relapsed/refractory acute lymphoblastic leukemia (ALL), highlighting its potential as a powerful treatment for B cell malignancies.

The ongoing phase I study using a non-viral gene transfer method (piggyBac-transposon system) for CD19 CAR T cell therapy in pediatric and young adult patients indicates a promising direction for expanding treatment options in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene-modified T-cell therapy using chimeric antigen receptors for pediatric hematologic malignancies. Nakazawa, Y.[2017]

References

1. Japan pubmed.ncbi.nlm.nih.gov

Biology and clinical application of CAR T cells for B cell malignancies. [2023]

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

CD19-CAR trials. [2022]

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

Overcoming key challenges in cancer immunotherapy with engineered T cells. [2021]

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

CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Review: Current clinical applications of chimeric antigen receptor (CAR) modified T cells. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

Parallel Comparison of 4-1BB or CD28 Co-stimulated CD19-Targeted CAR-T Cells for B Cell Non-Hodgkin's Lymphoma. [2020]

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

Risks and Benefits of Chimeric Antigen Receptor T-Cell (CAR-T) Therapy in Cancer: A Systematic Review and Meta-Analysis. [2020]

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

CAR T Cell Therapy-Related Cardiovascular Outcomes and Management: Systemic Disease or Direct Cardiotoxicity? [2021]

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

Sleeping beauty generated CD19 CAR T-Cell therapy for advanced B-Cell hematological malignancies. [2023]

11. England pubmed.ncbi.nlm.nih.gov

Single CAR-T cell treatment controls disseminated ovarian cancer in a syngeneic mouse model. [2023]

12. Japan pubmed.ncbi.nlm.nih.gov

Gene-modified T-cell therapy using chimeric antigen receptors for pediatric hematologic malignancies. [2017]