CAR T-Cell Therapy for Leukemia

Overseen By Maria Iglesias

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Crystal Mackall, MD

Must not be taking: Interleukin-2, Interleukin-15

Disqualifiers: Other malignancy, Uncontrolled infection, HIV, others

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

Compensation: Varies

Number of Visits: 10

56 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial studies the side effects of CD19/CD22 chimeric antigen receptor (CAR) T cells when given together with chemotherapy and NKTR-255, and to see how well they work in treating patients with CD19 positive B acute lymphoblastic leukemia that has come back or does not respond to treatment. 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. These proteins are commonly found on diffuse large B-cell lymphoma and B acute lymphoblastic leukemia. Drugs used in chemotherapy, such as cyclophosphamide and fludarabine phosphate, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. NKTR-255 is an investigational IL-15 receptor agonist designed to boost the immune system's natural ability to fight cancer. Giving CD19/CD22-CAR T cells and chemotherapy in combination with NKTR-255 may work better in treating patients with diffuse large B-cell lymphoma or B acute lymphoblastic leukemia.

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

The trial protocol does not specify if you need to stop all current medications. However, you must stop any systemic therapy at least 2 weeks or 5 half-lives before leukapheresis, except for certain maintenance chemotherapy, which should be stopped at least 1 week or 5 half-lives prior. Please consult with the trial team for guidance on your specific medications.

What data supports the effectiveness of the treatment CD19/CD22 Chimeric Antigen Receptor (CAR) T Cells for leukemia?

Research shows that CAR T-cell therapy targeting CD19 has achieved high remission rates in B-cell acute lymphoblastic leukemia (B-ALL), and combining CD19 with CD22 targeting may enhance effectiveness and reduce relapse rates. Studies indicate that targeting both CD19 and CD22 antigens can improve leukemia control and prevent antigen loss, which is a common cause of treatment resistance. ^{1 2 3 4 5}

What safety data exists for CAR T-Cell Therapy in humans?

CAR T-Cell Therapy, used for conditions like leukemia, has shown significant side effects such as cytokine release syndrome (CRS) and neurotoxicity, which can be severe and sometimes life-threatening. Other reported side effects include hematological issues, infections, and organ-related problems, but these are generally manageable with proper monitoring and treatment. ^{6 7 8 9 10}

How is the CD19/CD22 CAR T-cell treatment for leukemia different from other treatments?

The CD19/CD22 CAR T-cell treatment is unique because it targets two antigens simultaneously, CD19 and CD22, which helps prevent the cancer from escaping treatment by losing one of these targets. This dual-targeting approach aims to improve remission rates and reduce the chances of relapse compared to treatments that target only one antigen. ^{4 11 12 13 14}

Research Team

Lori Muffly, MD

Principal Investigator

Stanford University

Eligibility Criteria

Adults with recurrent or resistant B-cell acute lymphoblastic leukemia (B-ALL), including those with Philadelphia Chromosome positive ALL who've failed tyrosine kinase inhibitor therapy. Participants must have CD19 expression, be at least 18 years old, and have adequate organ function. They should not have received certain treatments recently and must agree to contraception.

Inclusion Criteria

- ANC ≥ 1000/µL

I have received a CD19/CD22 CAR-T cell therapy infusion.

My cancer returned to the brain after complete remission, and I have MRD confirmed twice.

Exclusion Criteria

I have a history of certain infections.

I have been cancer-free from another type of cancer for at least 3 years, or my doctor thinks I'm a good candidate despite being in remission for 1-2 years.

I am HIV positive.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Chemotherapy

Participants receive cyclophosphamide and fludarabine phosphate as a conditioning regimen

3 days

3 visits (in-person)

CAR T Cell Infusion

Participants receive CD19/CD22 CAR T cells infusion

1 day

1 visit (in-person)

NKTR-255 Administration

Eligible participants receive NKTR-255 intravenously, repeated every 28 days for up to 6 cycles

Up to 6 months

6 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 15 years

Treatment Details

Interventions

• CD19/CD22 Chimeric Antigen Receptor (CAR) T Cells
• Cyclophosphamide
• Fludarabine Phosphate
• NKTR-255

Trial Overview The trial is testing the effectiveness of combining CAR T-cell therapy targeting CD19/CD22 with chemotherapy drugs cyclophosphamide and fludarabine phosphate, alongside NKTR-255, a drug designed to enhance the immune system's cancer-fighting abilities.

Participant Groups

Group I: Treatment (CD19/CD22 CAR T cells, chemotherapy, NKTR-255) Experimental Treatment 6 Interventions

Patients receive cyclophosphamide IV over 60 minutes and fludarabine phosphate IV over 30 minutes on days -5 to -3. Patients then receive CD19/CD22 CAR T cells IV over 10-20 minutes on day 0. On Day 14 after CAR-T, eligible patients will be given NKTR-255 IV over 30 minutes, and it will be repeated every 28 days for up to 6 cycles. Patients that benefited from the first dose of CD19/CD22 CAR T cells, had no unacceptable side effects, and have enough cells left over may receive 2 or 3 additional doses of CD19/CD22 CAR T cells.

Who Is Running the Clinical Trial?

Crystal Mackall, MD

Lead Sponsor

Trials

6

Recruited

240+

California Institute for Regenerative Medicine (CIRM)

Collaborator

Trials

70

Recruited

3,300+

Findings from Research

In a phase 1 trial involving 21 patients, including 17 who had previously undergone CD19-targeted therapy, a new CD22-targeted CAR T cell therapy showed a complete remission rate of 73% in patients receiving sufficient doses (≥1 × 10^6 CD22-CAR T cells per kg).

The study highlights that while CD22-CAR T cells are effective against B-ALL, relapses were linked to lower CD22 site density, indicating that the density of target antigens plays a crucial role in the effectiveness of CAR T cell therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Fry, TJ., Shah, NN., Orentas, RJ., et al.[2022]

CAR-T cell therapy has shown high remission rates in pediatric patients with CD19+ B-cell malignancies, but challenges remain for treating solid tumors like osteosarcoma due to fewer targets and a hostile tumor environment.

The development of a CAR-T adaptor molecule (EC17 CAM) allows for targeted therapy against folate receptor-positive tumors, enhancing CAR-T cell activation and reducing the risk of severe cytokine release syndrome through careful dosing strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical Evaluation of Bispecific Adaptor Molecule Controlled Folate Receptor CAR-T Cell Therapy With Special Focus on Pediatric Malignancies. Lu, YJ., Chu, H., Wheeler, LW., et al.[2020]

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]

Chimeric-antigen-receptor T cells (CAR-T) targeting CD19 are associated with several adverse drug reactions (ADRs), with the most common being cytokine release syndrome (CRS), neurological disorders, and hematological disorders, as identified in a study analyzing 1783 safety reports.

While CAR-T therapy can lead to severe ADRs, particularly in the week following administration, the overall fatality rate from these reactions is relatively low at 5.5%, though serious conditions like hemophagocytic-lymphohistiocytosis and infections require careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor T-cells safety: A pharmacovigilance and meta-analysis study. Dolladille, C., Ederhy, S., Ezine, E., et al.[2021]

CD19CAR-T cell therapy is effective in treating relapsed and refractory B-lineage acute lymphoblastic leukemia, with four out of five patients achieving complete remission and minimal residual disease negativity.

The therapy can be safely administered with real-time monitoring of a 6-cytokine pattern, allowing for effective management of side effects like cytokine release syndrome and neurotoxicity using tocilizumab and steroids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor T cell therapy can be administered safely under the real-time monitoring of Th1/Th2 cytokine pattern using the cytometric bead array technology for relapsed and refractory acute lymphoblastic leukemia in children. Shen, D., Song, H., Xu, X., et al.[2021]

The compound CAR (cCAR) T-cell therapy, which targets both CD123 and CD33 antigens in acute myeloid leukemia (AML), demonstrated strong anti-tumor activity and improved survival in four different leukemia mouse models.

The inclusion of a safety-switch using alemtuzumab allows for the rapid termination of cCAR therapy if needed, enhancing the safety profile of this dual-targeting approach against AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Compound CAR T-cells as a double-pronged approach for treating acute myeloid leukemia. Petrov, JC., Wada, M., Pinz, KG., et al.[2021]

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 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]

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]

References

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

Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. [2022]

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

CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Preclinical Evaluation of Bispecific Adaptor Molecule Controlled Folate Receptor CAR-T Cell Therapy With Special Focus on Pediatric Malignancies. [2020]

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

Targeting Two Antigens Associated with B-ALL with CD19-CD123 Compound Car T Cell Therapy. [2021]

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

A novel and efficient tandem CD19- and CD22-directed CAR for B cell ALL. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Taming the beast: CRS and ICANS after CAR T-cell therapy for ALL. [2022]

7. England pubmed.ncbi.nlm.nih.gov

CD22 CAR T-cell associated hematologic toxicities, endothelial activation and relationship to neurotoxicity. [2023]

8. 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]

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

Chimeric antigen receptor T-cells safety: A pharmacovigilance and meta-analysis study. [2021]

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

Chimeric antigen receptor T cell therapy can be administered safely under the real-time monitoring of Th1/Th2 cytokine pattern using the cytometric bead array technology for relapsed and refractory acute lymphoblastic leukemia in children. [2021]

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

Compound CAR T-cells as a double-pronged approach for treating acute myeloid leukemia. [2021]

12. 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]

13. 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]

14. 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]