CAR T-Cell Therapy for Leukemia

Overseen By Maria Iglesias

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Stanford University

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate the effectiveness of a new treatment combination for individuals with a type of leukemia (blood cancer) that has returned or does not respond to treatment. The treatment uses specially modified immune cells, known as CD19/CD22 Chimeric Antigen Receptor (CAR) T Cells, to target the cancer, along with chemotherapy and a drug to enhance the immune system. The trial seeks participants with B acute lymphoblastic leukemia that has recurred or not improved after treatment. Participants must have a confirmed diagnosis of this leukemia and show signs of the disease despite previous treatments. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that CD19/CD22 CAR T-cell therapy is generally safe. Studies have found that patients with B-cell acute lymphoblastic leukemia (B-ALL) usually tolerate this treatment well. One review noted that patients treated with these CAR T cells had a good safety record, and many experienced remission, even if their B-ALL had returned or was hard to treat. Another study reported that this dual-targeted approach did not cause severe side effects for most patients.

For NKTR-255, research indicates that this experimental drug is also well-tolerated when used with CAR T-cell therapy. Early trials showed no serious side effects that would prevent patients from receiving higher doses. This suggests that NKTR-255 could be a safe addition to treatments that aim to help the immune system fight cancer.

Overall, the evidence supports the safety of both CD19/CD22 CAR T cells and NKTR-255, making them promising options for patients considering clinical trials. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using CAR T-Cell Therapy for leukemia because it uses the body's immune system to fight cancer in a new way. Unlike traditional treatments like chemotherapy, which attack rapidly dividing cells indiscriminately, CAR T-Cell Therapy specifically targets and attacks cancer cells by recognizing proteins like CD19 and CD22 on their surfaces. This targeted approach can lead to fewer side effects and potentially more effective results. Additionally, the inclusion of NKTR-255 after CAR T-Cell infusion is designed to enhance the persistence and activity of these engineered cells, further boosting the immune response against leukemia.

What evidence suggests that this trial's treatments could be effective for leukemia?

Research shows that CD19/CD22 CAR T-cell therapy holds promise for certain types of leukemia. In this trial, participants will receive CD19/CD22 CAR T-cell therapy. A study with patients whose B acute lymphoblastic leukemia had returned found that using both CD19 and CD22 CAR T-cells resulted in 70% of patients being alive after 18 months. Additionally, some participants in this trial will receive NKTR-255 alongside CAR T-cell therapy. Studies suggest that when NKTR-255 was combined with CAR T-cell therapy, 89% of patients went into remission, with no cancer detected. These treatments together may effectively target and fight leukemia cells. ^{1 4 6 7 8}

Who Is on the Research Team?

Lori Muffly, MD

Principal Investigator

Stanford University

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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?

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

Crystal Mackall, MD

Lead Sponsor

Trials

6

Recruited

240+

California Institute for Regenerative Medicine (CIRM)

Collaborator

Trials

70

Recruited

3,300+

Published Research Related to This Trial

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]

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 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]

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12050930/

Five-year outcome of CD19 followed by CD22 chimeric ... In conclusion, among B-ALL patients relapsed after allo-HCT, CD19 followed by CD22 CAR T-cell therapy resulted in an OS of 75% and an EFS of 50% at 5 years, ...

2. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/5877/527643/Long-Term-Outcomes-and-Adverse-Events-of-CAR-T-19

Long-Term Outcomes and Adverse Events of CAR T-19 Cell ... Anti-CD19 CAR T-cell therapy showed the highest efficacy with an event rate of 74.75% (95% CI: 61% to 80%, I² = 89.84%). Combination therapies ...

3. thelancet.com thelancet.com/journals/ebiom/article/PIIS2352-3964(25)00316-0/fulltext

Tandem CD19/CD22 CAR T-cells as potential therapy for ... At the 18-month follow up, overall survival (OS) was 70% (95% CI, 47%–100%). Interpretation. Tandem anti-CD19/CD22 CAR T-cell administration ...

4. ehoonline.biomedcentral.com ehoonline.biomedcentral.com/articles/10.1186/s40164-024-00593-5

Prominent efficacy and good safety of sequential CD19 and ... CD22 has emerged as an outstanding target for CAR-T therapy, demonstrating therapeutic effects comparable to those of CD19 CAR-T therapy in ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10557829/

Effectiveness and safety of CD22 and CD19 dual‐targeting ... A systematic review and meta‐analysis in which CD19‐CAR‐T cells were administered to 280 NHL adults reached a total OR and CR of 63% and 33%, ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S2352396425003160

Tandem CD19/CD22 CAR T-cells as potential therapy for ... The phase II ELIANA trial showed promising results; with an overall remission rate of 82%, overall survival (OS) was 63% (95% CI, 51 to 73) at 3 years. Relapse ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT05225831?cond=(hemolytic%20anemia%20cd19%20mediated%20with%20without%20immune%20mediated%20polyneuropathy)%20OR%20(cd19)&checkSpell=&rank=10

Safety and Efficacy of CD19/CD22 Dual Targeted CAR-T ... This is an open, single-arm, prospective clinical study to evaluate the safety and efficacy of anti CD19 and CD22 CAR-T cell in the treatment of R/R B-ALL.

8. onclive.com onclive.com/view/bicistronic-cd19-cd22-directed-car-t-cell-therapy-is-safe-elicits-durable-responses-in-pediatric-r-r-b-all

Bicistronic CD19/CD22-Directed CAR T-Cell Therapy Is ... At a median follow-up of 13.9 months, the 1-year event-free survival (EFS) rate was 75.5%, and the 1-year overall survival (OS) rate was 93.5% ...