SC-DARIC33 CAR T Cells for Acute Myeloid Leukemia

Overseen By Adam Lamble, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Seattle Children's Hospital

Must not be taking: Antiepileptics, Immunosuppressants, Virotherapy

Disqualifiers: Active malignancy, CNS disease, Severe infection, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

18 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called SC-DARIC33 for individuals with acute myeloid leukemia (AML) that has returned or is unresponsive to standard treatments. Researchers aim to determine if this treatment, which uses a special type of modified T cells (a kind of immune cell), is safe and can be administered to young patients. The trial seeks participants whose AML has recurred after treatment or has not improved after chemotherapy. Participants must have AML that shows a specific marker called CD33 and must be able to undergo apheresis, a process that collects blood cells for the treatment. 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 new therapy.

Will I have to stop taking my current medications?

Yes, you may need to stop taking some of your current medications. The trial requires that all chemotherapy and biologic therapy be stopped at least 7 days before enrollment, corticosteroids (unless for replacement) 7 days prior, tyrosine kinase inhibitors 3 days prior, and hydroxyurea 1 day prior. There are specific requirements for other treatments as well.

Is there any evidence suggesting that SC-DARIC33 is likely to be safe for humans?

Research has shown that SC-DARIC33, a new CAR T-cell therapy, has generally been safe in earlier studies. Some patients experienced side effects, but no severe reactions prevented doctors from increasing the dose. However, one study reported a serious negative reaction, indicating that while most patients responded well, there was a significant issue in one case. As this treatment remains in early trials, further research is necessary to confirm its safety for people. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for acute myeloid leukemia, which often include chemotherapy and bone marrow transplants, SC-DARIC33 is a CAR T-cell therapy that targets a specific protein on leukemia cells. Researchers are excited about SC-DARIC33 because it uses a unique mechanism where T-cells are engineered to better recognize and destroy cancer cells, potentially leading to more effective and targeted treatment. This therapy could offer a new avenue for patients who don't respond well to traditional treatments, providing hope for improved outcomes with fewer side effects.

What evidence suggests that SC-DARIC33 might be an effective treatment for acute myeloid leukemia?

Research has shown that SC-DARIC33, the treatment under study in this trial, could be a promising new option for acute myeloid leukemia (AML), particularly for cases that have returned or are difficult to treat. This treatment is a type of CAR T-cell therapy, which uses the patient's own modified immune cells to locate and destroy cancer cells. Early studies suggest that SC-DARIC33 can effectively target AML cells and may reduce side effects often seen with similar treatments. The method includes a controlled release system to manage the treatment's strength and safety. Although researchers are still gathering human data, this innovative design aims to improve outcomes for patients with challenging leukemia cases. ^{1 2 5 6 7}

Are You a Good Fit for This Trial?

This trial is for pediatric and young adult patients up to 30 years old with relapsed or refractory CD33+ acute myeloid leukemia (AML). They must have adequate organ function, not be pregnant or breastfeeding, agree to use effective contraception, and be able to undergo apheresis. Those with active severe infections, other cancers, primary immunodeficiency syndrome, or who can't tolerate lymphodepleting regimens are excluded.

Inclusion Criteria

Life expectancy ≥ 8 weeks

Has an appropriate stem cell donor source identified

My kidney, liver, heart, and lungs are working well.

Exclusion Criteria

Pregnant or breastfeeding

Any condition that would prohibit the subject from undergoing treatment under this protocol

I have had virotherapy before.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive SC-DARIC33 CAR T cell infusions to assess safety and feasibility

4 weeks

Multiple visits for infusion and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Regular visits for adverse event monitoring

What Are the Treatments Tested in This Trial?

Interventions

• SC-DARIC33

Trial Overview The study tests SC-DARIC33 CAR T cells in children and young adults with AML that's come back after treatment or hasn't responded at all. It's an early-phase trial assessing the safety of using genetically modified T cells designed to target cancerous cells expressing CD33.

How Is the Trial Designed?

Group I: DARIC-33 Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

Seattle Children's Hospital

Lead Sponsor

Trials

319

Recruited

5,232,000+

Regeneron Pharmaceuticals

Industry Sponsor

Trials

690

Recruited

948,000+

Founded

1988

Headquarters

Tarrytown, USA

Known For

Precision medicine

Top Products

Dupixent, EYLEA, Libtayo, Praluent

Leonard Schleifer

Regeneron Pharmaceuticals

Chief Executive Officer since 1988

MD and PhD in Medicine

George Yancopoulos

Regeneron Pharmaceuticals

Chief Medical Officer since 1997

MD from Harvard Medical School

2seventy bio

Industry Sponsor

Trials

3

Recruited

110+

Published Research Related to This Trial

Acute Myeloid Leukemia (AML) has a low 5-year survival rate of less than 30%, and current treatment options have not significantly changed in decades, highlighting the need for new therapies.

This review identifies potential target antigens for CAR T-cell therapy in AML, which could help overcome challenges in treating CD19-negative myeloid malignancies and guide future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targets for chimeric antigen receptor T-cell therapy of acute myeloid leukemia. Schorr, C., Perna, F.[2023]

CD123 is confirmed as a valid target for treating acute myeloid leukemia (AML), with both 41BB-based and CD28-based CAR T-cell therapies showing strong effectiveness in eliminating AML cells in laboratory and animal models.

However, these CAR T-cell therapies also destroy normal blood stem cells, which raises safety concerns and suggests they should primarily be used as a temporary solution before a stem cell transplant in patients with refractory or relapsed AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivo. Baroni, ML., Sanchez Martinez, D., Gutierrez Aguera, F., et al.[2021]

CAR T-cell therapy has the potential to improve outcomes for patients with acute myeloid leukemia (AML) by specifically targeting leukemia cells, but there are significant challenges to its effectiveness and safety.

Strategies being explored to enhance CAR T-cell therapy in AML include targeting specific leukemia antigens to reduce side effects, using checkpoint inhibitors to counteract immune suppression caused by leukemia, and developing allogenic CAR T cells to make the treatment more accessible to patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prospect of CAR T-cell therapy in acute myeloid leukemia. Badar, T., Manna, A., Gadd, ME., et al.[2022]

A new dual-CAR T-cell therapy strategy was developed to target acute myeloid leukemia (AML) while minimizing harmful side effects, particularly in elderly patients, by using a combination of low-affinity anti-CD123 and anti-CD33 receptors.

This approach demonstrated strong anti-tumor effects against AML without causing significant toxicity to healthy blood and endothelial cells, suggesting a safer option for treating patients with AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IL-3-zetakine combined with a CD33 costimulatory receptor as a dual CAR approach for safer and selective targeting of AML. Perriello, VM., Rotiroti, MC., Pisani, I., et al.[2023]

The study introduces a new third-generation CAR T-cell therapy (3G.CAR33-T) targeting CD33 for treating acute myeloid leukemia (AML), showing improved viability, proliferation, and cytotoxicity compared to second-generation CAR T-cells.

3G.CAR33-T cells effectively kill CD33-positive leukemia cells while sparing normal hematopoietic stem and progenitor cells, suggesting a safer treatment option that could be combined with genome-edited stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD33-directed immunotherapy with third-generation chimeric antigen receptor T cells and gemtuzumab ozogamicin in intact and CD33-edited acute myeloid leukemia and hematopoietic stem and progenitor cells. Liu, Y., Wang, S., Schubert, ML., et al.[2022]

A novel second-generation chimeric antigen receptor (CAR) targeting CD33 has been developed, showing effectiveness in redirecting T cells to kill acute myeloid leukemia (AML) cells, which express CD33 in about 90% of cases.

In pre-clinical studies, this CAR therapy demonstrated significant anti-leukemia effects both in vitro and in vivo, effectively preventing leukemia development and delaying disease progression in mice, supporting its potential as a clinical treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-CD33 chimeric antigen receptor targeting of acute myeloid leukemia. O'Hear, C., Heiber, JF., Schubert, I., et al.[2021]

CD4 is identified as a promising target for CAR-T cell therapy in treating acute myeloid leukemia (AML), as it is expressed in certain AML subtypes but not on normal hematopoietic stem cells, allowing for targeted treatment.

CD4 redirected CAR-T cells effectively eliminated CD4-expressing AML cells in laboratory settings and demonstrated strong anti-leukemic effects in a mouse model, suggesting potential for clinical application in refractory AML cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical Targeting of Human Acute Myeloid Leukemia Using CD4-specific Chimeric Antigen Receptor (CAR) T Cells and NK Cells. Salman, H., Pinz, KG., Wada, M., et al.[2020]

In a study testing CD33-CAR NK cells in patients with relapsed and refractory acute myeloid leukemia (AML), no significant adverse effects were observed at doses up to 5 billion cells per patient, suggesting a favorable safety profile.

CAR NK-92 cells can be produced at a lower cost than CAR T cells, indicating that with further optimization, they could become a more accessible treatment option for cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-man clinical trial of CAR NK-92 cells: safety test of CD33-CAR NK-92 cells in patients with relapsed and refractory acute myeloid leukemia. Tang, X., Yang, L., Li, Z., et al.[2021]

CAR T-cell therapy shows promise in improving outcomes for patients with acute myeloid leukemia (AML), a condition with historically poor prognosis.

A significant challenge for the effectiveness of CAR T-cell therapy in AML is the identification of specific target antigens on leukemia cells, as well as the risk of immune escape due to changes in these antigens and a suppressive tumor environment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current challenges for CAR T-cell therapy of acute myeloid leukemia. Sauer, T., Rooney, CM.[2020]

The study developed tremtelectogene empogeditemcel (trem-cel), a genetically modified hematopoietic stem cell product that lacks the CD33 protein, which is targeted by certain AML therapies, thus reducing the risk of toxicity to healthy cells.

Preclinical studies demonstrated that trem-cel can be manufactured with over 70% efficiency without affecting cell viability or function, and it showed resistance to the CD33-targeted drug gemtuzumab ozogamicin, supporting its potential safety and efficacy for treating acute myeloid leukemia in upcoming clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of a gene edited next-generation hematopoietic cell transplant to enable acute myeloid leukemia treatment by solving off-tumor toxicity. Lydeard, JR., Lin, MI., Ge, HG., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11060733/

Drug-regulated CD33-targeted CAR T cells control AML using ... The ongoing first-in-human trial of SC-DARIC33 for children and young adults with relapsed or refractory CD33+ AML will provide clinical and correlative data ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05105152

PLAT-08: a Study of SC-DARIC33 CAR T Cells in Pediatric ... A phase 1, open-label, non-randomized study enrolling pediatric and young adult patients with relapsed or refractory CD33+ leukemia with and without prior ...

3. targetedonc.com targetedonc.com/view/sc-daric33-demonstrates-potential-next-generation-approach-in-aml

SC-DARIC33 Demonstrates Potential Next-Generation ... Data on SC-DARIC33 reinforce the potential of the agent as a new T-cell therapy approach for patients with acute myeloid leukemia.

4. firstwordpharma.com firstwordpharma.com/story/5742231

2seventy bio Presents Late-Breaking Results for SC ... SC-DARIC33 tests the hypothesis that a pharmacologically regulated CAR can enable potent AML targeting while limiting toxicities associated with ...

5. synapse.patsnap.com synapse.patsnap.com/article/low-dose-rapamycin-regulated-sc-daric33-advancing-cd33-targeted-car-t-cell-therapy-for-acute-myeloid-leukemia

Low-Dose Rapamycin-Regulated SC-DARIC33 The study concludes that low doses of RAPA are adequate for regulating DARIC33. A phase 1 clinical trial is planned to evaluate the safety of ...

6. onclive.com onclive.com/view/phase-1-trial-of-sc-daric33-in-pediatric-r-r-cd33-aml-on-hold-after-serious-grade-5-ae

Phase 1 Trial of SC-DARIC33 in Pediatric R/R CD33+ AML ... The phase 1 PLAT-08 trial investigating SC-DARIC33 in pediatric and young-adult patients with relapsed/refractory CD33-positive acute myeloid leukemia has been ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S0006497121028925

A Pharmacologically Controlled CD33-Targeted Anti-AML ... To establish safety of SC-DARIC33 in humans, an upcoming phase 1 trial clinical trial evaluating SC-DARIC33 in pediatric AML patients will test ...