SC-DARIC33 CAR T Cells for Acute Myeloid Leukemia
Recruiting in Palo Alto (17 mi)
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Seattle Children's Hospital
Must not be taking: Antiepileptics, Immunosuppressants, Virotherapy
Disqualifiers: Active malignancy, CNS disease, Severe infection, others
No Placebo Group
Trial Summary
What is the purpose of this trial?
This trial tests a new treatment using a patient's own enhanced immune cells to fight hard-to-treat leukemia in young patients. The modified cells are designed to better detect and destroy cancer cells when activated by a special agent. This approach has shown remarkable results in treating young patients with acute lymphoblastic leukemia (ALL) and adults with lymphoma and multiple myeloma.
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.
What data supports the effectiveness of the treatment SC-DARIC33 CAR T Cells for Acute Myeloid Leukemia?
Research shows that CAR T-cell therapy, which includes treatments like SC-DARIC33, can specifically target and kill leukemia cells. Studies have demonstrated that similar CAR T-cell therapies targeting CD33, a marker found on most acute myeloid leukemia cells, effectively killed leukemia cells in lab tests and delayed disease progression in animal models.12345
What safety data exists for SC-DARIC33 CAR T Cells in humans?
The safety of CD33-targeted therapies, similar to SC-DARIC33, has been evaluated in various studies. For instance, CD33-CAR NK cells showed no significant adverse effects in patients with acute myeloid leukemia at certain doses, and a dual CAR approach targeting CD33 demonstrated powerful antitumor efficacy without relevant toxicity on healthy cells.13678
What makes the SC-DARIC33 treatment unique for acute myeloid leukemia?
SC-DARIC33 is a novel CAR T-cell therapy that specifically targets the CD33 protein on leukemia cells, which is present in about 90% of acute myeloid leukemia cases. This approach is unique because it uses genetically engineered T cells to directly attack leukemia cells, offering a targeted treatment option that differs from traditional chemotherapy and has the potential to reduce relapse rates.237910
Eligibility Criteria
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.
See 8 more
Exclusion Criteria
Pregnant or breastfeeding
Any condition that would prohibit the subject from undergoing treatment under this protocol
I have had virotherapy before.
See 9 more
Trial Timeline
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
Treatment Details
Interventions
- SC-DARIC33 (CAR T-cell Therapy)
Trial OverviewThe 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.
Participant Groups
1Treatment groups
Experimental Treatment
Group I: DARIC-33Experimental Treatment1 Intervention
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Seattle Children's HospitalSeattle, WA
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Who Is Running the Clinical Trial?
Seattle Children's HospitalLead Sponsor
Regeneron PharmaceuticalsIndustry Sponsor
2seventy bioIndustry Sponsor
References
Targets for chimeric antigen receptor T-cell therapy of acute myeloid leukemia. [2023]Acute Myeloid Leukemia (AML) is an aggressive myeloid malignancy associated with high mortality rates (less than 30% 5-year survival). Despite advances in our understanding of the molecular mechanisms underpinning leukemogenesis, standard-of-care therapeutic approaches have not changed over the last couple of decades. Chimeric Antigen Receptor (CAR) T-cell therapy targeting CD19 has shown remarkable clinical outcomes for patients with acute lymphoblastic leukemia (ALL) and is now an FDA-approved therapy. Targeting of myeloid malignancies that are CD19-negative with this promising technology remains challenging largely due to lack of alternate target antigens, complex clonal heterogeneity, and the increased recognition of an immunosuppressive bone marrow. We carefully reviewed a comprehensive list of AML targets currently being used in both proof-of-concept pre-clinical and experimental clinical settings. We analyzed the expression profile of these molecules in leukemic as well normal tissues using reliable protein databases and data reported in the literature and we provide an updated overview of the current clinical trials with CAR T-cells in AML. Our study represents a state-of-art review of the field and serves as a potential guide for selecting known AML-associated targets for adoptive cellular therapies.
Prospect of CAR T-cell therapy in acute myeloid leukemia. [2022]Long-term outcome of patients with acute myeloid leukemia (AML) remains dismal, especially for those with high-risk disease or who are refractory to conventional therapy. CAR T-cell therapy provides unique opportunity to improve outcome by specifically targeting leukemia cells through genetically engineered T cells.
Anti-CD33 chimeric antigen receptor targeting of acute myeloid leukemia. [2021]Current therapies for acute myeloid leukemia are associated with high failure and relapse rates. Adoptive immunotherapies, which have shown promise in the treatment of hematologic malignancies, have the potential to target acute myeloid leukemia through pathways that are distinct and complementary to current approaches. Here, we describe the development of a novel adoptive immunotherapy specific for this disease. We generated a second generation CD33-specific chimeric antigen receptor capable of redirecting cytolytic effector T cells against leukemic cells. CD33 is expressed in approximately 90% of acute myeloid leukemia cases and has demonstrated utility as a target of therapeutic antibodies. Chimeric antigen receptor-modified T cells efficiently killed leukemia cell lines and primary tumor cells in vitro. The anti-leukemia effect was CD33-specific, mediated through T-cell effector functions, and displayed tumor lysis at effector:target ratios as low as 1:20. Furthermore, the CD33-redirected T cells were effective in vivo, preventing the development of leukemia after prophylactic administration and delaying the progression of established disease in mice. These data provide pre-clinical validation of the effectiveness of a second-generation anti-CD33 chimeric antigen receptor therapy for acute myeloid leukemia, and support its continued development as a clinical therapeutic.
Current challenges for CAR T-cell therapy of acute myeloid leukemia. [2020]KEY IDEAS Chimeric antigen receptor (CAR) T-cell therapy has the potential to improve the dismal outcome of patients diagnosed with acute myeloid leukemia (AML). A major challenge for CAR T-cell therapy of AML patients is identifying leukemia-specific target antigens. Immune escape through down-regulation of target antigens and/or a suppressive tumor microenvironment jeopardizes the success of CAR T-cell therapy.
Preclinical Targeting of Human Acute Myeloid Leukemia Using CD4-specific Chimeric Antigen Receptor (CAR) T Cells and NK Cells. [2020]Acute myeloid leukemia (AML) is an aggressive malignancy lacking targeted therapy due to shared molecular and transcriptional circuits as well as phenotypic markers with normal hematopoietic stem cells (HSCs). Identifying leukemia specific markers expressed on AML or AML subtypes for therapeutic targeting is of exquisite clinical value. Here we show that CD4, a T lymphocytes membrane glycoprotein that interacts with major histocompatibility complex class II antigens and is also expressed in certain AML subsets but not on HSCs is a proper target for genetically engineered chimeric antigen receptor T cells (CAR-T cells). Treatment with CD4 redirected CAR-T cell (CD4CAR) specifically eliminated CD4-expressing AML cell lines in vitro and exhibited a potent anti-leukemic effect in a systemic AML murine model in vivo. We also utilized natural killers as another vehicle for CAR engineered cells and this strategy similarly and robustly eliminated CD4- expressing AML cells in vitro and had a potent in vivo anti-leukemic effect and was noted to have shorter in vivo persistence. Our data offer a proof of concept for immunotherapeutic targeting of CD4 as a strategy to treat CD4 expressing refractory AML as a bridge to stem cell transplant (SCT) in a first in human clinical trial.
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. [2021]CAR T cells have shown clinical efficacy for acute lymphoblastic leukemia, but this therapy has not been effective for acute myeloid leukemia (AML), and other treatment options are needed. Theoretically, CAR-NK cells have a more favorable toxicity profile compared to CAR T cells, especially in avoiding adverse effects such as cytokine release syndrome. However, the clinical evidence for this has not yet been reported. In the current study, we tested the safety of CD33-CAR NK cells in patients with relapsed and refractory AML. At doses up to 5 × 109 (5 billion) cells per patient, no significant adverse effects were observed. CAR NK-92 cells can be produced at much lower cost compared to CAR T cells, and we believe after being optimized, they will be widely accessible for the treatment of cancer.
Development of a gene edited next-generation hematopoietic cell transplant to enable acute myeloid leukemia treatment by solving off-tumor toxicity. [2023]Immunotherapy of acute myeloid leukemia (AML) has been challenging because the lack of tumor-specific antigens results in "on-target, off-tumor" toxicity. To unlock the full potential of AML therapies, we used CRISPR-Cas9 to genetically ablate the myeloid protein CD33 from healthy donor hematopoietic stem and progenitor cells (HSPCs), creating tremtelectogene empogeditemcel (trem-cel). Trem-cel is a HSPC transplant product designed to provide a reconstituted hematopoietic compartment that is resistant to anti-CD33 drug cytotoxicity. Here, we describe preclinical studies and process development of clinical-scale manufacturing of trem-cel. Preclinical data showed proof-of-concept with loss of CD33 surface protein and no impact on myeloid cell differentiation or function. At clinical scale, trem-cel could be manufactured reproducibly, routinely achieving >70% CD33 editing with no effect on cell viability, differentiation, and function. Trem-cel pharmacology studies using mouse xenograft models showed long-term engraftment, multilineage differentiation, and persistence of gene editing. Toxicology assessment revealed no adverse findings, and no significant or reproducible off-target editing events. Importantly, CD33-knockout myeloid cells were resistant to the CD33-targeted agent gemtuzumab ozogamicin in vitro and in vivo. These studies supported the initiation of the first-in-human, multicenter clinical trial evaluating the safety and efficacy of trem-cel in patients with AML (NCT04849910).
IL-3-zetakine combined with a CD33 costimulatory receptor as a dual CAR approach for safer and selective targeting of AML. [2023]Acute myeloid leukemia (AML) still represents an unmet clinical need for adult and pediatric patients. Adoptive cell therapy by chimeric antigen receptor (CAR)-engineered T cells demonstrated a high therapeutic potential, but further development is required to ensure a safe and durable disease remission in AML, especially in elderly patients. To date, translation of CAR T-cell therapy in AML is limited by the absence of an ideal tumor-specific antigen. CD123 and CD33 are the 2 most widely overexpressed leukemic stem cell biomarkers but their shared expression with endothelial and hematopoietic stem and progenitor cells increases the risk of undesired vascular and hematologic toxicities. To counteract this issue, we established a balanced dual-CAR strategy aimed at reducing off-target toxicities while retaining full functionality against AML. Cytokine-induced killer (CIK) cells, coexpressing a first-generation low affinity anti-CD123 interleukin-3-zetakine (IL-3z) and an anti-CD33 as costimulatory receptor without activation signaling domains (CD33.CCR), demonstrated a powerful antitumor efficacy against AML targets without any relevant toxicity on hematopoietic stem and progenitor cells and endothelial cells. The proposed optimized dual-CAR cytokine-induced killer cell strategy could offer the opportunity to unleash the potential of specifically targeting CD123+/CD33+ leukemic cells while minimizing toxicity against healthy cells.
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. [2022]Immunotherapies, such as chimeric antigen receptor (CAR) modified T cells and antibody-drug conjugates (ADCs), have revolutionized the treatment of cancer, especially of lymphoid malignancies. The application of targeted immunotherapy to patients with acute myeloid leukemia (AML) has been limited in particular by the lack of a tumor-specific target antigen. Gemtuzumab ozogamicin (GO), an ADC targeting CD33, is the only approved immunotherapeutic agent in AML. In our study, we introduce a CD33-directed third-generation CAR T-cell product (3G.CAR33-T) for the treatment of patients with AML. 3G.CAR33-T cells could be expanded up to the end-of-culture, that is, 17 days after transduction, and displayed significant cytokine secretion and robust cytotoxic activity when incubated with CD33-positive cells including cell lines, drug-resistant cells, primary blasts as well as normal hematopoietic stem and progenitor cells (HSPCs). When compared to second-generation CAR33-T cells, 3G.CAR33-T cells exhibited higher viability, increased proliferation and stronger cytotoxicity. Also, GO exerted strong antileukemia activity against CD33-positive AML cells. Upon genomic deletion of CD33 in HSPCs, 3G.CAR33-T cells and GO preferentially killed wildtype leukemia cells, while sparing CD33-deficient HSPCs. Our data provide evidence for the applicability of CD33-targeted immunotherapies in AML and its potential implementation in CD33 genome-edited stem cell transplantation approaches.
41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivo. [2021]Acute myeloid leukemia (AML) is a hematopoietic malignancy which is biologically, phenotypically and genetically very heterogeneous. Outcome of patients with AML remains dismal, highlighting the need for improved, less toxic therapies. Chimeric antigen receptor T-cell (CART) immunotherapies for patients with refractory or relapse (R/R) AML are challenging because of the absence of a universal pan-AML target antigen and the shared expression of target antigens with normal hematopoietic stem/progenitor cells (HSPCs), which may lead to life-threating on-target/off-tumor cytotoxicity. CD33-redirected and CD123-redirected CARTs for AML are in advanced preclinical and clinical development, and they exhibit robust antileukemic activity. However, preclinical and clinical controversy exists on whether such CARTs are myeloablative.