CAR T Cell Therapy for Acute Myeloid Leukemia
Recruiting in Palo Alto (17 mi)
+6 other locations
Age: Any Age
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Memorial Sloan Kettering Cancer Center
Disqualifiers: Pregnancy, HIV, HBV, HCV, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This trial is testing the safety of using specially modified immune cells to treat cancer patients who haven't responded to other treatments. The goal is to find the highest dose that causes few or mild side effects.
Will I have to stop taking my current medications?
The trial requires that participants stop taking any systemic immunosuppressive agents at least 30 days before treatment, but a physiologic dose of corticosteroids is allowed. The protocol does not specify other medication restrictions, so it's best to discuss your current medications with the study team.
What data supports the effectiveness of the treatment CD371-YSNVZ-IL18 CAR T cells for acute myeloid leukemia?
Research shows that CAR T-cell therapy has been successful in targeting specific leukemia cells in other studies, such as those targeting CD117 and CD4 markers in acute myeloid leukemia. This suggests potential for similar therapies like CD371-YSNVZ-IL18 CAR T cells to be effective.
12345What safety data exists for CAR T Cell Therapy in humans?
CAR T Cell Therapy can cause side effects like cytokine release syndrome (a condition where the immune system releases too many proteins into the blood too quickly) and neurotoxicity (damage to the nervous system), although these are not common. Careful monitoring is needed due to potential toxicities, especially when targeting certain antigens in blood cancers.
12678What makes the CD371-YSNVZ-IL18 CAR T cell treatment unique for acute myeloid leukemia?
The CD371-YSNVZ-IL18 CAR T cell treatment is unique because it targets specific antigens on leukemia cells, which is challenging due to the lack of leukemia-specific targets in acute myeloid leukemia (AML). This therapy aims to overcome immune escape and the suppressive tumor environment, which are significant hurdles in treating AML with CAR T cells.
157910Eligibility Criteria
This trial is for people with a type of blood cancer called Acute Myeloid Leukemia (AML) that has CD371+ expression. It's open to all ages, but kids must be over 1 year old and weigh at least 10kg. Adults need functioning liver and kidneys, no active graft-versus-host disease post-transplant, and can't have had certain treatments recently. Pregnant women or those who could become pregnant must use contraception.Inclusion Criteria
My AML did not respond to initial treatment attempts.
I am 16 or older and can care for myself with minimal assistance.
My first AML relapse occurred 12 months or more after my initial treatment, and repeating the same treatment is not expected to help.
+38 more
Exclusion Criteria
I'm sorry, but it seems like the criterion you provided was incomplete. Could you please provide the full criterion so that I can rewrite it for you?
I have or had brain involvement with my cancer but it's been treated.
I am not pregnant or breastfeeding and if I can become pregnant, I am using effective birth control.
+4 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive CD371-YSNVZ-IL18 CAR T cells to determine the Maximum Tolerated Dose
up to 6 months
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
Researchers are testing a new therapy using special immune cells called CD371-YSNVZ-IL18 CAR T cells to treat AML. They want to find the highest dose that's still safe with few or mild side effects by gradually increasing the amount given to participants.
3Treatment groups
Experimental Treatment
Group I: Step-Down DoseExperimental Treatment1 Intervention
Participants with Relapsed/Refractory Acute Myeloid Leukemia (R/R AML)
Group II: Dose Level 2Experimental Treatment1 Intervention
Participants with Relapsed/Refractory Acute Myeloid Leukemia (R/R AML)
Group III: Dose Level 1Experimental Treatment1 Intervention
Participants with Relapsed/Refractory Acute Myeloid Leukemia (R/R AML)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Memorial Sloan Kettering Cancer Center (All protocol activites)New York, NY
Memorial Sloan Kettering Nassau (Limited Protocol Activites)Rockville Centre, NY
Memorial Sloan Kettering Cancer Center @ Suffolk-Commack (Limited protocol activities)Commack, NY
Memorial Sloan Kettering Westchester (Limited Protocol Activities)Harrison, NY
More Trial Locations
Loading ...
Who Is Running the Clinical Trial?
Memorial Sloan Kettering Cancer CenterLead Sponsor
References
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.
Anti-human CD117 CAR T-cells efficiently eliminate healthy and malignant CD117-expressing hematopoietic cells. [2021]Acute myeloid leukemia (AML) initiating and sustaining cells maintain high cell-surface similarity with their cells-of-origin, i.e., hematopoietic stem and progenitor cells (HSPCs), and identification of truly distinguishing leukemia-private antigens has remained elusive to date. To nonetheless utilize surface antigen-directed immunotherapy in AML, we here propose targeting both, healthy and malignant human HSPC, by chimeric antigen receptor (CAR) T-cells with specificity against CD117, the cognate receptor for stem cell factor. This approach should spare most mature hematopoietic cells and would require CAR T termination followed by subsequent transplantation of healthy HSPCs to rescue hematopoiesis. We successfully generated anti-CD117 CAR T-cells from healthy donors and AML patients. Anti-CD117 CAR T-cells efficiently targeted healthy and leukemic CD117-positive cells in vitro. In mice xenografted with healthy human hematopoiesis, they eliminated CD117-expressing, but not CD117-negative human cells. Importantly, in mice xenografted with primary human CD117-positive AML, they eradicated disease in a therapeutic setting. Administration of ATG in combination with rituximab, which binds to the co-expressed CAR T-cell transduction/selection marker RQR8, led to CAR T-cell depletion. Thus, we here provide the first proof of concept for the generation and preclinical efficacy of CAR T-cells directed against CD117-expressing human hematopoietic cells.
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.
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.
Chimeric antigen receptors for adoptive T cell therapy in acute myeloid leukemia. [2021]Currently, conventional therapies for acute myeloid leukemia (AML) have high failure and relapse rates. Thus, developing new strategies is crucial for improving the treatment of AML. With the clinical success of anti-CD19 chimeric antigen receptor (CAR) T cell therapies against B-lineage malignancies, many studies have attempted to translate the success of CAR T cell therapy to other malignancies, including AML. This review summarizes the current advances in CAR T cell therapy against AML, including preclinical studies and clinical trials, and discusses the potential AML-associated surface markers that could be used for further CAR technology. Finally, we describe strategies that might address the current issues of employing CAR T cell therapy in AML.
CD38 as a pan-hematologic target for chimeric antigen receptor T cells. [2023]Many hematologic malignancies are not curable with chemotherapy and require novel therapeutic approaches. Chimeric antigen receptor (CAR) T-cell therapy is 1 such approach that involves the transfer of T cells engineered to express CARs for a specific cell-surface antigen. CD38 is a validated tumor antigen in multiple myeloma (MM) and T-cell acute lymphoblastic leukemia (T-ALL) and is also overexpressed in acute myeloid leukemia (AML). Here, we developed human CD38-redirected T cells (CART-38) as a unified approach to treat 3 different hematologic malignancies that occur across the pediatric-to-adult age spectrum. Importantly, CD38 expression on activated T cells did not impair CART-38 cells expansion or in vitro function. In xenografted mice, CART-38 mediated the rejection of AML, T-ALL, and MM cell lines and primary samples and prolonged survival. In a xenograft model of normal human hematopoiesis, CART-38 resulted in the expected reduction of hematopoietic progenitors, which warrants caution and careful monitoring of this potential toxicity when translating this new immunotherapy into the clinic. Deploying CART-38 against multiple CD38-expressing malignancies is significant because it expands the potential for this novel therapy to affect diverse patient populations.
Chimeric Antigen Receptor T Cells in Acute Myeloid Leukemia. [2023]Up to 30% of patients with acute myeloid leukemia (AML) who undergo chimeric antigen receptor (CAR) T-cell therapy have evidence of response, although trials are highly heterogeneous. These responses are rarely deep or durable. CD123, CD33, and CLL-1 have emerged as the most common targets for CAR T cells in AML. CAR T cells against myeloid antigens cause myeloablation as well as cytokine release syndrome, although neurotoxicity is rarely seen. Future efforts should focus on AML-specific antigen discovery or engineering, and on further enhancing the activity of CAR T cells.
Next generations of CAR-T cells - new therapeutic opportunities in hematology? [2022]In recent years, the introduction of chimeric antigen receptor (CAR) T-cell therapies into clinics has been a breakthrough in treating relapsed or refractory malignancies in hematology and oncology. To date, Food and Drug Administration (FDA) has approved six CAR-T therapies for specific non-Hodgkin lymphomas, B-cell acute lymphoblastic leukemia, and multiple myeloma. All registered treatments and most clinical trials are based on so-called 2nd generation CARs, which consist of an extracellular antigen-binding region, one costimulatory domain, and a CD3z signaling domain. Unfortunately, despite remarkable overall treatment outcomes, a relatively high percentage of patients do not benefit from CAR-T therapy (overall response rate varies between 50 and 100%, with following relapse rates as high as 66% due to limited durability of the response). Moreover, it is associated with adverse effects such as cytokine release syndrome and neurotoxicity. Advances in immunology and molecular engineering have facilitated the construction of the next generation of CAR-T cells equipped with various molecular mechanisms. These include additional costimulatory domains (3rd generation), safety switches, immune-checkpoint modulation, cytokine expression, or knockout of therapy-interfering molecules, to name just a few. Implementation of next-generation CAR T-cells may allow overcoming current limitations of CAR-T therapies, decreasing unwanted side effects, and targeting other hematological malignancies. Accordingly, some clinical trials are currently evaluating the safety and efficacy of novel CAR-T therapies. This review describes the CAR-T cell constructs concerning the clinical application, summarizes completed and ongoing clinical trials of next-generation CAR-T therapies, and presents future perspectives.
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.
Ligand-based targeting of c-kit using engineered γδ T cells as a strategy for treating acute myeloid leukemia. [2023]The application of immunotherapies such as chimeric antigen receptor (CAR) T therapy or bi-specific T cell engager (BiTE) therapy to manage myeloid malignancies has proven more challenging than for B-cell malignancies. This is attributed to a shortage of leukemia-specific cell-surface antigens that distinguish healthy from malignant myeloid populations, and the inability to manage myeloid depletion unlike B-cell aplasia. Therefore, the development of targeted therapeutics for myeloid malignancies, such as acute myeloid leukemia (AML), requires new approaches. Herein, we developed a ligand-based CAR and secreted bi-specific T cell engager (sBite) to target c-kit using its cognate ligand, stem cell factor (SCF). c-kit is highly expressed on AML blasts and correlates with resistance to chemotherapy and poor prognosis, making it an ideal candidate for which to develop targeted therapeutics. We utilize γδ T cells as a cytotoxic alternative to αβ T cells and a transient transfection system as both a safety precaution and switch to remove alloreactive modified cells that may hinder successful transplant. Additionally, the use of γδ T cells permits its use as an allogeneic, off-the-shelf therapeutic. To this end, we show mSCF CAR- and hSCF sBite-modified γδ T cells are proficient in killing c-kit+ AML cell lines and sca-1+ murine bone marrow cells in vitro. In vivo, hSCF sBite-modified γδ T cells moderately extend survival of NSG mice engrafted with disseminated AML, but therapeutic efficacy is limited by lack of γδ T-cell homing to murine bone marrow. Together, these data demonstrate preclinical efficacy and support further investigation of SCF-based γδ T-cell therapeutics for the treatment of myeloid malignancies.