ADCLEC.syn1 CAR T-Cell Therapy for Acute Myeloid Leukemia
Recruiting in Palo Alto (17 mi)
+6 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Memorial Sloan Kettering Cancer Center
Must not be taking: Steroids, Chemotherapy
Disqualifiers: Acute promyelocytic leukemia, CNS disease, Cardiovascular disease, HIV, others
No Placebo Group
Trial Summary
What is the purpose of this trial?
The purpose of this study is to test the safety of ADCLEC.syn1 CAR T cells in people with relapsed or refractory AML. The researchers will try to find the highest dose of ADCLEC.syn1 CAR T cells that causes few or mild side effects in participants. Once the researchers find this dose, it will test it in a new group of participants to see if it is effective in treating their relapsed/refractory AML.
Will I have to stop taking my current medications?
The trial requires stopping certain medications before participation. Steroids above a certain dose must be stopped 7 days before a procedure, and chemotherapy should be stopped one week prior. Hydroxyurea can be used up to 72 hours before certain procedures.
What data supports the effectiveness of the ADCLEC.syn1 CAR T-Cell Therapy treatment for Acute Myeloid Leukemia?
Research shows that CAR T-cell therapy, like ADCLEC.syn1, has been successful in treating certain blood cancers by targeting specific cancer cells. Studies suggest that ADCLEC.syn1 can effectively target leukemia cells while minimizing harm to normal cells, showing promise in treating acute myeloid leukemia.12345
Is ADCLEC.syn1 CAR T-Cell Therapy safe for humans?
ADCLEC.syn1 CAR T-Cell Therapy has shown potential in targeting acute myeloid leukemia (AML) while minimizing harm to normal cells. However, like other CAR T-cell therapies, it may cause side effects such as myeloablation (reduction of bone marrow activity) and cytokine release syndrome (a severe immune reaction).24678
How is ADCLEC.syn1 CAR T-Cell Therapy different from other treatments for acute myeloid leukemia?
ADCLEC.syn1 CAR T-Cell Therapy is unique because it targets two specific markers (ADGRE2 and CLEC12A) on leukemia cells, which helps to selectively attack cancer cells while sparing normal cells. This dual targeting approach reduces the risk of damaging healthy blood-forming cells, a common issue with other CAR T-cell therapies for acute myeloid leukemia.2491011
Eligibility Criteria
Adults with relapsed or refractory Acute Myeloid Leukemia (AML) who are in good physical condition (ECOG 0-1), have a suitable stem cell donor, and functioning major organs can join this trial. Those with acute promyelocytic leukemia, certain infections like HBV/HCV, other active cancers needing treatment, recent heart issues, uncontrolled infections or previous CAR therapy cannot participate.Inclusion Criteria
My kidney and liver functions are within the required limits.
I have a matching donor for a stem cell transplant.
I am fully active or can carry out light work.
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Exclusion Criteria
I have not taken clofarabine or cladribine in the last 3 months.
I have been diagnosed with acute promyelocytic leukemia.
I have brain-related symptoms or confirmed brain disease.
See 10 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Conditioning Chemotherapy
Participants receive conditioning chemotherapy prior to CAR T cell infusion
1 week
Inpatient or outpatient
Treatment
Participants receive ADCLEC.syn1 CAR T cell infusions with dose escalation to determine the maximum tolerated dose
2-7 days post-chemotherapy
Inpatient
Dose Expansion
Selected dose levels are tested in additional patients to determine the recommended phase 2 dose (RP2D)
Variable, up to 2 years
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Treatment Details
Interventions
- ADCLEC.syn1 CAR T cells (CAR T-cell Therapy)
- Conditioning chemotherapy (Chemotherapy)
Trial OverviewThe study is testing the safety of ADCLEC.syn1 CAR T cells along with conditioning chemotherapy in AML patients. It aims to find the highest dose that's safe with few side effects and then test its effectiveness against AML that has come back or hasn't responded to other treatments.
Participant Groups
1Treatment groups
Experimental Treatment
Group I: ADCLEC.syn1 CAR T cellsExperimental Treatment2 Interventions
The dose escalation cohort size of 3 patients in each cohort will be infused with escalating doses of ADCLEC.syn1 CAR T cells to inform the RP2D. There are 4 planned flat-dose levels: 25 × 10\^6, 75 × 10\^6 , 225 × 10\^6 , and 450 × 10\^6 CAR T cells and 1 de-escalation dose: 10 × 10\^6 CAR T cells. After dose escalation, one or two dose levels will be selected for dose expansion cohort(s).Two to 7 days following completion of the conditioning chemotherapy, the frozen CAR T cells will be thawed and administered. Conditioning chemotherapy may occur either outpatient or inpatient, and T cell infusions will occur as inpatient. Up to approximately 12 additional patients each if two doses are selected or approximately 16 additional patients, if one dose is selected, will be treated in the dose expansion phase to determine RP2D.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Memorial Sloan Kettering Nassau (Limited Protocol Activities)Uniondale, NY
Memorial Sloan Kettering Monmouth (Limited Protocol Activities)Middletown, NJ
Memorial Sloan Kettering Bergen (Limited Protocol Activities)Montvale, NJ
Memorial Sloan Kettering Cancer CenterNew York, NY
More Trial Locations
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Who Is Running the Clinical Trial?
Memorial Sloan Kettering Cancer CenterLead Sponsor
TakedaIndustry Sponsor
References
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.
CAR T Cells for Acute Myeloid Leukemia: State of the Art and Future Directions. [2023]Relapse after conventional chemotherapy remains a major problem in patients with myeloid malignancies such as acute myeloid leukemia (AML), and the major cause of death after diagnosis of AML is from relapsed disease. The only potentially curative treatment option currently available is allogeneic hematopoietic stem cell transplantation (allo-HSCT), which through its graft-vs.-leukemia effects has the ability to eliminate residual leukemia cells. Despite its long history of success however, relapse following allo-HSCT is still a major challenge and is associated with poor prognosis. In the field of adoptive therapy, CD19-targeted chimeric antigen receptor (CAR) T cells have yielded remarkable clinical success in certain types of B-cell malignancies, and substantial efforts aimed at translating this success to myeloid malignancies are currently underway. While complete ablation of CD19-expressing B cells, both cancerous and healthy, is clinically tolerated, the primary challenge limiting the use of CAR T cells in myeloid malignancies is the absence of a dispensable antigen, as myeloid antigens are often co-expressed on normal hematopoietic stem/progenitor cells (HSPCs), depletion of which would lead to intolerable myeloablation. This review provides a discussion on the current state of CAR T cell therapy in myeloid malignancies, limitations for clinical translation, as well as the most recent approaches to overcome these barriers, through various genetic modification and combinatorial strategies in an attempt to make CAR T cell therapy a safe and viable option for patients with myeloid malignancies.
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.
Cooperative CAR targeting to selectively eliminate AML and minimize escape. [2023]Acute myeloid leukemia (AML) poses a singular challenge for chimeric antigen receptor (CAR) therapy owing to its phenotypic heterogeneity and similarity to normal hematopoietic stem/progenitor cells (HSPCs). Here we expound a CAR strategy intended to efficiently target AML while minimizing HSPC toxicity. Quantification of target expression in relapsed/refractory patient samples and normal HSPCs reveals a therapeutic window for gated co-targeting of ADGRE2 and CLEC12A: We combine an attenuated ADGRE2-CAR with a CLEC12A-chimeric costimulatory receptor (ADCLEC.syn1) to preferentially engage ADGRE2posCLEC12Apos leukemic stem cells over ADGRE2lowCLEC12Aneg normal HSPCs. ADCLEC.syn1 prevents antigen escape in AML xenograft models, outperforms the ADGRE2-CAR alone and eradicates AML despite proximate myelopoiesis in humanized mice. Off-target HSPC toxicity is similar to that of a CD19-CAR and can be mitigated by reducing CAR T cell-derived interferon-γ. Overall, we demonstrate the ability of target density-adapted cooperative CAR targeting to selectively eliminate AML and potentially obviate the need for hematopoietic rescue.
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.
How close are we to CAR T-cell therapy for AML? [2021]Chimeric antigen receptor (CAR) T-cell therapy for acute myeloid leukemia (AML) has thus far been elusive, in part owing to the absence of truly AML-specific surface antigens, making AML difficult to target. However, progress has been made toward the use of CAR T-cell therapy in this disease, prompting the topic of this paper. Discussion and clinical examples of potential solutions to creating a safe and effective CAR T cell for AML include: (1) Decreasing the potency or activity of CAR T cells to enhance the therapeutic window; (2) Using transient or depletable CAR T cells as part of pre-transplant conditioning; and (3) Using a gene-edited allogeneic donor hematopoietic stem cell transplant in order to allow safe and protracted anti-AML CAR T-cell function.
Safety profile of chimeric antigen receptor T-cell immunotherapies (CAR-T) in clinical practice. [2021]Two chimeric antigen receptor T-cell (CAR-T) therapies have been approved in the United States (USA) in 2017 and Europe (EU) in 2018: axicabtagene ciloleucel and tisagenlecleucel. They contain the patient's own T cells, which are extracted, genetically modified, and reinfused. Alongside the good efficacy results, the assessment of safety profile of these new therapies represents a great challenge. Our aim was to analyze the reports of the adverse drug reactions (ADR) after CAR-T administration as occurred in the real clinical setting.
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.
CD70 CAR T cells in AML: Form follows function. [2022]Using a multimodal approach toward developing a new CD70-targeted Chimeric antigen receptor (CAR) T cell in acute myeloid leukemia, Leick et al.1 report on their synergetic strategy, which incorporates both CAR T cell construct modifications with enhancement of leukemia antigen expression to improve CAR T cell functionality.
Combinatorial antigen targeting strategies for acute leukemia: application in myeloid malignancy. [2023]Efforts to safely and effectively treat acute myeloid leukemia (AML) by targeting a single leukemia-associated antigen with chimeric antigen receptor (CAR) T cells have met with limited success, due in part to heterogeneous expression of myeloid antigens. The authors hypothesized that T cells expressing CARs directed toward two different AML-associated antigens would eradicate tumors and prevent relapse.
Adapter CAR T cells to counteract T-cell exhaustion and enable flexible targeting in AML. [2023]Although the landscape for treating acute myeloid leukemia (AML) patients has changed substantially in recent years, the majority of patients will eventually relapse and succumb to their disease. Allogeneic stem cell transplantation provides the best anti-AML treatment strategy, but is only suitable in a minority of patients. In contrast to B-cell neoplasias, chimeric antigen receptor (CAR) T-cell therapy in AML has encountered challenges in target antigen heterogeneity, safety, and T-cell dysfunction. We established a Fab-based adapter CAR (AdCAR) T-cell platform with flexibility of targeting and control of AdCAR T-cell activation. Utilizing AML cell lines and a long-term culture assay for primary AML cells, we were able to demonstrate AML-specific cytotoxicity using anti-CD33, anti-CD123, and anti-CLL1 adapter molecules in vitro and in vivo. Notably, we show for the first time the feasibility of sequential application of adapter molecules of different specificity in primary AML co-cultures. Importantly, using the AML platform, we were able to demonstrate that chronic T-cell stimulation and exhaustion can be counteracted through introduction of treatment-free intervals. As T-cell exhaustion and target antigen heterogeneity are well-known causes of resistance, the AdCAR platform might offer effective strategies to ameliorate these limitations.