VCAR33 for Leukemia
Recruiting in Palo Alto (17 mi)
+12 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Vor Biopharma
Must not be taking: Immunosuppressants
Disqualifiers: Multiple alloHCT, Active GVHD, CNS disease, others
No Placebo Group
Approved in 1 Jurisdiction
Trial Summary
What is the purpose of this trial?This is a Phase 1/2, multicenter, open-label, first-in-human (FIH) study of donor-derived anti-CD33 Chimeric Antigen Receptor (CAR) T cell therapy (VCAR33) in patients with relapsed or refractory Acute Myeloid Leukemia (AML) after human leukocyte antigen (HLA)-matched allogeneic hematopoietic cell transplant (alloHCT).
Will I have to stop taking my current medications?
The trial information does not specify if you need to stop taking your current medications. However, if you are taking systemic immunosuppressive agents for GVHD, you may not be eligible unless your condition is controlled with only topical therapy.
What data supports the effectiveness of the treatment VCAR33 for Leukemia?
Research shows that targeting the CD33 protein on leukemia cells with CAR T-cell therapy can effectively kill cancer cells in acute myeloid leukemia (AML). Studies have demonstrated that these modified T-cells can specifically attack and destroy leukemia cells, leading to potential clearance of the disease without harming normal cells.
12345Is VCAR33 safe for humans?
Research on CD33-targeted CAR T-cell therapies, like VCAR33, shows they can effectively target leukemia cells, but they may also harm normal blood cells, leading to potential safety concerns. Efforts to modify these therapies to reduce long-term side effects, such as temporary expression of the treatment, are being explored to improve safety.
12467How is the VCAR33 treatment different from other treatments for leukemia?
VCAR33 is unique because it uses genetically engineered T cells to specifically target the CD33 antigen on leukemia cells, potentially reducing the risk of relapse by eliminating both bulk disease and leukemic stem cells. This approach is different from traditional chemotherapy as it aims to precisely attack cancer cells while sparing normal cells, potentially leading to fewer side effects.
12348Eligibility Criteria
Adults with Acute Myeloid Leukemia that has returned or resisted treatment after a specific type of bone marrow transplant (HLA-matched alloHCT) can join. They must have received the transplant from a donor who matches them on eight key genetic markers and is willing to undergo a procedure for this trial. Patients should be in good physical condition, with their major organs functioning well.Inclusion Criteria
I am 18 years old or older.
Patient must have adequate organ function as defined by: Cardiac: Left ventricular ejection fraction (LVEF) ≥ 45% or fractional shortening ≥ 28%, Pulmonary: Baseline oxygen saturation > 92% on room air at rest, Hepatic: Total bilirubin < 3x institutional upper limit of normal (ULN) (except in case of patients with documented Gilbert's disease < 5x ULN) and aspartate aminotransferase (AST/SGOT)/alanine aminotransferase (ALT/SGPT) < 5x institutional ULN, Renal: Serum creatinine must be ≤ 1.2x institutional ULN or creatinine clearance ≥ 60 mL/min for patients with creatinine levels above institutional normal, Original alloHCT donor is available and willing to undergo apheresis
I received a bone marrow transplant from a fully matched donor or was in the VBP101 study.
+2 more
Exclusion Criteria
I have had more than one allogeneic stem cell transplant.
Patients with any history of Grade III or IV acute GVHD or severe chronic GVHD unless approved by the Sponsor Medical Monitor
I had a stem cell transplant from a donor who was not a full match or used umbilical cord blood.
+4 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive donor-derived anti-CD33 CAR T cell therapy (VCAR33) to assess safety and efficacy
6-8 weeks
Dose-limiting toxicity observation
Participants are monitored for dose-limiting toxicities to determine the maximum tolerated dose
3 weeks
Follow-up
Participants are monitored for safety and effectiveness after treatment
12 weeks
Participant Groups
The trial is testing VCAR33, which is a new therapy involving T cells (a type of immune cell) engineered to target leukemia cells in patients whose AML has come back or hasn't responded after receiving an HLA-matched alloHCT. It's an early-stage trial to see how safe it is and how well it works.
6Treatment groups
Experimental Treatment
Group I: Morphologic Disease: Cohort 3Experimental Treatment1 Intervention
VCAR33 Dose Level 3
Group II: Morphologic Disease: Cohort 2Experimental Treatment1 Intervention
VCAR33 Dose Level 2
Group III: Morphologic Disease: Cohort 1Experimental Treatment1 Intervention
VCAR33 Dose Level 1
Group IV: MRD Positive: Cohort 3Experimental Treatment1 Intervention
VCAR33 Dose Level 3
Group V: MRD Positive: Cohort 2Experimental Treatment1 Intervention
VCAR33 Dose Level 2
Group VI: MRD Positive: Cohort 1Experimental Treatment1 Intervention
VCAR33 Dose Level 1
VCAR33 is already approved in United States for the following indications:
🇺🇸 Approved in United States as VCAR33 for:
- Acute Myeloid Leukemia (AML)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
National Institutes of Health, Clinical CenterBethesda, MD
Icahn School of Medicine at Mount SinaiNew York, NY
Winship Cancer Institute Emory UniversityAtlanta, GA
Masonic Cancer Center, University of MinnesotaMinneapolis, MN
More Trial Locations
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Who Is Running the Clinical Trial?
Vor BiopharmaLead Sponsor
References
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.
Genetic Inactivation of CD33 in Hematopoietic Stem Cells to Enable CAR T Cell Immunotherapy for Acute Myeloid Leukemia. [2022]The absence of cancer-restricted surface markers is a major impediment to antigen-specific immunotherapy using chimeric antigen receptor (CAR) T cells. For example, targeting the canonical myeloid marker CD33 in acute myeloid leukemia (AML) results in toxicity from destruction of normal myeloid cells. We hypothesized that a leukemia-specific antigen could be created by deleting CD33 from normal hematopoietic stem and progenitor cells (HSPCs), thereby generating a hematopoietic system resistant to CD33-targeted therapy and enabling specific targeting of AML with CAR T cells. We generated CD33-deficient human HSPCs and demonstrated normal engraftment and differentiation in immunodeficient mice. Autologous CD33 KO HSPC transplantation in rhesus macaques demonstrated long-term multilineage engraftment of gene-edited cells with normal myeloid function. CD33-deficient cells were impervious to CD33-targeting CAR T cells, allowing for efficient elimination of leukemia without myelotoxicity. These studies illuminate a novel approach to antigen-specific immunotherapy by genetically engineering the host to avoid on-target, off-tumor toxicity.
Compound CAR T-cells as a double-pronged approach for treating acute myeloid leukemia. [2021]Acute myeloid leukemia (AML) bears heterogeneous cells that can consequently offset killing by single-CAR-based therapy, which results in disease relapse. Leukemic stem cells (LSCs) associated with CD123 expression comprise a rare population that also plays an important role in disease progression and relapse. Here, we report on the robust anti-tumor activity of a compound CAR (cCAR) T-cell possessing discrete scFv domains targeting two different AML antigens, CD123, and CD33, simultaneously. We determined that the resulting cCAR T-cells possessed consistent, potent, and directed cytotoxicity against each target antigen population. Using four leukemia mouse models, we found superior in vivo survival after cCAR treatment. We also designed an alemtuzumab safety-switch that allowed for rapid cCAR therapy termination in vivo. These findings indicate that targeting both CD123 and CD33 on AML cells may be an effective strategy for eliminating both AML bulk disease and LSCs, and potentially prevent relapse due to antigen escape or LSC persistence.
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.
Gene-edited stem cells enable CD33-directed immune therapy for myeloid malignancies. [2020]Antigen-directed immunotherapies for acute myeloid leukemia (AML), such as chimeric antigen receptor T cells (CAR-Ts) or antibody-drug conjugates (ADCs), are associated with severe toxicities due to the lack of unique targetable antigens that can distinguish leukemic cells from normal myeloid cells or myeloid progenitors. Here, we present an approach to treat AML by targeting the lineage-specific myeloid antigen CD33. Our approach combines CD33-targeted CAR-T cells, or the ADC Gemtuzumab Ozogamicin with the transplantation of hematopoietic stem cells that have been engineered to ablate CD33 expression using genomic engineering methods. We show highly efficient genetic ablation of CD33 antigen using CRISPR/Cas9 technology in human stem/progenitor cells (HSPC) and provide evidence that the deletion of CD33 in HSPC doesn't impair their ability to engraft and to repopulate a functional multilineage hematopoietic system in vivo. Whole-genome sequencing and RNA sequencing analysis revealed no detectable off-target mutagenesis and no loss of functional p53 pathways. Using a human AML cell line (HL-60), we modeled a postremission marrow with minimal residual disease and showed that the transplantation of CD33-ablated HSPCs with CD33-targeted immunotherapy leads to leukemia clearance, without myelosuppression, as demonstrated by the engraftment and recovery of multilineage descendants of CD33-ablated HSPCs. Our study thus contributes to the advancement of targeted immunotherapy and could be replicated in other malignancies.
Efficacy and safety of universal (TCRKO) ARI-0001 CAR-T cells for the treatment of B-cell lymphoma. [2022]Autologous T cells expressing the Chimeric Antigen Receptor (CAR) have been approved as advanced therapy medicinal products (ATMPs) against several hematological malignancies. However, the generation of patient-specific CAR-T products delays treatment and precludes standardization. Allogeneic off-the-shelf CAR-T cells are an alternative to simplify this complex and time-consuming process. Here we investigated safety and efficacy of knocking out the TCR molecule in ARI-0001 CAR-T cells, a second generation αCD19 CAR approved by the Spanish Agency of Medicines and Medical Devices (AEMPS) under the Hospital Exemption for treatment of patients older than 25 years with Relapsed/Refractory acute B cell lymphoblastic leukemia (B-ALL). We first analyzed the efficacy and safety issues that arise during disruption of the TCR gene using CRISPR/Cas9. We have shown that edition of TRAC locus in T cells using CRISPR as ribonuleorproteins allows a highly efficient TCR disruption (over 80%) without significant alterations on T cells phenotype and with an increased percentage of energetic mitochondria. However, we also found that efficient TCRKO can lead to on-target large and medium size deletions, indicating a potential safety risk of this procedure that needs monitoring. Importantly, TCR edition of ARI-0001 efficiently prevented allogeneic responses and did not detectably alter their phenotype, while maintaining a similar anti-tumor activity ex vivo and in vivo compared to unedited ARI-0001 CAR-T cells. In summary, we showed here that, although there are still some risks of genotoxicity due to genome editing, disruption of the TCR is a feasible strategy for the generation of functional allogeneic ARI-0001 CAR-T cells. We propose to further validate this protocol for the treatment of patients that do not fit the requirements for standard autologous CAR-T cells administration.
CD33-specific chimeric antigen receptor T cells exhibit potent preclinical activity against human acute myeloid leukemia. [2022]Patients with chemo-refractory acute myeloid leukemia (AML) have a dismal prognosis. Chimeric antigen receptor T (CART) cell therapy has produced exciting results in CD19+ malignancies and may overcome many of the limitations of conventional leukemia therapies. We developed CART cells to target CD33 (CART33) using the anti-CD33 single chain variable fragment used in gemtuzumab ozogamicin (clone My96) and tested the activity and toxicity of these cells. CART33 exhibited significant effector functions in vitro and resulted in eradication of leukemia and prolonged survival in AML xenografts. CART33 also resulted in human lineage cytopenias and reduction of myeloid progenitors in xenograft models of hematopoietic toxicity, suggesting that permanently expressed CD33-specific CART cells would have unacceptable toxicity. To enhance the viability of CART33 as an option for AML, we designed a transiently expressed mRNA anti-CD33 CAR. Gene transfer was carried out by electroporation into T cells and resulted in high-level expression with potent but self-limited activity against AML. Thus our preclinical studies show potent activity of CART33 and indicate that transient expression of anti-CD33 CAR by RNA modification could be used in patients to avoid long-term myelosuppression. CART33 therapy could be used alone or as part of a preparative regimen prior to allogeneic transplantation in refractory AML.
In Vitro and In Vivo Antitumor Effect of Anti-CD33 Chimeric Receptor-Expressing EBV-CTL against CD33 Acute Myeloid Leukemia. [2021]Genetic engineering of T cells with chimeric T-cell receptors (CARs) is an attractive strategy to treat malignancies. It extends the range of antigens for adoptive T-cell immunotherapy, and major mechanisms of tumor escape are bypassed. With this strategy we redirected immune responses towards the CD33 antigen to target acute myeloid leukemia. To improve in vivo T-cell persistence, we modified human Epstein Barr Virus-(EBV-) specific cytotoxic T cells with an anti-CD33.CAR. Genetically modified T cells displayed EBV and HLA-unrestricted CD33 bispecificity in vitro. In addition, though showing a myeloablative activity, they did not irreversibly impair the clonogenic potential of normal CD34(+) hematopoietic progenitors. Moreover, after intravenous administration into CD33(+) human acute myeloid leukemia-bearing NOD-SCID mice, anti-CD33-EBV-specific T cells reached the tumor sites exerting antitumor activity in vivo. In conclusion, targeting CD33 by CAR-modified EBV-specific T cells may provide additional therapeutic benefit to AML patients as compared to conventional chemotherapy or transplantation regimens alone.