VCAR33 for Leukemia

Recruiting at 13 trial locations

Overseen By Jennifer Whangbo, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Vor Biopharma

Must not be taking: Immunosuppressants

Disqualifiers: Multiple alloHCT, Active GVHD, CNS disease, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6-8 weeks

38 Participants Needed

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. ^{1 2 3 4 5}

Is 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. ^{1 2 4 6 7}

How 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. ^{1 2 3 4 8}

Eligibility 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.

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.

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

Treatment Details

Interventions

• VCAR33

Trial Overview 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.

Participant Groups

Group I: Morphologic Disease: Cohort 3 Experimental Treatment 1 Intervention

VCAR33 Dose Level 3

Group II: Morphologic Disease: Cohort 2 Experimental Treatment 1 Intervention

VCAR33 Dose Level 2

Group III: Morphologic Disease: Cohort 1 Experimental Treatment 1 Intervention

VCAR33 Dose Level 1

Group IV: MRD Positive: Cohort 3 Experimental Treatment 1 Intervention

VCAR33 Dose Level 3

Group V: MRD Positive: Cohort 2 Experimental Treatment 1 Intervention

VCAR33 Dose Level 2

Group VI: MRD Positive: Cohort 1 Experimental Treatment 1 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)

Who Is Running the Clinical Trial?

Vor Biopharma

Lead Sponsor

Trials

3

Recruited

80+

Findings from Research

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]

Researchers developed a method to create CD33-deficient hematopoietic stem and progenitor cells (HSPCs) that can resist CD33-targeted CAR T cell therapy, allowing for specific targeting of acute myeloid leukemia (AML) without harming normal myeloid cells.

In studies with immunodeficient mice and rhesus macaques, the CD33-deficient HSPCs showed normal function and long-term engraftment, demonstrating a promising strategy for reducing toxicity in immunotherapy while effectively eliminating leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic Inactivation of CD33 in Hematopoietic Stem Cells to Enable CAR T Cell Immunotherapy for Acute Myeloid Leukemia. Kim, MY., Yu, KR., Kenderian, SS., et al.[2022]

The compound CAR (cCAR) T-cell therapy, which targets both CD123 and CD33 antigens in acute myeloid leukemia (AML), demonstrated strong anti-tumor activity and improved survival in four different leukemia mouse models.

The inclusion of a safety-switch using alemtuzumab allows for the rapid termination of cCAR therapy if needed, enhancing the safety profile of this dual-targeting approach against AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Compound CAR T-cells as a double-pronged approach for treating acute myeloid leukemia. Petrov, JC., Wada, M., Pinz, KG., et al.[2021]

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]

The study presents a novel approach to treat acute myeloid leukemia (AML) by using CD33-targeted CAR-T cells and antibody-drug conjugates (ADCs) alongside genetically engineered hematopoietic stem cells (HSPCs) that lack the CD33 antigen, which helps avoid severe toxicities associated with current therapies.

Using CRISPR/Cas9 technology, researchers successfully ablated CD33 in HSPCs without impairing their ability to engraft and repopulate the blood system, leading to effective leukemia clearance in a model without causing myelosuppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene-edited stem cells enable CD33-directed immune therapy for myeloid malignancies. Borot, F., Wang, H., Ma, Y., et al.[2020]

The study demonstrated that using CRISPR/Cas9 to knock out the TCR gene in ARI-0001 CAR-T cells can effectively disrupt the TCR without significantly altering the T cell phenotype, achieving over 80% efficiency.

While this method shows promise for creating allogeneic CAR-T cells with maintained anti-tumor activity, there are potential safety risks due to possible large deletions in the genome that require careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of universal (TCRKO) ARI-0001 CAR-T cells for the treatment of B-cell lymphoma. Maldonado-Pérez, N., Tristán-Manzano, M., Justicia-Lirio, P., et al.[2022]

CART33, a chimeric antigen receptor T cell therapy targeting CD33, showed significant effectiveness in eradicating acute myeloid leukemia (AML) in preclinical models, leading to prolonged survival.

To reduce the risk of long-term toxicity associated with permanent CART cell expression, a transiently expressed mRNA anti-CD33 CAR was developed, demonstrating potent but self-limited activity against AML, making it a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD33-specific chimeric antigen receptor T cells exhibit potent preclinical activity against human acute myeloid leukemia. Kenderian, SS., Ruella, M., Shestova, O., et al.[2022]

Genetically engineered T cells targeting the CD33 antigen showed promising in vitro bispecificity and did not harm normal blood cell progenitors, suggesting a safer approach for treating acute myeloid leukemia (AML).

In vivo studies in mice demonstrated that these CAR-modified T cells effectively localized to tumor sites and exhibited antitumor activity, indicating potential for enhanced treatment outcomes in AML patients compared to traditional therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In Vitro and In Vivo Antitumor Effect of Anti-CD33 Chimeric Receptor-Expressing EBV-CTL against CD33 Acute Myeloid Leukemia. Dutour, A., Marin, V., Pizzitola, I., et al.[2021]

References

1. United States 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. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Genetic Inactivation of CD33 in Hematopoietic Stem Cells to Enable CAR T Cell Immunotherapy for Acute Myeloid Leukemia. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Compound CAR T-cells as a double-pronged approach for treating acute myeloid leukemia. [2021]

4. Italy pubmed.ncbi.nlm.nih.gov

Anti-CD33 chimeric antigen receptor targeting of acute myeloid leukemia. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Gene-edited stem cells enable CD33-directed immune therapy for myeloid malignancies. [2020]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy and safety of universal (TCRKO) ARI-0001 CAR-T cells for the treatment of B-cell lymphoma. [2022]

7. England pubmed.ncbi.nlm.nih.gov

CD33-specific chimeric antigen receptor T cells exhibit potent preclinical activity against human acute myeloid leukemia. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

In Vitro and In Vivo Antitumor Effect of Anti-CD33 Chimeric Receptor-Expressing EBV-CTL against CD33 Acute Myeloid Leukemia. [2021]