Trem-cel, a CRISPR/Cas9 Gene-Edited Allograft Lacking CD33, Shows Rapid Primary Engraftment with CD33-Negative Hematopoiesis in Patients with High-Risk Acute Myeloid Leukemia (AML) and Avoids Hematopoietic Toxicity During Gemtuzumab Ozogamicin (GO) Maintenance Post-Hematopoietic Cell Transplant (HCT)
We are developing trem-cel as a Hematopoietic Stem Cell Transplant (HCT) product to replace the current standard of care in transplant settings. Once trem-cel has engrafted, patients can be treated with anti-CD33 therapies, such as Mylotarg™ or our CAR-T therapy product candidate VCAR33ALLO, with reduced on-target off-tumor toxicity.
VBP101, a Phase 1/2a clinical trial in patients with CD33-positive AML who are at high risk of relapse, is actively enrolling patients. The key goals of the trial are to evaluate tolerability and feasibility of the trem-cel stem cell transplant, with a focus on confirming that trem-cel can engraft normally. Following engraftment, patients will be eligible to be treated with Mylotarg, a CD33-directed Antibody Drug Conjugate (ADC) therapy, to potentially prolong leukemia-free survival and to provide evidence that trem-cel protects healthy blood cells against the myelosuppression that typically accompanies treatment with Mylotarg.
Trem-cel has been granted Orphan Drug Designation and Fast Track designation from the U.S. Food and Drug Administration.
A number of biologics investigated by third parties as potential therapeutics in AML and other blood cancers have been based on targeting CD33, which is expressed, on average, between 85 to 90% of bulk AML patient samples and over 75% of leukemic stem cells. [Source: Perna, Sadelain, et al. Cancer Cell. 2017]
CD33 is an attractive target for the development of AML therapeutics based on preclinical and clinical results from third parties demonstrating the ability of anti-CD33 directed therapies to deplete tumor cells. [References: 1. Sievers EL, et al. Blood. 1999;93(11):3678-3684. 2. Stein EM, et al. Blood. 2018;131(4):387-396]
However, CD33-directed therapeutic approaches have had limited impact in improving the prognosis of patients with AML due in part to on-target, off-tumor toxicity. This on-target toxicity can have myelosuppressive effects, such as neutropenia, which is an abnormally low number of certain white blood cells, and thrombocytopenia, which is an abnormally low number of platelets.
The only CD33 targeted therapy approved by the FDA for the treatment of AML is gemtuzumab ozogamicin, which is marketed by Pfizer under the brand name Mylotarg. Mylotarg is an ADC that targets CD33 on AML cells and is designed to deliver a potent cytotoxin directly to tumor cells.
However, due to the expression of CD33 on a broad set of hematologic progenitor cells, Mylotarg not only attacks AML cells, but it also depletes healthy blood cells, including HSCs and other progenitor cells that express CD33. In part, due to its toxicity profile, Mylotarg is currently used in a limited setting, in both first line and relapsed/refractory AML.
Without a solution to the problem of CD33 on-target off-tumor toxicity, we expect all CD33-targeted therapies to produce thrombocytopenia and neutropenia which may result in the same limits on clinical usage as Mylotarg.
We believe engineering the HSCs prior to transplant to remove CD33 is a unique approach designed to protect from on-target off-tumor toxicity and unlock the potential of CD33 as a therapeutic target. By removing CD33 expression in healthy blood cells, we expect to render these cells and their progeny treatment resistant to CD33-directed therapies, thereby providing robust protection from these therapies’ cytotoxic effects.
Trem-cel clinical data
Recent clinical data presented at the 65th American Society of Hematology (ASH) Annual Meeting demonstrated that all patients transplanted with trem-cel achieved primary engraftment as well as a high level of CD33-negative hematopoiesis. All patients achieved high levels of myeloid donor chimerism by day 28. Additionally, all three patients treated with Mylotarg have demonstrated durable hematologic protection from deep cypotenias through repeat doses, suggesting that trem-cel transplants shielded patients’ healthy cells from the on-target toxicity (myelosuppression) typically seen with Mylotarg treatment.
Cell doses for all patients were successfully manufactured and met release criteria, and all had a high level of CD33 editing efficiency.
Removal of CD33—no observed impact on biology
Data from our VBP101 trial suggest that CD33 may be biologically dispensable, as the time for neutrophil engraftment in all patients treated with trem-cel (8-11 days) was comparable to that of unedited transplants. In addition to pre-clinical and clinical data generated by Vor Bio, academic laboratories at Columbia University, the University of Pennsylvania, and the Fred Hutchinson Cancer Research Center have each conducted in vitro and in vivo experiments in model organisms with very similar findings, demonstrating that CD33 might be removed from HSCs without any deleterious impact on cell biology.
Further evidence of the non-essential nature of CD33 comes from existing human genetics data. To date, the gnomAD database maintained by the Broad Institute has identified 65 individuals with homozygous loss of function mutations in the CD33 gene who do not have any reported deleterious phenotypes. Similarly, we also identified 176 individuals with homozygous loss-of-function mutations in CD33 through the database maintained by the UK Biobank. This critical evidence supports the non-essential nature of CD33 function in humans, mitigating concerns associated with introducing CD33Del eHSCs in humans.
About the VBP101 clinical trial of trem-cel in combination with Mylotarg
VBP101 is our ongoing first-in-human Phase 1/2a trial of trem-cel in combination with Mylotarg.
The VBP101 trial is actively enrolling patients. This trial will provide important validating evidence of the potential of trem-cel and our broader eHSC approach. Clinical data presented at ASH 2023 was shared in December 2023.
Trem-cel with other targeted therapies
Mylotarg is currently the only anti-CD33 therapy approved by the FDA and is an Antibody Drug Conjugate (ADC). We believe that other anti-CD33 therapies that are not yet approved, such as our CAR-T product candidate, VCAR33ALLO (NCT05984199), may ultimately be better targeted therapies due to higher expected potency.
Different therapeutics may also be more suitable in various clinical settings and disease states. We therefore plan to support research and development efforts studying the benefits of trem-cel and other eHSC approaches with several targeted therapies using different treatment modalities with the intent of optimizing the potential for trem-cel and other eHSC programs to become a new standard of care in transplantation.
Trem-cel and Myelodysplastic Syndrome and Myeloproliferative Neoplasm
Other blood cancers overexpress CD33, including myelodysplastic syndrome (MDS) and myeloproliferative neoplasms (MPN). MDS consists of a spectrum of bone marrow cancers that are characterized by reduction in blood cell counts and an increase in immature blood cells in bone marrow.
MDS evolves into AML in up to 30% of cases. Similarly, MPNs are a group of blood cancers such as chronic myelogenous leukemia, chronic neutrophilic leukemia, polycythemia vera, primary myelofibrosis, and essential thrombocythemia where excessive fully differentiated blood cells are produced by the bone marrow, and these conditions can also evolve into more aggressive AML. Patients with these conditions can be segmented into different risk categories based on cell counts and cytogenetics, with intermediate- or high-risk patients often treated with HCT, and together MDS and MPN are the most common indications for allogeneic HCT outside of AML. Scientific evidence produced by third parties shows that blast cells responsible for MDS and MPN express CD33 and other myeloid cell surface targets. We believe trem-cel has the potential to enable the use of anti-CD33 therapies in those settings, and we are exploring the potential use of trem-cel in combination with targeted therapies in these indications.