CD33 expression

CD33PAN moieties were detected at a higher frequency on human leukemic stem cells, and CD33PAN CAR T cells had greater in vitro efficacy against primary human AML cells. Together, our studies demonstrate improved efficacy with CAR T cells binding CD33 close to the cell membrane, providing the rationale to investigate CD33PAN CAR T cells further toward possible clinical application.

P1, N=18, Suspended, Uma Borate | Recruiting --> Suspended

P1/2, N=52, Recruiting, Center for International Blood and Marrow Transplant Research | Active, not recruiting --> Recruiting | Trial primary completion date: Dec 2024 --> Dec 2029

P2, N=16, Active, not recruiting, Robert Redner, MD | Completed --> Active, not recruiting | Trial completion date: Feb 2023 --> Dec 2028

P1, N=18, Recruiting, Uma Borate | Trial primary completion date: Jan 2024 --> Jan 2025

P1/2, N=24, Recruiting, Vor Biopharma | N=18 --> 24 | Trial completion date: Sep 2025 --> Jan 2027 | Trial primary completion date: Dec 2023 --> Feb 2025

Depletion of CD123 and CD33 expressing cells was observed, without signs of cytokine release syndrome nor clinical signs of toxicity. Taken together, the CD33/CD123 dual-targeting NANOBODY® TCE exhibits potent and safe anti-AML activity and promises a broad patient coverage.

Sinusoidal obstruction syndrome occurred in two children. The use of GO in severely pretreated children, including those under 15 years of age, with previous failure of AML treatment is a feasible and effective bridging therapy to allo-HSCT with an acceptable toxicity profile.

P1, N=18, Active, not recruiting, John Quigley | Recruiting --> Active, not recruiting

Trem-cel (formerly VOR33) is manufactured from CD34+ cells isolated from matched-donor apheresis and modified by CRISPR/Cas9 gene-editing to remove CD33, with the goal of protecting normal hematopoietic cells from post-HCT CD33-directed therapies...Donors undergo mobilization with G-CSF and plerixafor prior to apheresis and manufacturing of trem-cel... Initial results demonstrate trem-cel has rapid primary neutrophil engraftment similar to non-edited CD34-selected grafts (Luznik et al 2022, JCO 40:356-368) and a high CD33 editing efficiency leading to a majority of myeloid cells lacking CD33 expression and supporting the biologic dispensability of CD33. The exposure at 0.5mg/m2 GO dose corresponded to higher doses of GO in AML patients, possibly due to reduction of the CD33 hematopoietic antigen sink. Minimal cytopenias have been observed thus far after treatment with GO, supporting the hypothesis that CD33 deletion can protect donor cells from CD33-targeted therapies.

We observed that AML samples with comparable FEC levels or clinical characteristics could be defined by different sets of unbalanced processes, implying that this information might be used to determine tailored therapies in subgroups of individuals with similar clinical or thermodynamic characteristics. We showed that mapping FEC into an AML state-space given by ST critical points could provide a high resolution, patient-specific disease characterization, and these methods could be used in personalized diagnostics and individualized treatment procedures.

All-trans retinoic acid and arsenic trioxide is able to cure 90% of APL patients by targeting PML-RARα...The PI3K inhibitor LY294002 and the autophagy inhibitor Baf A1 were combined and applied to observe the changes in the levels of PML A216V-RARα, mTOR and p62 after blocking the PI3K or autophagy pathway... The arsenic-resistant cell line HL60-PML A216V-RARα was successfully established. Compared with the control group, A, ITS and AITS groups all inhibited the growth of HL60-PML A216V-RARα cells in a time-dependent manner ( P < 0. 0001).

This study presents an innovative approach with the potential to predict GO responders versus non-responders in AML. A single phenotypic biomarker overcomes the need to determine CD33 expression levels in each patient or to assess the presence of specific polymorphic variants, as well as additional molecular biomarkers. Patient Micro Avatars present a compelling alternative to comprehensively identify patients who are most likely to benefit from GO treatment.

P1/2, N=52, Active, not recruiting, Center for International Blood and Marrow Transplant Research | Recruiting --> Active, not recruiting | N=37 --> 52

Our findings demonstrated that ZNF384 rearrangement might induce antigen editing during treatment-related selective pressures in adult B cell acute lymphoid leukemia, especially in CAR-T therapy. More efforts are needed to reveal mechanisms behind it to help reduce antigen loss and relapse rate after CAR-T therapy.

This analysis suggests that stem cell program reactivation and atypical marker expression characterize early WM clones that are ultimately replaced by clones exhibiting more typical B-cell markers with disease progression. The findings may be relevant to treatment selection and provide a framework for investigating subtype and early/late evolutionary staging in the treatment approach to WM.

However, targeting CD33 e.g. with the antibody-drug conjugate (ADC) gemtuzumab ozogamicin often leads to prolonged cytopenia due to suppression of normal myelopoiesis...Similar to HSPCs devoid of CD33 these engineered cells could enable tumor-selective immunotherapy using ADCs or CAR T cells but with preserved CD33 expression and function. Furthermore, since base editing is suitable for multiplexing, they may in the future be multiplexed to protect CD33 and other targets for combination immunotherapy.

Tremtelectogene empogeditemcel (trem-cel; formerly VOR33) is a hematopoietic stem and progenitor cell product, manufactured from CD34+ cells isolated from a patient-matched donor, that has been modified by CRISPR/Cas9 gene-editing to lack CD33...Donors undergo mobilization with G-CSF and plerixafor prior to apheresis...Patients undergo either a busulfan- or TBI-based myeloablative conditioning regimen prior to transplantation with trem-cel... To date, 6 patients between 32-68 y (median 63.5 y) have been treated with trem-cel at a median dose of 5.2 x 106 CD34+ cells/kg (2.6 - 7.6) and CD33 editing efficiency of 88% (80 – 91). Primary neutrophil engraftment occurred in all patients after a median of 10 days (9 – 11) and platelet recovery occurred after a median of 16 days (15-22) excluding one patient with documented anti-platelet antibody (Fig 1). At the day 28 assessment, full peripheral blood (PB) myeloid chimerism was achieved in all patients and CD33 expression by flow was absent in a median of 94% of neutrophils (86–99) and 92% of monocytes (82 - 94), respectively.

To summarize, we show that normal myeloid cells have beneficial effects on CAR T cell function, and targeting these same myeloid cells is detrimental to CAR T cell activity. These findings provide insight into the reason for suboptimal CAR T cell activity in AML, and show that independent of target antigen and CAR construct, the nature of the cells being targeted can change the effectiveness of this therapy.

Patients with both non-mutated KIT exon 17 and negative MRD have the best prognosis, while positive MRD and KIT exon 17 mutations are associated with poorer outcomes. These findings indicated that integrated analysis of flow-MRD and KIT exon 17 status enables optimal risk assignment strategies in pediatric AML with RUNX1::RUNX1T1.

CD33 is widely expressed by myeloid cells and is a validated drug target in acute myeloid leukemia (AML), as shown by the benefit of some patients from the CD33 antibody-drug conjugate gemtuzumab ozogamicin (GO)...In summary, our findings demonstrate that BMS-986357 TriNKET® has potent CD33-dependent cytolytic activity in vitro against human AML cells, supporting the drug's exploration in early phase clinical trials. One such trial (NCT04789655) has opened accrual for adults with relapsed/refractory AML.

CD33-M2T has demonstrated clear advantages over anti-CD33 monoclonal antibodies (e. g. , gemtuzumab, lintuzumab), including the ability to bind to the truncated alternatively spliced version of CD33, long duration of action, and no overt toxicities in mice. Conclusions These experiments demonstrate the preclinical potential of an innovative immunotherapy targeting CD33-positive childhood AML.

Myeloblasts become megakaryoblastic over time in some MDS patients, and examining the megakaryocyte lineage (not only as a diagnostic work-up but also as follow-up) is needed to detect CD41+ MDS. The immunophenotypic features revealed in this study may have diagnostic relevance for CD41+ MDS patients.

Induction consisted of G-CSF, 300mcg/d, given D1-6, cladribine 5mg/m2, given D2-6, cytarabine 2g/m2, given D2-6, and mitoxantrone 10mg/m2, given D2-4. CLAG-M followed by Lintuzumab-Ac225 yielded significantly better clinical outcomes in high-risk populations, particularly in patients previously treated with venetoclax combinations. The results further support the late-stage clinical development of Lintuzumab-Ac225 in combination with CLAG-M in R/R AML.

P1, N=102, Not yet recruiting, Institute of Hematology & Blood Diseases Hospital

Acute myeloid leukemia with altered SRSF2 shows a variable degree of morphologic dysplasia without uniform immunophenotypic aberrancies. SRSF2 mutations appear to be independent poor prognostic factors, but allo-SCT has improved the clinical outcomes in patients with SRSF2-mutant AML.

The primary endpoints of the trial of event-free survival and overall survival were not met. However, an anti-leukaemic efficacy of gemtuzumab ozogamicin in participants with NPM1-mutated acute myeloid leukaemia is shown by a significantly lower cumulative incidence of relapse rate, suggesting that the addition of gemtuzumab ozogamicin might reduce the need for salvage therapy in these participants. The results from this study provide further evidence that gemtuzumab ozogamicin should be added in the standard of care treatment in adults with NPM1-mutated acute myeloid leukaemia.

P2, N=16, Completed, Robert Redner, MD | Recruiting --> Completed | N=53 --> 16 | Trial completion date: Dec 2029 --> Feb 2023 | Trial primary completion date: Dec 2028 --> Jan 2023

P1/2, N=18, Recruiting, Vor Biopharma | Trial primary completion date: May 2023 --> Dec 2023

In real-world practice, CD13/CD33 expression can predict the risk of MRD in patients without TKI experience, but has no adverse effect on the prognosis of adult B-ALL patients. Incorporating CD13/CD33 into the standard antibody panels of B-ALL diagnosis and MRD measurements can help predict relapse risk and decisions on therapy options.

Also, we addressed predictors of response, being CD33 expression and SNPs, PgP-1 and Annexin A5. The near finalized intent-to-file clinical trial in the MyeChild consortium investigates whether fractionated dosing has additional value for pediatric AML, which may pave the way for a broader application of GO in pediatric AML.

P2, N=53, Recruiting, Robert Redner, MD | Trial completion date: Nov 2024 --> Dec 2029 | Trial primary completion date: Oct 2024 --> Dec 2028

P2, N=36, Recruiting, University of Washington | Trial completion date: Jun 2024 --> Dec 2024 | Trial primary completion date: Jun 2024 --> Dec 2024

Clinical Trial Registry : NCT04849910 Background: In order to reduce AML relapse post-HCT, a CD33 CRISPR/Cas9 gene-edited donor allograft, tremtelectogene empogeditemcel (trem-cel), formerly VOR33, was developed to enable post-HCT CD33-directed therapies while protecting healthy donor cells from on-target myelosuppression... A 64 y-old F patient with relapsed CD33+ TP53 mutant AML, adverse cytogenetics, and CRi with measurable residual disease (MRD; 1.8% bone marrow [BM] blasts), underwent myeloablative busulfan/melphalan/fludarabine/ATG conditioning followed by HCT with trem-cel. Trem-cel was manufactured from G-CSF + plerixafor-mobilized cells from an HLA-matched (10/10) unrelated donor and was composed of 7.6 x 106 CD34+ cells/kg with 88% CD33 deletion... This is the first report of successful engraftment of a CD33-edited allogeneic donor graft and toleration of post-HCT GO. Engraftment was comparable to similarly treated patients who received non-edited CD34-selected grafts (median 11 days) (Luznik et al 2022, JCO 40:356-368). Consistent with high CD33 editing efficiency in trem-cel, the majority of PB and BM myeloid cells lacked CD33 expression.

Background: In order to reduce AML relapse post-HCT, a CD33 CRISPR/Cas9 gene-edited donor allograft, tremtelectogene empogeditemcel (trem-cel), formerly VOR33, was developed to enable post-HCT CD33-directed therapies while protecting healthy donor cells from on-target myelosuppression... A 64 y-old F patient with relapsed CD33 + TP53 mutant AML, adverse cytogenetics, and CRi with measurable residual disease (MRD; 1.8% bone marrow [BM] blasts), underwent myeloablative busulfan/melphalan/fludarabine/ATG conditioning followed by HCT with trem-cel. Trem-cel was manufactured from G-CSF + plerixafor-mobilized cells from an HLA-matched (10/10) unrelated donor and was composed of 7.6 x 10 6 CD34 + cells/kg with 88% CD33 deletion... This is the first report of successful engraftment of a CD33-edited allogeneic donor graft and toleration of post-HCT GO. Engraftment was comparable to similarly treated patients who received non-edited CD34-selected grafts (median 11 days) (Luznik et al 2022, JCO 40:356-368). Consistent with high CD33 editing efficiency in trem-cel, the majority of PB and BM myeloid cells lacked CD33 expression.

Acute leukemia in Yemen was equally prevalent between adults and children with slightly more prevalent among males. Flow cytometry, even with a 3-colour strategy, is able to give useful diagnostic information about cell lineage of acute leukaemias. This has proven beneficial for patient management.

P1, N=12, Not yet recruiting, German Cancer Research Center

P1/2, N=214, Recruiting, Technische Universität Dresden | Active, not recruiting --> Recruiting | N=11 --> 214 | Trial primary completion date: Aug 2021 --> Apr 2027

We plan to expand accrual to this cohort adding 6-12 pts. This trial is registered at clinicaltrials.gov as NCT040768.

These results showed similar trends to the clinical samples implying that differences in CD33 SNPs affect the amount of total CD33 expression on the cell surface itself.Conclusion :The CD33 rs12459419 SNP regulated the expression level of total CD33 in clinical samples and gene-edited cell lines.There was no obvious difference in the expression levels of total CD33 and CD33FL at the cell surface between the CC and CT types, but it was higher than that of the TT type. The difference in CD33 expression may influence the therapeutic efficacy of GO.