c-KIT-targeted antibody-drug conjugate 
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  • ||||||||||  Venclexta (venetoclax) / Roche, AbbVie, Melflufen (melphalan flufenamide) / Oncopeptides, OPDC3 / Oncopeptides
    Efficacy of the Peptide Drug Conjugates Melflufen and OPDC3 in Venetoclax Resistant Acute Myeloid Leukemia (Halls G-H (San Diego Convention Center)) -  Nov 6, 2024 - Abstract #ASH2024ASH_2690;    
    Background: The combination of BCL2 inhibitor venetoclax with a hypomethylating agent (azacitidine or decitabine) or low dose cytarabine has transformed acute myeloid leukemia (AML) treatment, especially for older patients who are unfit for intensive chemotherapy. Based on ex vivo, functional assessment, the peptide drug conjugates melflufen and OPDC3 are highly active in AML, especially in models with primary or acquired resistance to venetoclax and support further investigations of these drugs in venetoclax-resistant AML.
  • ||||||||||  doxycycline / Generic mfg.
    CCRL2 As a Novel Target in Acute Erythroid Leukemia (Seaport Ballroom ABCD (Manchester Grand Hyatt San Diego)) -  Nov 6, 2024 - Abstract #ASH2024ASH_2077;    
    Anti-CCRL2 ADC induces apoptosis and suppresses the clonogenicity of AEL cells showing no toxicity against healthy hematopoietic cells. CCRL2 is a promising target in AEL and the anti-CCRL2 ADC shows single-agent activity in this disease and can be potentially combined with currently available therapies for further improvement of its efficacy.
  • ||||||||||  Preclinical, Journal, IO biomarker:  CD56-targeted in vivo genetic engineering of natural killer cells mediates immunotherapy for acute myeloid leukemia. (Pubmed Central) -  Oct 31, 2024   
    The in vitro NK (EzH2-) cells and pEzH2@CSNPs@CD56 reduced splenomegaly while immunophenotyping revealed in vivo downregulation of the c-Kit+ leukemia stem cell population along with upregulation of the differentiation markers CD11b and Gr-1 in the peripheral blood and bone marrow of AML1-ETO9a-induced xenograft nude mice. CD56+CD3- and CD56+CD38+ cell populations were significantly increased in the peripheral blood and bone marrow, which indicated NK cell-mediated AML cell killing took place suggesting that use of pEzH2@CSNPs@CD56 is a safe and viable strategy for NK cell-mediated anti-AML immunotherapy.
  • ||||||||||  miransertib (MK-7075) / Merck (MSD), Gilotrif (afatinib) / Boehringer Ingelheim
    Journal:  The Combination of Afatinib With Dasatinib or Miransertib Results in Synergistic Growth Inhibition of Stomach Cancer Cells. (Pubmed Central) -  Mar 28, 2024   
    Of various human epidermal growth factor receptor (HER) inhibitors, only the anti-HER2 monoclonal antibody (mAb) Herceptin/trastuzumab and the antibody-drug conjugate trastuzumab deruxtecan (T-Dxd) has been approved for the treatment of patients with stomach cancer...Of various HER inhibitors, the irreversible pan-HER family inhibitors (e.g., afatinib) were more effective than the reversible dual epidermal growth factor receptor (EGFR)/HER2 tyrosine kinase inhibitor (TKI) lapatinib and the EGFR-specific TKI erlotinib in inhibiting the growth of HSCCLs. Of agents targeting different downstream cell signaling molecules, dasatinib targeting Ab1/Src/C-Kit, trametinib targeting MERK1/2 and miransertib targeting AKT1/2/3 inhibited growth of majority of HSCCLs, with the IC50 values ranging from 2 nM to 7
  • ||||||||||  NN3201 / Novelty Nobility
    NN3201, a novel c-Kit targeting ADC, exhibits robust preclinical anti-tumor efficacy in SCLC and GIST models (Section 21) -  Mar 5, 2024 - Abstract #AACR2024AACR_5310;    
    While imatinib, a small molecule c-Kit inhibitor, has been a beneficial treatment for GIST, resistance eventually develops to the drug, moreover, shows limited efficacy in c-Kit overexpressing tumors such as SCLC...Enhanced anti-tumor activity and delayed tumor growth were observed in an SOC-treated (etoposide and carboplatin) SCLC xenograft model, by NN3201 in comparison to second line SOC (topotecan or irinotecan)...We confirmed HNSTD (Highest Non-Severely Toxic Dose) of NN3201 to be 2 mg/kg through exploratory and GLP repeat dose toxicity studies as no serious irreversible toxicity was observed. Accumulating data suggest that NN3201 is a promising therapeutic alternative for the treatment of SCLC and GIST regardless of wild-type or activating mutations in c-Kit.
  • ||||||||||  Epitope editing enables targeted immunotherapy of acute myeloid leukemia (Room 14 - Mezzanine Level - Convention Center) -  Feb 5, 2024 - Abstract #AACR2024AACR_786;    
    Conclusion. We believe that epitope-engineering of HSPCs is a novel and highly promising technology that can enable safer and more effective immunotherapies when on-target/off-tumor toxicities are the key limiting factor to successful clinical translation.
  • ||||||||||  bortezomib / Generic mfg., lenalidomide / Generic mfg.
    Journal, Combination therapy, IO biomarker:  Myxoma Virus Combination Therapy Enhances Lenalidomide and Bortezomib Treatments for Multiple Myeloma. (Pubmed Central) -  Jan 22, 2024   
    The addition of MYXV resulted in a statistically significant increase in early apoptosis in both newly diagnosed and refractory MM patients. Our results highlight that patient-based therapy should also be considered for the effective management of MM.
  • ||||||||||  MGTA-117 / Magenta Therap, busulfan / Generic mfg.
    Journal, Gene therapy:  Fertility-preserving myeloablative conditioning using single-dose CD117 antibody-drug conjugate in a rhesus gene therapy model. (Pubmed Central) -  Nov 3, 2023   
    Thus, the myeloablative capacity of single-dose CD117-ADC is sufficient for efficient engraftment of gene-modified HSCs while preserving fertility and reducing adverse effects related to toxicity in non-human primates. This targeted conditioning approach thus provides the proof-of-principle to improve risk-benefit ratio in a variety of HSC-based gene therapy products in humans.
  • ||||||||||  Mylotarg (gemtuzumab ozogamicin) / UCB, PDL, Pfizer
    Base Edited HSPCs Are Shielded from Targeted CD33 Therapy but Preserve CD33 Expression (SDCC - Halls G-H) -  Nov 3, 2023 - Abstract #ASH2023ASH_4365;    
    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.
  • ||||||||||  Thymoglobulin (anti-thymocyte globulin (rabbit)) / Sanofi, briquilimab (JSP191) / Jasper Therap
    Radiation and Busulfan-Free Hematopoietic Stem Cell Transplantation Using Briquilimab (JSP191) Anti-CD117 Antibody-Conditioning, Transient Immunosuppression and TCRa (Marriott Marquis - Marriott Grand) -  Nov 3, 2023 - Abstract #ASH2023ASH_1255;    
    Overall, these data indicate that an ADC-based targeted approach offers safer conditioning and could improve the risk-benefit profile in HSC gene therapy. Objective: To reduce acute and long-term treatment-related toxicities, we have developed a first of its kind treatment intended to improve the safety of allo-HSCT through: 1) a TBI- and busulfan-free conditioning regimen consisting of briquilimab, rabbit ATG (rATG - Thymoglobulin), fludarabine, cyclophosphamide and rituximab - briquilimab (formerly called JSP191) is a monoclonal antibody (mAb) that targets human CD117 to deplete host HSCs enabling blood and immune reconstitution with minimal toxicity with the other agents being used for transient immune suppression to prevent immunologic rejection; 2) transplantation of TCRa
  • ||||||||||  Characterization and Cure of a New Mouse Model of alpha-Thalassemia Major (Room 409 AB) -  May 3, 2023 - Abstract #ASGCT2023ASGCT_2073;    
    Objective: To reduce acute and long-term treatment-related toxicities, we have developed a first of its kind treatment intended to improve the safety of allo-HSCT through: 1) a TBI- and busulfan-free conditioning regimen consisting of briquilimab, rabbit ATG (rATG - Thymoglobulin), fludarabine, cyclophosphamide and rituximab - briquilimab (formerly called JSP191) is a monoclonal antibody (mAb) that targets human CD117 to deplete host HSCs enabling blood and immune reconstitution with minimal toxicity with the other agents being used for transient immune suppression to prevent immunologic rejection; 2) transplantation of TCRa The features of these animals (hypoxia, persistent and high levels of RBC in circulation) are remarkably similar to patients affected by Bart
  • ||||||||||  Preclinical, Journal:  In Vivo RNA Delivery to Hematopoietic Stem and Progenitor Cells via Targeted Lipid Nanoparticles. (Pubmed Central) -  Mar 30, 2023   
    This targeted delivery system does not require stem cell harvest, culture, or mobilization of HSCs to facilitate delivery. We also show that delivery of Cre recombinase mRNA at a dose of 1 mg kg can facilitate gene editing to almost all (?90%) hematopoietic stem and progenitor cells (HSPCs) in vivo, and edited cells retain their stemness and functionality to generate high levels of edited mature immune cells.
  • ||||||||||  MGTA-117 / Magenta Therap
    Journal:  Non-Genotoxic Restoration of the Hematolymphoid System in Fanconi Anemia. (Pubmed Central) -  Mar 4, 2023   
    In addition, they show that if sufficient immunosuppression is given to obtain initial donor HSC engraftment, resulting turnover of a majority of the hematolymphoid system can occur likely due to the survival advantage of WT HSCs over FA HSCs. Such non-toxic all antibody-based conditioning strategy could be transformative for FA patients and those with other hematolymphoid diseases.
  • ||||||||||  Immunophenotypic profile of acute leukemia in yemen (In-Person) -  Jan 13, 2023 - Abstract #HEMATOLOGY2023HEMATOLOGY_19;    
    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.