Stem Cell Trafficking and Mobilization

Hematopoietic stem cell transplants (HSCT) are currently the only cure for many hematological diseases including both malignant and non-malignant diseases such as hemoglobinopathies, autoimmune diseases, and inherited disorders of metabolism. One of the key difficulties for this therapy is obtaining enough hematopoietic stem or progenitor cells (HSPC) from a patient or donor to enable a transplant.

(Dr. Michael Rettig, Peter Ruminski, Dr. Darja Karpova, Megh Singh, Dr. Ezhil Chendamarai, Stephanie Christ, and Julie Ritchey)

 
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From Rettig, Ansstas, Dipersio, Leukemia 26 (2012):34-53.

 

We are targeting key elements of the hematopoietic niche for optimal stem cell mobilization and leukemia chemosensitization.

 

Novel hematopoietic stem cell (HSC) mobilization regimens that are less toxic, more rapid, and more potent than currently approved treatments (G-CSF alone or in combination with the CXCR4 inhibitor plerixafor) are needed to improve outcomes, reduce cost, and shorten treatment time. We are combining novel VLA-4 inhibitors with known CXCR4 inhibitors and/or a CXCR2 agonist to create a rapid, safe and efficient stem cell mobilization regimen.  Similar strategies might mobilize leukemic blasts from the bone marrow rendering them more sensitive to salvage chemotherapy.  This could thereby prolong the survival of patients with relapsed/refractory disease.

Our medicinal chemists are developing proprietary high potency VLA-4 inhibitors with superior pharmacologic properties. Our lead compound has excellent aqueous solubility and mobilizes more murine HSPCs for a significantly longer time period than previously reported small molecule VLA-4 inhibitors when administered alone or in combination with a CXCR4 inhibitor. When combined with plerixafor, it mobilizes an equivalent amount of HSPCs over a 6 hour period after just one dose, as opposed to 5 days or more of daily G-CSF dosing. We are continuing to optimize these compounds to develop a superior HSPC mobilization regimen for use in HSCT and gene therapy.

We also collaborate with other academic or industry partners to assess their proprietary mobilizing agents in preclinical studies, clinical trials, and correlative research associated with the trials.

 

 Key Publications

 

  • Uy GL, Rettig MP, Motabi IH,McFarland K, Trinkaus KM, Hladnik LM, Dulkarni S, Abboud CN, Cashen AF, Stockerl-Goldstein KE, Vij R, Westervelt P, and DiPersio JF.  A phase I/II study of chemosensitization with the CXCR4 antagonist plerixafor in relapsed or refractory acute myeloid leukemia.  Blood 119(17);3917-24:2012.  PMID 22308295

  • Schroeder MA, Rettig MP, Lopez S, Christ S, Fiala M, Eades W, Mir FA, Shao J, McFarland K, Trinkaus K, Shannon W, Deych E, Yu J, Vij R, Stockerl-Goldstein K, Cashen AF, Uy GL, Abboud CN, Westervelt P, and DiPersio JF.  Mobilization of allogeneic peripheral blood stemcell donors with intravenous plerixafor mobilizes a unique graft.  Blood 2017 May 11;129(19):2680-2692. doi: 10.1182/blood-2016-09-739722. Epub 2017 Mar 14. PMID: 28282847.

  • Karpova D, Ritchey JK, Holt MS, Abou-Ezzi G, Monlish D, Batoon L, Millard S, Spohn G, Wiercinska E, Chendamarai E, Yang W, Christ S, Gehrs L, Schuettpelz LG, Dembowsky K, Pettit AR, Rettig MP, Bonig H, and DiPersio JF.  Continuous blockade of CXCR4 results in dramatic mobilization and expansion of hematopoietic stem and progenitor cells.  Blood 2017 May 25;129(21):2939-49. doi: 10.1182/blood-2016-10-746909. Epub 2017 Apr 11. PMID 28400375.

  • Karpova D, Rettig MP, Ritchey J, Cancilla D, Christ S, Gehrs L, Chendamarai E, Evbuomwan MO, Holt M, Zhang J, Abou-Ezzi G, Celik H, Wiercinska E, Yang W, Gao F, Eissenberg LG, Heier RF, Arnett SD, Meyers MJ, Prinsen MJ, Griggs DW, Trumpp A, Ruminski PG, Morrow DM, Bonig HB, Link DC and DiPersio JF.  Targeting VLA4 Integrin and CXCR2 Mobilies Serially Repopulating Hematopoietic Stem Cells.  J. Clin Invest. 2019 May 14;129(7):2745-2759. doi: 10.1172/JCI124738.  PMID: 31085833.

  • Ghobadi A, Fiala MA, Rettig MP, Schroeder MA, Uy GL, Stockerl Goldstein KE, Westervelt P, Vij R, DiPersio JF. A Phase I Study of the Safety and Feasibility of Bortezomib in Combination With G-CSF for Stem Cell Mobilization in Patients With  Multiple Myeloma. Clin Lymphoma Myeloma Leuk 2019 Oct;19(10):e588-e593

  • Karpova D, Rettig MP, DiPersio JF. Mobilized Peripheral Blood: An Updated Perspective. F1000Res 2019 Dec 20;8

  • Cancilla D, Rettig MP, DiPersio JF. Targeting CXCR4 in AML and ALL. Front Oncol 2020 Sep 4;10:1672

  • Karpova D, Rettig MP, Ritchey J, Cancilla D, Christ S, Gehrs L,  Chendamarai E, Evbuomwan MO, Holt M, Zhang J, Abou-Ezzi G, Celik H,  Wiercinska E, Yang W, Gao F, Eissenberg LG, Heier RF, Arnett SD, Meyers  MJ, Prinsen MJ, Griggs DW, Trumpp A, Ruminski PG, Morrow DM, Bonig  HB, Link DC, DiPersio JF. Targeting VLA4 Integrin and CXCR2 Mobilizes Serially Repopulating Hematopoietic Stem Cells. J Clin Invest 2019 May 14;130

  • Fontana F, Scott MJ, Allen JS, Yang X, Cui G, Pan D, Yanaba N, Fiala MA,  O'Neal J, Schmieder-Atteberry AH, Ritchey J, Rettig M, Simons K,  Fletcher S, Vij R, DiPersio JF, Lanza GM. VLA4-Targeted Nanoparticles Hijack Cell Adhesion-Mediated Drug Resistance to Target Refractory Myeloma Cells and Prolong Survival. Clin Cancer Res 2021 Apr 1;27(7):1974-1986

  • Huselton E, Rettig MP, Fletcher T, Ritchey J, Gehrs L, McFarland K, Christ  S, Eades WC, Trinkaus K, Romee R, Kulkarni S, Ghobadi A, Abboud C,  Cashen AF, Stockerl-Goldstein K, Uy GL, Vij R, Westervelt P, DiPersio JF,  Schroeder MA. A Phase I Trial Evaluating the Effects of Plerixafor, G-CSF, and Azacitidine for the Treatment of Myelodysplastic Syndromes. Leuk Lymphoma 2021 Jun;62(6):1441-1449

  • Huselton E, Rettig MP, Campbell K, Cashen AF, DiPersio JF, Gao F,  Jacoby MA, Pusic I, Romee R, Schroeder MA, Uy GL, Marcus S,  Westervelt P. Combination of Dociparstat Sodium (DSTAT), a CXCL12/CXCR4 Inhibitor, With Azacitidine for the Treatment of Hypomethylating  Agent Refractory AML and MDS. Leuk Res 2021 Nov;110:106713

  • Hathi D, Chanswangphuwana C, Cho N, Fontana F, Maji D, Ritchey J, O'Neal J, Ghai A, Duncan K, Akers WJ, Fiala M, Vij R, DiPersio JF, Rettig M, Shokeen M. Ablation of VLA4 in Multiple Myeloma Cells Redirects Tumor Spread and Prolongs Survival. Sci Rep 2022 Jan 7;12(1):30

  • Yao L, Wang JT, Jayasinghe RG, O'Neal J, Tsai CF, Rettig MP, Song Y, Liu R, Zhao Y, Ibrahim OM, Fiala MA, Fortier JM, Chen S, Gehrs L, Rodrigues FM, Wendl MC, Kohnen D, Shinkle A, Cao S, Foltz SM, Zhou DC, Storrs E, Wyczalkowski MA, Mani S, Goldsmith SR, Zhu Y, Hamilton M, Liu T, Chen F, Vij R, Ding L, DiPersio JF. Single-Cell Discovery and Multiomic Characterization of Therapeutic Targets in Multiple Myeloma. Cancer Res 2023 Apr 14;83(8):1214-1233

  • Crees ZD, Rettig MP, Jayasinghe RG, Stockerl-Goldstein K, Larson SM, Arpad I, Milone GA, Martino M, Stiff P, Sborov D, Pereira D, Micallef I, Moreno-Jimenez G, Mikala G, Coronel MLP, Holtick U, Hiemenz J, Qazilbash MH, Hardy N, Latif T, Garcia-Cadenas I, Vainstein-Haras A, Sorani E, Gliko-Kabir I, Goldstein I, Ickowicz D, Shemesh-Darvish L, Kadosh S, Gao F, Schroeder MA, Vij R, DiPersio JF. Motixafortide and G-CSF to Mobilize Hematopoietic Stem Cells for Autologous Transplantation in Multiple Myeloma: A Randomized Phase 3 Trial. Nat Med 2023 Apr;29(4):869-879

  • Crees ZD, Rettig MP, DiPersio JF. Innovations in Hematopoietic Stem-Cell Mobilization: A Review of the Novel CXCR4 Inhibitor Motixafortide.  Ther Adv Hematol 2023 May 23;14:20406207231174304

  • Crees ZD, Rettig MP, Bashey A, Devine SM, Jaglowski SM, Wan F, Zhou A, Harding M, Vainstein-Haras A, Sorani E, Gliko-Kabir I, Grossman BJ, Westervelt P, DiPersio JF, Uy GL. Hematopoietic Stem Cell Mobilization for Allogeneic Stem Cell Transplantation by Motixafortide, a Novel CXCR4 Inhibitor. Blood Adv 2023 Jun 16:bloodadvances2023010407; [ahead of print]