Hematopoiesis, Malignant Hematology, Immunology
Abbreviation used: EDT, Experimental and Developmental Therapeutics
Dr. Hal Broxmeyer’s group found that inhibition of CD26/DPPIV on donor mouse bone marrow cells with small peptides (ILE-PPO-ILE=Diprotin A, or VAL-PYR) enhanced the engraftment of a long-term repopulating self-renewing population of HSC in lethally-irradiated congenic mice in a competitive and non-competitive transplant setting. This group, along with other colleagues, also showed that pretreating CD34+ cells from normal donors with Diprotin A enhanced their engraftment in sub-lethally-irradiated mice with a NOD/SCID genotype. Based on these and other studies, a pilot study was initiated under the direction of Dr. Sherif Farag in which single collections of cord blood (with either four of six or five of six HLA matched cells) were transplanted into end-stage patients with leukemia and lymphoma who were given myeloablative conditioning and treated with an orally active DPPIV inhibitor. More than 15 patients have been treated, with encouraging results. More patients will be treated to statistically analyze the results.
Dr. Louis Pelus’s group found that the non-steroidal anti-inflammatory drug (NSAID), Meloxicam, enhances mobilization of HSCs and hematopoietic progenitor cells (HPCs) from mice and baboons. Drs. Farag and Pelus demonstrated that Meloxicam increases HSC/HPC mobilization in normal healthy volunteers. A pilot study to enhance mobilization of HSC/HPC by Meloxicam, alone and in combination with granulocyte-colony stimulating factor (G-CSF) is underway.
Drs. Christopher Touloukian, Robert Nelson, Kenneth Cornetta and Theodore Logan (EDT) have a pilot phase I study in preparation to treat patients with metastatic melanoma through infusion of gene-modified autologous G-CSF peripheral blood mobilized CD34+ cells. They hope to determine overall safety and toxicity.
Drs. Michael Robertson and Mark Kaplan continue their clinical collaboration evaluating the treatment of patients with relapsed/refractory B cell lymphoma in a phase I clinical trial of IL-18 and Rituximab.
Drs. Robertson and Shivani Srivastava are working on IL-18 augmentation of antibody dependent cellular toxicity (ADCC) against rituximab-sensitized human B cell lines in vitro.
Drs. Reuben Kapur, H. Scott Boswell and colleagues have discovered a potential therapeutic target for treating hematological malignancies involving mutation of FLT3, KIT and BCR-ABL that may otherwise be resistant to imatinab and similar next generation tyrosine kinase inhibitors. Also, they found that using genetic approaches and a novel SHP2 inhibitor, II-BO8, identified from a focused library of indole-based salicylic acid derivatives, along with targeting a lipid kinase, may be useful for treating myeloproliferative neoplasms.