Studies by several investigators have shown that 12-0-tetradecanoylphorbol-13-acetate (TPA) is an extraordinarily potent stimulator of differentiation of cultured human promyelocytic leukemia cells in vitro. In the present study, TPA was administered to humans by i.v. infusion without irreversible toxicity, and it was shown to have pharmacological activity for the treatment of myelocytic leukemia in patients refractory to cytosine arabinoside (Ara C), retinoic acid, and other antileukemic drugs. Marked decreases in bone marrow myeloblasts as well as temporary remission of disease symptoms were observed when TPA was administered alone or in combination with vitamin D 3 and Ara C. Additional studies with TPA after the determination of optimum dosing regimens are needed to determine whether long-lasting or permanent remissions of myelocytic leukemia can be achieved. Transient and reversible side effects were observed after a 1-mg i.v. dose of TPA, but these adverse effects became less intense or disappeared when a lower dose of TPA was used. The results of this study indicate a therapeutic effect of TPA in patients with myelocytic leukemia.

Fifty-two patients with solid tumors had depressed white blood cell and neutrophil counts because of prior treatment with cytotoxic cancer chemotherapeutic drugs. These patients were given one or more i.v. infusions of 0.125-0.25 mg of 12-O-tetradecanoylphorbol-13-acetate (TPA), and this treatment increased the low white blood cell and neutrophil counts toward the normal range. The average white blood cell and neutrophil counts were 2.55 ؋ 10 9 ͞liter and 1.76 ؋ 10 9 ͞liter, respectively, before treatment with TPA. After one or more i.v. infusions of TPA, the white blood cell and neutrophil counts increased to peak values of 5.92 ؋ 10 9 ͞liter and 4.76 ؋ 10 9 ͞liter, respectively, within a few days. Most patients had increased levels of white blood cells and neutrophils by 24 hr after a single i.v. infusion of 0.25 mg TPA. Elevated levels were observed for at least 3 days. This study demonstrates that treatment with parenteral TPA is feasible with useful biological activity. Only mild and reversible side effects were observed.12-O-Tetradecanoylphorbol-13-acetate (TPA) has a broad range of cellular and potentially useful pharmacological effects (1-3), but it was only recently studied in humans. In a pilot study, we found a therapeutic effect of intravenous infusions of TPA in patients with myelocytic leukemia who were refractory to other chemotherapeutic drugs (4). Myeloblasts in the bone marrow and peripheral blood were decreased, and several remissions were obtained (4). During the course of this earlier study in leukemia patients, we observed that TPA administration increased white blood cell (WBC) counts and neutrophils in several of the patients who previously had low WBC counts. Because granulocyte colony-stimulating factor (G-CSF) and granulocyte-monocyte colony-stimulating factor (GM-CSF) were not available to many patients, we obtained permission from the Central Hospital (Nan Yang, Henan) and the People's First Hospital of Nan Yang (Nan Yang, Henan) in the People's Republic of China to study the effects of i.v. infusions of TPA in patients who had low WBC counts because of prior treatment of solid tumors with one or more cytotoxic cancer chemotherapeutic drugs. In the present study, we show that i.v. infusion of TPA causes a rapid increase in WBC counts and neutrophils in the peripheral blood. METHODSTPA. Sterile ampules of TPA [0.25 or 0.5 mg in 2 ml of ethanol͞saline (65:35)] were prepared as described in our accompanying paper in this issue of the Proceedings (4). The ampules of TPA were supplied by Xichuan Pharmaceutical Co. (Nan Yang, Henan). Appropriate amounts of TPA were added to 200 ml of sterile saline for intravenous infusion. The intravenous infusion solutions were administered very slowly over a 1-hr interval.Peripheral Blood. Hemoglobin (Hb), WBC, red blood cells, neutrophils, lymphocytes, and platelets in peripheral blood were determined by routine clinical methods.Clinical Tests Used for Assessing Potential TPA Toxicity. Electrocardiogram evaluations were routinely undertaken, an...

To make primary origin clear and start systemic antitumor therapy is beneficial for patients with bone marrow metastases.

Background. Malignant fibrous histiocytoma (MFH) of the bone is a rare tumor. Most studies comparing limb salvage and amputation have reported that limb salvage had no adverse effect on the long-term survival of patients. This study evaluates the oncological outcomes of limb salvage procedures that were used for 15 patients with MFH of the humerus.

BackgroundAdenosine and TGFβ are two key immune suppressors in tumor microenvironment (“TME”) that cause broad immune suppression resulting in resistance to current CPI immunotherapies. Cancers frequently express transforming growth factor-β (TGFβ), which drives immune dysfunction in the tumor microenvironment by inducing regulatory T cells (Tregs), inhibiting CD8+ activation and infiltration into TME, and promoting epithelial–mesenchymal transition (EMT). We observed that TGFβ induces the expression of CD39, a critical enzyme that regulates adenosine generation. CD39 is highly expressed in Tregs within TME, it drives the production of adenosine, an immunoinhibitory molecule that partly mediates Treg inhibitory function. To inhibit CD39-Adenosine and TGFβ simultaneously to create an immune favorable tumor microenvironment, we designed a bi-specific antibody targeting both CD39 and TGFβ (ES014), which aims to inhibit the generation of adenosine and iTreg in TME. The immuno-stimulating effect of ES014 was demonstrated in a PD-1-unresponsive mouse model where tumor growth was significantly inhibited after the treatment of the bi-specific antibody.MethodsThe bifunctional antibody–ligand trap ES014 was created by fusing the TGFβ receptor II ectodomain to an antibody targeting CD39. ES014 molecule could simultaneously inhibit CD39 enzymatic function to prevent extracellular ATP from degradation and neutralize autocrine/paracrine TGFβ in the target cell microenvironment. The immunological function of ES014 was studied in an in vitro Elpiscience proprietary ImmunoShine platform which includes T cell activation and apoptosis assay, iTreg differentiation and suppression assay, NK cell activation assay and DC maturation activity. The in vivo efficacy of ES014 was investigated in a human PBMC engrafted cancer model.ResultsWe demonstrated that ES014 bispecific antibody can inhibit CD39 enzymatic activity and neutralizes TGFβ-induced effect, resulting in greater T cell activation and suppression of Treg differentiation. Interestingly, we found ES014 molecule demonstrated a unique mechanism by significantly protecting effector T cell from anti-Fas induced apoptosis or activation induced cell death (AICD) that is not observed in monotherapy or combo treatment. The ES014 molecule is more effective in inhibiting tumor growth as compared with anti-CD39 antibody or TGFβ-trap in a human PBMC engrafted in vivo model.ConclusionsWe find that by simultaneously targeting CD39 and TGFβ by a novel bi-specific molecule ES014, a more immune-favorable TME and synergistic anti-tumor effects can be achieved. Our pre-clinical data demonstrate that ES014 counteracts TGFβ-mediated inhibitory effect and adenosine induced immune tolerance and has a unique ability to protect T cell from apoptosis. ES014 demonstrated strong efficacy in in vivo tumor growth inhibition.