Mesenchymal stromal cells as vehicles of tetravalent bispecific Tandab (CD3/CD19) for the treatment of B cell lymphoma combined with IDO pathway inhibitor d-1-methyl-tryptophan

Abstract

BackgroundAlthough blinatumomab, a bispecific T cell engaging antibody, exhibits high clinical response rates in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia (B-ALL) and B cell non-Hodgkin’s lymphoma (B-NHL), it still has some limitations because of its short half-life. Mesenchymal stromal cells (MSCs) represent an attractive approach for delivery of therapeutic agents to cancer sites owing to their tropism towards tumors, but their immunosuppression capabilities, especially induced by indoleamine 2,3-dioxygenase (IDO), should also be taken into consideration.MethodsHuman umbilical cord-derived MSCs (UC-MSCs) were genetically modified to secrete Tandab (CD3/CD19), a tetravalent bispecific tandem diabody with two binding sites for CD3 and two for CD19. The tropism of MSCs towards Raji cells in vitro was determined by migration assays, and the homing property of MSCs in vivo was analyzed with firefly luciferase-labeled MSCs (MSC-Luc) by bioluminescent imaging (BLI). The cytotoxicity of T cells induced by MSC-secreting Tandab (CD3/CD19) was detected in vitro and in vivo in combination with d-1-methyl-tryptophan (D-1MT), an IDO pathway inhibitor.ResultsThe purified Tandab (CD3/CD19) was functional with high-binding capability both for CD3-positive cells and CD19-positive cells and was able to induce specific lysis of CD19-positive cell lines (Raji, Daudi, and BJAB) in the presence of T cells. Additionally, results from co-culture killing experiments demonstrated that Tandab (CD3/CD19) secreted from MSCs was also effective. Then, we confirmed that D-1MT could enhance the cytotoxicity of T cells triggered by MSC-Tandab through reversing T cell anergy with down-regulation of CD98 and Jumonji and restoring the proliferation capacity of T cells. Furthermore, MSC-Luc could selectively migrate to tumor site in a BALB/c nude mouse model with Raji cells. And mice injected with MSC-Tandab in combination with D-1MT significantly inhibited the tumor growth.ConclusionsThese results suggest that UC-MSCs releasing Tandab (CD3/CD19) is an efficient therapeutic tool for the treatment of B cell lymphoma when combined with D-1MT.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0397-z) contains supplementary material, which is available to authorized users.

JNKi- and DAC-programmed mesenchymal stem/stromal cells from hESCs facilitate hematopoiesis and alleviate hind limb ischemia

“…5 The Enterprise Postdoctoral Working Station, Tianjin Chase Sun Pharmaceutical Co., Ltd., Tianjin 301700, China. 6 Precision Medicine Division, Health-Biotech (Tianjin) Stem Cell Research Institute Co., Ltd., Tianjin 301700, China. 7 Jiangxi Research Center of Stem Cell Engineering, Jiangxi Health-Biotech Stem Cell Technology Co., Ltd., Shangrao 334000, China.…”

“…Conclusively, the therapeutics of hESC-MSCs revealed beneficial effects on structural and functional recovery of ischemic muscles in the hind limb ischemia model. Previously, we and other investigators have demonstrated the unique properties of adult tissue-derived MSCs in fundamental research and clinical application [6,8,12,13,19]. However, those cell sources have a number of limitations as well, such as limited long-term in vitro proliferative capacity, donor-specific variability in quality, onset of replicative senescence, and decreased therapeutic potency after continuous in vitro passages [13].…”

“…Owning to the self-renewal capacity, multi-lineage differentiation potential, immunosuppressive property, and paracrine mechanism, mesenchymal stem/stromal cells (MSCs) have been demonstrated a promising source for regenerative medicine [1]. To date, adult tissue-derived MSCs are most commonly used for more than 300 clinical trials [2,3], especially for cell-based therapies in amounts of disease treatments, including diabetes, hypertension, arthritis, liver cirrhosis, autoimmune disorders, wound repair, myocardial ischemia, and hematopoietic reconstitution [4][5][6][7][8][9][10][11]. However, these adult MSCs have several disadvantages and limitations [12], including the instability and heterogeneity of the source, and decreased therapeutic efficacy after ex vivo expansion [13].…”

Advances in targeted therapy for malignant lymphoma

“…In vitro, TandAb can induce the specific lysis of CD19 + cell lines in the presence of T cells, and an IDO inhibitor could enhance the cytotoxicity of T cells triggered by MSC-TandAb. 419 Clinical studies of IDO inhibitors in lymphomas are still lacking. V-domain immunoglobulin suppressor of T-cell activation (VISTA) is another checkpoint molecule that has a strong inhibitory influence on T cells.…”

Rhein enhances the cytotoxicity of effector lymphocytes in colon cancer under hypoxic conditions

“…no. 06366236001; Roche Molecular Diagnostics, Pleasanton, CA, USA) to produce the lentivirus (17). HT29 cells were transduced with the lentivirus for 48 h and selected with 30 µg/ml puromycin (cat.…”