Bispecific antibody releasing-mesenchymal stromal cell machinery for retargeting T cells towards acute myeloid leukemia blasts.

R Aliperta,I Michalk,M P Bachmann,C Arndt,G Ehninger,M Bornhäuser,S Koristka,M Cartellieri,A Ehninger,M Von Bonin,A Feldmann,J Bachmann

doi:10.1038/bcj.2015.73

R Aliperta, I Michalk + Show 10 more

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https://doi.org/10.1038/bcj.2015.73

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Bispecific antibodies (bsAbs) engaging T cells are emerging as a promising immunotherapeutic tool for the treatment of hematologic malignancies. Because their low molecular mass, bsAbs have short half-lives. To achieve clinical responses, they have to be infused into patients continously, for a long period of time. As a valid alternative we examined the use of mesenchymal stromal cells (MSCs) as autonomous cellular machines for the constant production of a recently described, fully humanized anti-CD33-anti-CD3 bsAb, which is capable of redirecting human T cells against CD33-expressing leukemic cells. The immortalized human MSC line SCP-1 was genetically modified into expressing bsAb at sufficient amounts to redirect T cells efficiently against CD33 presenting target cells, both in vitro and in an immunodeficient mouse model. Moreover, T cells of patients suffering from acute myeloid leukemia (AML) in blast crisis eliminated autologous leukemic cells in the presence of the bsAb secreting MSCs over time. The immune response against AML cells could be enhanced further by providing T cells an additional co-stimulus via the CD137-CD137 ligand axis through CD137L expression on MSCs. This study demonstrates that MSCs have the potential to be used as cellular production machines for bsAb-based tumor immunotherapy in the future.

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T-cell engaging bispecific antibodies are a promising tool for cancer treatment
The hMSC lines were generated from the human telomerase reverse transcriptase-immortalized single-cell derived hMSC line single-cell-picked clone 1 (SCP-1) and genetically modified using lentiviral gene transfer to stably express the bsAb CD33–CD3
The parental SCP-1 cell line was examined for surface expression of the typical mesenchymal stromal cells (MSCs) marker proteins CD90, CD105 and CD73 and the absence of CD33, CD45 (Figure 1b) and CD34

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Introduction

T-cell engaging bispecific antibodies (bsAbs) are a promising tool for cancer treatment. A continuous delivery of bsAbs seems to be necessary to sustain plasma levels in clinically relevant concentrations, as bsAbs have short half-lifes in vivo and are rapidly cleared from circulation due to their small molecule size.[6,7] An alternative to this approach, is the adoptive transfer of gene-modified cells, which produce and secrete bsAbs continuously in the body of the patient throughout their life-time Due to their unique immunologic properties, human mesenchymal stromal cells (MSCs) seem to be a good choice for the generation of such cellular bsAb production machineries.[8,9] Experimental and clinical studies revealed that MSCs had limited immunogenicity and are even poorly recognized by HLA incompatible hosts.[10,11,12] More importantly, MSCs tend to accumulate next to tumors, including metastatic lesions. Studies showed that after an adoptive stem cell transplantation in patients with acute myeloide leukemia (AML), the transfer of MSCs provided an immunosuppressive environment, helpful to reduce graft versus host disease reactions.[16,17] This leads to the question, if an in situ production of bsAbs via MSCs interferes with the activation of bsAb redirected T lymphocytes

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