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Tocilizumab, but Not Dexamethasone, Prevents CRS Without Affecting Open access Short report Tocilizumab, but not dexamethasone, J Immunother Cancer: first published as 10.1136/jitc-2020-000621 on 30 May 2020. Downloaded from prevents CRS without affecting antitumor activity of bispecific antibodies 1,2,3,4 1,2 1,2 3,4 Joseph Kauer , Sebastian Hörner, Lukas Osburg, Stefanie Müller, Melanie Märklin,3,4 Jonas S Heitmann,3,4 Latifa Zekri,1,2 Hans- Georg Rammensee,1,2,3 Helmut R Salih,3,4 Gundram Jung1,2 To cite: Kauer J, Hörner S, ABSTRACT However, a recent publication reports inhi- Osburg L, et al. Tocilizumab, but Bispecific antibodies (bsAb) and chimeric antigen receptor bition of bsAb-mediated T cell activation and not dexamethasone, prevents (CAR) T cells allow for antibody guided recruitment of T cells CRS without affecting antitumor tumor cell killing by dexamethasone during against tumors. Both are successfully used for treatment of 6 activity of bispecific antibodies. long- term stimulation. Moreover, steroid CD19 expressing leukemias, but may cause cytokine release Journal for ImmunoTherapy medication did not significantly increase the syndrome (CRS) as a major dose- limiting side effect. For of Cancer 2020;8:e000621. maximal tolerated dose of a CEAxCD3 bsAb in doi:10.1136/jitc-2020-000621 CRS prevention, steroids are recommended prior to bsAb 7 treatment, despite their well-kno wn lymphotoxic activity. a recent clinical study. The IL-6 receptor antibody tocilizumab is established for Meanwhile, the IL-6 receptor antibody tocili- ► Additional material is zumab is approved for treatment of severe published online only. To view treatment of CRS induced by CAR T cells, but was not please visit the journal online considered for CRS prevention in bsAb therapy. We here CRS induced by CAR T cells based on several 8 9 (http:// dx. doi. org/ 10. 1136/ jitc- compared the influence of dexamethasone and tocilizumab case reports and there is growing evidence 2020- 000621). on bsAb-media ted T cell proliferation and tumor lysis in supporting its efficacy in treating established vitro and in vivo and found that dexamethasone profoundly bsAb- mediated CRS.10 11 When we compared Accepted 09 April 2020 inhibited T cell proliferation and antitumor activity as induced the influence of dexamethasone to that of by two different bsAb, particularly at low effector:target tocilizumab on bsAb- induced T cell prolifera- ratios, whereas tocilizumab did not affect efficacy. When we tion and tumor cell lysis, we found that dexa- applied tocilizumab early during treatment of three patients methasone profoundly inhibited therapeutic © Author(s) (or their with a newly developed PSMAxCD3 bsAb, significant CRS attenuation despite high IL-6 serum levels was observed. activity, whereas tocilizumab did not. Based on employer(s)) 2020. Re- use these findings we used early tocilizumab treat- permitted under CC BY- NC. No Thus, early IL-6 blockade may reduce the undesired ment for prevention of CRS in three patients commercial re- use. See rights sequelae of CRS upon bsAb therapy without affecting http://jitc.bmj.com/ and permissions. Published by therapeutic activity, allowing in turn for safe application of with prostate carcinoma treated with the newly BMJ. effective doses. developed PSMAxCD3 bsAb CC-1. 1Department of Immunology, University of Tübingen Interfaculty Institute of Cell INTRODUCTION METHODS Biology, Tubingen, Germany 2 Bispecific antibodies (bsAb) and chimeric Cells and reagents German Cancer Consortium on October 1, 2021 by guest. Protected copyright. (DKTK), DKFZ partner site antigen receptor (CAR) T cells are Blood was drawn from healthy donors . Tübingen, Tübingen, Germany, successful strategies for cancer immuno- Peripheral blood mononuclear cells (PBMCs) 1 2 Tübingen, Germany therapy. However, both reagent types were isolated using density gradient centrif- 3DFG Cluster of Excellence can cause life- threatening cytokine release ugation with Biocoll cell separation solution 2180, 'Image- guided and syndrome (CRS).1 3 In case of blinatumomab, (Biochrom, Berlin, Germany). The prostate Functional Instructed Tumor Therapy' (IFIT), University of a benchmark bsAb with CD19xCD3 specificity, carcinoma cell line LNCaP and the acute Tübingen, Tübingen, Germany, this side effect limits safely applicable doses to lymphatic leukemia cell line Nalm-16 were Tübingen, Germany approximately 30 µg/day resulting in serum purchased from the German Collection of 4Clinical Collaboration Unit levels <1 ng/mL1, which appears not suffi- Microorganisms and Cell Cultures (DMSZ, Translational Immunology, cient to achieve optimal therapeutic activity. Braunschweig, Germany) and were routinely Department of Internal Medicine, German Cancer Consortium To prevent CRS, dexamethasone (16 mg) is tested negative for mycoplasma. PBMCs and (DKTK), University Hospital usually applied prior to the first cycle of blina- cell lines were kept in RPMI 1640 supple- 4 12 Tübingen, Tübingen, Germany, tumomab and other bsAbs. However, there mented as described earlier. Dexametha- Tübingen, Germany are conflicting data as to whether this medi- sone (Sigma-Aldrich) was dissolved in RPMI cation does affect bsAb- mediated T cell activa- 1640 including 10% FCS and kept at −20°C Correspondence to Professor Gundram Jung; tion and tumor cell killing. Brandl et al did not until use. Dexamethasone (Sigma- Aldrich) gundram. jung@ uni- tuebingen. report any inhibitory effect of dexamethasone was dissolved in RPMI 1640 including 10% de on blinatumomab- mediated tumor cell lysis.5 FCS and stored at −20°C. Kauer J, et al. J Immunother Cancer 2020;8:e000621. doi:10.1136/jitc-2020-000621 1 Open access Antibodies and flow cytometry agents were added and cell indices were measured every J Immunother Cancer: first published as 10.1136/jitc-2020-000621 on 30 May 2020. Downloaded from The recombinant bsAb CC-1 (PSMAxCD3 specificity, 15 min to determine viability of the tumor cells. online supplementary figure 1A) was generated at our institution in the IgGsc format based on the format Animal model published by Coloma and Morrison1 (Zekri et al, manu- Animal experiments were performed in accordance with the script submitted December 2019). The PSMA and CD3 German Animal Protection Law and after authorization by binding sites are comprised of the newly generated the competent authority of the state of Baden-Württemberg (Regierungspräsidium Tübingen, authorization number hybridoma- derived IgG2b antibody 10B3 and a single scid tm1Wjl chain derived from the CD3 antibody UCHT-1, respec- M9/17). Six weeks old NOD.Cg-Prkdc Il2rg /SzJ tively. Fc receptor binding and complement fixation was (NSG) mice (Charles River Laboratories, Wilmington, USA) were injected subcutaneously with 1,000,000 PSMA+ attenuated by introducing mutations in the CH2 domain (online supplementary figure S1A). LNCaP tumor cells into the flank. After formation of large The humanized anti- IL-6 receptor antibody tocilizumab palpable tumors (approximately 4 mm after 7 days), mice was purchased in clinical quality from Hoffmann-La were injected intravenously with 5 µg dexamethasone or Roche (Basel, Switzerland). The bispecific CD19xCD3 200 µg tocilizumab (d1). One hour later, 10,000,000 human BiTE antibody blinatumomab (online supplementary PBMCs were applied intraperitoneally as well as 2 µg of a figure S2A) was purchased from Amgen (Thousand Oaks, PSMAxCD3 antibody CC-1 (intravenous). Treatment with USA). Flourochrome- labeled antibodies against CD4, the same amount of PMBC in combination with CC-1 was repeated at days 8 and 15. Tumor size was measured every 2 CD8, CD10, CD276 and the respective isotype control days and mice were euthanized if signs of sickness occurred antibodies were purchased from BioLegend (San Diego, or tumor size exceeded 14 mm. USA). CD45- AmCyan was purchased from BD Biosciences (Franklin Lakes, USA). Patients For flow cytometry based lysis assays, 50,000 PSMA+ + Patients with castrate- resistant metastatic prostate carci- LNCaP cells or 100,000 CD19 Nalm-16 cells were incu- noma were treated with the bispecific PSMAxCD3 bated in 96 well plates together with 32,500–1,000,000 antibody CC-1 and tocilizumab in an individualized exper- PBMCs, bsAb at 1 µg/mL and blocking reagents (0,1 µg/ imental approach. CC-1 was produced in compliance mL dexamethasone or 10 µg/mL tocilizumab). After with good manufacturing process standards according 3 days, flow cytometric analysis was performed. LNCaP to section 13 (2b) of the German Medicines Act and - + - cells were defined as CD45 CD276 , Nalm-16 as CD45 applied using an individual dose escalation protocol. + + + + CD10 , and T cells as CD45 CD4 or CD45 CD8. Abso- Body temperature was monitored at least every 2 hours. lute cell numbers were determined by the acquisition of For monitoring purposes, IL-6, C reactive protein (CRP) a defined amount of compensation particles (BD Biosci- and solubIe IL-2 receptor (sIL- 2R) levels were assessed 2 ences) per sample. Binding of antibodies to Fc receptors daily using ELISA at the central laboratory of the Univer- was blocked with Flebogamma DIF (Grifols, Barcelona, sity Hospital Tübingen. After the first occurrence of fever http://jitc.bmj.com/ Spain) at 50 µg/mL. Data acquisition was performed ≥38.5°C, 400 mg tocilizumab was applied. Patient samples using a FACSCanto II (BD Biosciences). For data analysis, were tested for human antihuman antibodies by ELISA FlowJo V.10 software (Tree Star, Ashland, OR) was used. at the University Hospital Tübingen. To this end, (Fab)2 fragments of CC-1 were coated as capture antibody. T cell proliferation assay After blocking, serum samples of patients were added PBMCs from healthy donors (100,000 cells/well) and and specific binding of human antihuman antibodies on October 1, 2021 by guest. Protected copyright. irradiated (100 Gy) target cells (E:T ratio 1:1) were to (Fab)2 fragments was detected by addition of goat- seeded in triplicates in 96 well plates and incubated antihuman HRP- conjugated secondary antibodies. with bsAb (1 µg/mL). After 48 hours, cells were pulsed with 3H- methyl thymidine (0.5 µCi/well) and incubated Statistical analysis for another 20 hours until they were harvested on filter Data are displayed as mean±SD.
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