Combination of T-DM1 and platinum-based chemotherapy in patient-derived xenograft models of muscle-invasive bladder cancer

Document Type : Original Article


1 Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

2 Gene Therapy Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran

3 Department of Pathology, Labbafinejad Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran

4 Department of Oncology, Shohada-e-Tajrish Medical Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

5 Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran


Objective(s): To assess the efficacy and safety of T-DM1, as an anti-HER2 antibody-drug conjugate (ADC), alone and in combination with two platinum-based chemotherapy regimens in patient-derived xenografts (PDXs) of muscle-invasive bladder cancer (MIBC) established in immunodeficient mice. 
Materials and Methods: After treatment initiation, tumor size was measured twice a week. Percent of tumor growth inhibition (TGI) and tumor response rates were calculated as efficacy endpoints. To evaluate treatment toxicity, relative body weight (RBW) was calculated for each group. For comparison of TGIs between treatment groups, the Kruskal-Wallis test was used. Also, the significance of the overall response (OR) rate between placebo groups with treatment groups was analyzed using Fisher’s exact test. Immunohistochemistry and fluorescence in situ hybridization techniques were used to evaluate the level of HER2 expression.
Results: Our data showed that T-DM1 alone induced a moderate antitumor activity. While chemotherapy regimens induced a slight TGI when administered alone, interestingly, they showed strong antitumor activity when administered combined with T-DM1. The OR rates were higher when T-DM1 was combined with chemotherapy regimens than T-DM1 alone. When compared with the placebo group, the OR rates of combination groups were statistically significant. Our data also showed that the administered dose of each drug was well tolerated in mice. 
Conclusion: The combination of T-DM1 and platinum-based chemotherapy may represent a new treatment option for bladder tumors with even low HER2 expression, and could also provide substantial novel insight into tackling the challenges of MIBC management.


1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin 2020; 70:7-30.
2. Schardt J, Roth B, Seiler R. Forty years of cisplatin-based chemotherapy in muscle-invasive bladder cancer: are we understanding how, who and when? World J Urol 2019; 37:1759-1765.
3. Khongorzul P, Ling CJ, Khan FU, Ihsan AU, Zhang J. Antibody-drug conjugates: A comprehensive review. Mol Cancer Res 2020; 18:3-19.
4. Ravi P, McGregor BA. Antibody-drug conjugates for the treatment of urothelial carcinoma. Expert Opin Biol Ther 2021; 21:915-922.
5. Grivas P, Yu EY. Role of targeted therapies in management of metastatic urothelial cancer in the era of immunotherapy. Curr Treat Options Oncol 2019; 20:67.
6. Koshkin VS, O’Donnell P, Yu EY, Grivas P. Systematic review: targeting HER2 in bladder cancer. Bladder Cancer 2019; 5:1-12.
7. Shree T, Olson OC, Elie BT, Kester JC, Garfall AL, Simpson K, et al. Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer. Genes Dev 2011; 25:2465-2479.
8. Razzaghdoust A, Muhammadnejad S, Parvin M, Mofid B, Zangeneh M, Basiri A. Development and immunohistochemical characterization of patient-derived xenograft models for muscle invasive bladder cancer. Iran J Basic Med Sci 2021; 24:1650-1655.
9. Percie du Sert N, Hurst V, Ahluwalia A, Alam S, Avey MT, Baker M, et al. The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research. PLoS Biol 2020; 18:e3000410.
10. Charan J, Kantharia ND. How to calculate sample size in animal studies? J Pharmacol Pharmacother 2013; 4:303-306.
11. Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm 2016; 7:27-31.
12. Decaudin D, El Botty R, Diallo B, Massonnet G, Fleury J, Naguez A, et al. Selumetinib-based therapy in uveal melanoma patient-derived xenografts. Oncotarget 2018; 9:21674-21686.
13. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45:228-247.
14. Brown RE, Buryanek J, Katz AM, Paz K, Wolff JE. Alveolar rhabdomyosarcoma: morphoproteomics and personalized tumor graft testing further define the biology of PAX3-FKHR (FOXO1) subtype and provide targeted therapeutic options. Oncotarget 2016; 7:46263.
15. Razzaghdoust A, Rahmatizadeh S, Mofid B, Muhammadnejad S, Parvin M, Torbati PM, et al. Data-driven discovery of molecular targets for antibody-drug conjugates in cancer treatment. Biomed Res Int 2021; 2021:2670573.
16. Razzaghdoust A, Ghajari M, Basiri A, Torbati PM, Jafari A, Fattahi MR, et al. Association of immunohistochemical markers of tumor subtype with response to neoadjuvant chemotherapy and survival in patients with muscle-invasive bladder cancer. Investig Clin Urol 2021; 62:274-281.
17. Rather GM, Lin S-Y, Lin H, Banach-Petrosky W, Hirshfield KM, Lin C-Y, et al. Activated matriptase as a target to treat breast cancer with a drug conjugate. Oncotarget 2018; 9:25983-25992.
18. Cazes A, Betancourt O, Esparza E, Mose ES, Jaquish D, Wong E, et al. A MET targeting antibody-drug conjugate overcomes gemcitabine resistance in pancreatic cancer. Clin Cancer Res 2021; 27:2100-2110.
19. Jabeen A, Huang S, Hartley JA, Van Berkel PH, Zammarchi F. Combination of camidanlumab tesirine, a CD25-targeted ADC, with gemcitabine elicits synergistic anti-tumor activity in preclinical tumor models. Blood 2020; 136:31-32.
20. Wan YL, Sapra P, Bolton J, Chua JX, Durrant LG, Stern PL. Combination treatment with an antibody-drug conjugate (A1mcMMAF) targeting the oncofetal glycoprotein 5T4 and carboplatin improves survival in a xenograft model of ovarian cancer. Target Oncol 2019; 14:465-477.
21. Al-Lazikani B, Banerji U, Workman P. Combinatorial drug therapy for cancer in the post-genomic era. Nat Biotechnol 2012; 30:679-692.
22. Staudacher AH, Brown MP. Antibody drug conjugates and bystander killing: is antigen-dependent internalisation required? Br J Cancer 2017; 117:1736-1742.
23. Hayashi T, Seiler R, Oo HZ, Jäger W, Moskalev I, Awrey S, et al. Targeting HER2 with T-DM1, an antibody cytotoxic drug conjugate, is effective in HER2 over expressing bladder cancer. J Urol 2015; 194:1120-1131.
24. Phillips GD, Fields CT, Li G, Dowbenko D, Schaefer G, Miller K, et al. Dual targeting of HER2-positive cancer with trastuzumab emtansine and pertuzumab: critical role for neuregulin blockade in antitumor response to combination therapy. Clin Cancer Res 2014; 20:456-468.
25. Sampath D, Fields C, Li G, Prior W, Parsons K, Friedman L, et al. Abstract S3-6: Combination therapy of the novel PI3K inhibitor GDC-0941 and dual PI3K/mTOR inhibitor GDC-0980 with trastuzumab-DM1 antibody drug conjugate enhances anti-tumor activity in preclinical breast cancer models in vitro and in vivo. Cancer Res 2010; 70:S3-6-S3-6.
26. Chari RV. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res 2008; 41:98-107.
27. Remillard S, Rebhun LI, Howie GA, Kupchan SM. Antimitotic activity of the potent tumor inhibitor maytansine. Science 1975; 189:1002-1005.
28. Galsky MD, Chen GJ, Oh WK, Bellmunt J, Roth BJ, Petrioli R, et al. Comparative effectiveness of cisplatin-based and carboplatin-based chemotherapy for treatment of advanced urothelial carcinoma. Ann Oncol 2012; 23:406-410.
29. Barok M, Tanner M, Köninki K, Isola J. Trastuzumab-DM1 is highly effective in preclinical models of HER2-positive gastric cancer. Cancer Lett 2011; 306:171-179.
30. Kovtun YV, Audette CA, Ye Y, Xie H, Ruberti MF, Phinney SJ, et al. Antibody-drug conjugates designed to eradicate tumors with homogeneous and heterogeneous expression of the target antigen. Cancer Res 2006; 66:3214-3221.
31. Al Shoyaib A, Archie SR, Karamyan VT. Intraperitoneal route of drug administration: Should it be used in experimental animal studies? Pharm Res 2019; 37:12-12.