Combination Therapy with Cisplatin and Anti–4-1BB: Synergistic Anticancer Effects and Amelioration of Cisplatin-Induced Nephrotoxicity

Abstract

Anti-4-1BB and cisplatin showed synergistic anticancer effects in the CT-26 colon carcinoma model, producing complete regression in >60% of mice with either preventive or therapeutic treatment. The tumor-free mice formed longlasting CD8 + T cell-dependent tumor-specific memory. Anti-4-1BB induced rapid repopulation of T and B cells from cisplatin-mediated lymphopenia and differentiation and expansion of IFN-; + CD11c + CD8 + T cells. Cisplatin facilitated expansion of naïve, effector, and memory CD8 + T cells; combination therapy produced almost twice as many lymphoid cells as anti-4-1BB alone. Cisplatin increased 4-1BB on antigen-primed T cells and induced 4-1BB de novo on kidney tubular epithelium. Cross-linking of 4-1BB protected the T cells and kidney epithelium from cisplatin-mediated apoptosis by increasing expression of antiapoptotic molecules. Thus, cisplatin-induced 4-1BB provided a mechanism for amelioration of the lymphopenia and nephrotoxicity inherent in cisplatin treatment. We concluded that chemoimmunotherapy with anti-4-1BB and cisplatin is synergistic in tumor killing and prevention of organ-specific toxicity. [Cancer Res 2008;68(18):7264-9]

Combinatorial Therapy for Liver Metastatic Colon Cancer: Dendritic Cell Vaccine and Low-Dose Agonistic Anti-4-1BB Antibody Co-Stimulatory Signal

“…Although the anti-tumor effect of 4-1BB ligation (over 100 mg Ab) alone or in combination with DC vaccine [16][17][18][19][20][21] has been acknowledged on a clinical basis, toxicity to CD4 þ T cells limits the usage. Also, the dual role of 4-1BB ligation in immune-stimulation and immune-regulation has been reported, suggesting the possibility of unfavorable tumorigenic response [12][13][14][15].…”

Clinical Development of Immunostimulatory Monoclonal Antibodies and Opportunities for Combination

“…Agonist antibodies to CD137 and CD137-ligand costimulate T cells after TCR stimulation, enhanced cytolytic effector functions, and protecting lymphocytes from programmed cell death (78,79). Furthermore, anti-CD137 mAb immunotherapy can be combined with other treatments: in preclinical models very encouraging results were obtained combining this class of drug with radiotherapy, chemotherapy, and immunotherapy (80)(81)(82).…”

“…OX40 (CD134 or TNFRSF4) is a costimulatory molecule expressed on the surface of activated T lymphocytes (84). Agonists of OX40 have been used successfully in a variety of preclinical tumor models with promising results (85)(86)(87)(88), and a variety of combinatorial strategies to increase anti-OX40 antibody therapy with vaccines, chemotherapy, radiotherapy, and immunotherapy have been explored (79)(80)(81)(82)(83)(84)(85)(86)(87)(88)(89)(90)(91). A mouse anti-human OX40 mAb has shown activity in nonhuman primates and has been tested in phase I clinical trials in 30 patients at different dosages with minimal toxicity although patients showed elevated levels of neutralizing human anti-mouse antibodies (92).…”

Agonist Anti-CD137 mAb Act on Tumor Endothelial Cells to Enhance Recruitment of Activated T Lymphocytes

“…Interestingly, treatment with agonist anti-CD137 mAb can overcome tumor antigen tolerance (16) in a number of models and more importantly, can be successfully combined with both other immunotherapeutic strategies (17)(18)(19)(20) and conventional immune-unrelated treatment approaches (17,21). Some of those combinations attain extraordinary therapeutic activity in mouse models (22).…”