Background Regulatory T cells (Tregs) contribute to an immunosuppressive tumor microenvironment. High tumor infiltration by Tregs and a low ratio of Teffector cells/Tregs is often associated with poor prognosis in solid tumors.1 Tregs represent a major obstacle to cancer immunotherapies, including checkpoint inhibitors and interleukin-2 (IL-2) and are associated with tumors resistance to radiotherapy.2 CD25-ADC (a.k.a. sur301) is an antibody-drug conjugate (ADC) composed of rat monoclonal antibody PC61, directed against mouse CD25, conjugated to tesirine, a pyrrolobenzodiazepine (PBD) dimer-based protease-cleavable linker.3 Previously we showed that single low doses of CD25-ADC resulted in potent and durable antitumor activity in established syngeneic solid tumor models and the combination of a suboptimal dose was synergistic with PD-1 blockade. Tumor eradication by CD25-ADC was CD8+ T cell-dependent and it induced protective immunity. Importantly, while CD25-ADC mediated a significant and sustained intratumoral Tregs depletion, accompanied by a concomitant increase in the number of activated and proliferating tumor-infiltrating CD8+ Teffs cells, systemic Tregs depletion was transient, alleviating concerns of potential autoimmune side effects.4
Methods Here we evaluated the anti-tumor activity of CD25-ADC combined with tumor-targeted radiotherapy (RT) or systemic IL-2 in syngeneic solid tumor models.
Results To investigate the combination with radiotherapy, single low doses of CD25-ADC (0.25 or 0.5 mg/kg) were administered intravenously either alone or in combination with image-guided focal radiation in the CT26 syngeneic model. Both doses of CD25-ADC alone induced significant anti-tumor activity compared to the vehicle control. Combination of CD25-ADC, at 0.25 or 0.5 mg/kg, with focal radiotherapy resulted in synergistic anti-tumor activity with 60% and 80% tumor-free survivors (TFS), respectively, at the end of the study. Moreover, re-challenged TFS did not develop new tumors, demonstrating development of tumor-specific protective immunity.The combination of CD25-ADC and systemic IL-2 was investigated in the MC38 syngeneic model. CD25-ADC was administered intravenously either alone (0.25 or 0.5 mg/kg, single dose) or in combination with IL-2 (0.1 or 0.8 mg/kg). Single doses of CD25-ADC elicited significant anti-tumor activity compared to the vehicle control. Combination of CD25-ADC with IL-2 resulted in enhanced anti-tumor activity in both combination groups compared to the respective single agents and the combination was synergistic at the highest IL-2 dose.
Conclusions Together, these new preclinical data show novel promising combination regimens for CD25-ADC and other commonly used anti-cancer treatments and they provide rationale for the investigation of camidanlumab tesirine (ADCT-301), a PBD-based ADC targeting human CD25, in similar clinical combinations settings.
Shang, B., et al., Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: a systematic review and meta-analysis. Sci Rep 2015;5: p. 15179.
Liu S, et al., Effects of radiation on T regulatory cells in normal states and cancer: mechanisms and clinical implications. Am J Cancer Res 2015;5(11):p. 3276–85.
Zammarchi, F., et al., A CD25-targeted pyrrolobenzodiazepine dimer-based antibody-drug conjugate shows potent anti-tumor activity in pre-clinical models of solid tumors either alone or in combination with a PD-1 inhibitor. Journal for ImmunoTherapy of Cancer 2018. 6(Supplement 1).
Zammarchi, F., et al., A CD25-targeted antibody-drug conjugate depletes regulatory T cells and eliminates established syngeneic tumors via antitumor immunity. Journal for ImmunoTherapy of Cancer 2020. In press.
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