Intratumoral delivery of brachytherapy and immunotherapy by a thermally triggered polypeptide depot

Biomaterial-based approaches for a combination of radiotherapy and immunotherapy can improve outcomes in metastatic cancer through local delivery of both therapeutic modalities to the primary tumor to control local tumor growth and distant metastases. This study describes an injectable depot for sustained intratumoral (i.t.) delivery of an iodine-131 (¹³¹I) radionuclide and a CpG oligodeoxynucleotide immunostimulant, driven by the thermally sensitive phase transition behavior of elastin-like polypeptides (ELPs). We synthesized and characterized an ELP with an oligolysine tail (ELP-K₁₂) that forms an electrostatic complex with CpG for delivery from an ELP depot and evaluated the ability of the complex to enhance local and systemic tumor control as a monotherapy and in combination with ¹³¹I-ELP brachytherapy. I.t delivery of CpG from an ELP-K₁₂ depot dramatically prolongs i.t. retention to more than 21 days as compared to soluble CpG that is only retained within the tumor for <24 h. ELP-K₁₂ also enhances CpG delivery by increasing cellular uptake of CpG to generate greater toll-like receptor 9 (TLR9) activation than CpG alone. I.t. treatment with an ELP-K₁₂/CpG depot slows primary tumor growth and reduces lung metastases in a poorly immunogenic 4 T1 syngeneic breast cancer model whereas i.t treatment of CpG alone has no significant effect on primary tumor growth or metastases. Notably, a combination of ¹³¹I-ELP brachytherapy and ELP-K₁₂/CpG delivered i.t. inhibited 4 T1 tumor growth and strongly decreased the development of lung metastases, leading to a synergistic improvement in mouse survival. These preclinical results demonstrate that injectable ELP depots may provide a useful approach for the delivery of combination radio- and immuno-therapy to treat metastatic disease.