746 Checkpoint inhibitor sensitization and systemic anti-tumor immunity generated by local gene delivery nanoparticles
Year: 2024
Type: conference-abstract
Abstract: Background Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, but novel treatment strategies are needed for resistant or recurrent cases. We previously demonstrated that polymeric nanoparticles (NPs) delivering plasmids encoding 4-1BBL and IL-12 elicit productive immune responses in vivo.1–3 Here, we assess 4-1BBL/IL-12 NPs in two additional murine cancer models with varying degrees of sensitivity to ICI to investigate their ability to synergize with ICI and generate systemic immunity. Methods MC38 colorectal cancer was established on the flank or E0771 breast carcinoma was established on the mammary fat pad in C57BL/6J mice. Animals were untreated or received intratumoral injections of control NPs or 4-1BBL/IL-12 NPs on days 9, 11, 16, and 18. A subset of animals also received systemic anti-PD1 on the same days and twice a week for four additional weeks. Mice were sacrificed when surface area reached 200 mm2 or for moribund states. In E0771, all animals with fully regressed primary tumors were rechallenged with a second tumor on the opposite flank. Significance was assessed via log-rank (Mantel-Cox) test with Bonferroni correction, or two-way ANOVA comparing conditions to no treatment or anti-PD1 only. Results In MC38, 4-1BBL/IL-12 NPs alone or with anti-PD1 led to modest decreases in tumor size (figure 1A-B), though survival was not improved with NPs alone (figure 2A). Systemic anti-PD1 led to a slight increase in median survival compared to no treatment (37 versus 29 days, figure 2A-B), but combined with 4-1BBL/IL-12 NPs led to 4/7 animals with fully regressed tumors (figure 2B). In E0771, 4-1BBL/IL-12 NPs alone and with anti-PD1 slowed tumor growth significantly (figure 3A-B). 4-1BBL/IL-12 NPs alone led to significantly improved survival compared to untreated animals (p=0.0006) and 6/8 long-term tumor-free survivors (figure 4A), and anti-PD1 led to 4/8 long-term tumor-free survivors (figure 4B). Notably, 4-1BBL/IL-12 NPs with anti-PD1 led to 100% tumor-free survival (figure 4B). On day 83, all animals with fully regressed primary E0771 tumors were rechallenged with a tumor on the opposite flank. In all cases, the primary tumor did not recur, the flank tumor was rejected, and all mice remained tumor-free through day 151. Conclusions Here, we demonstrate that 4-1BBL/IL-12 NPs can sensitize resistant cancer to ICI. We further show that locally administered 4-1BBL/IL-12 NPs, with and without systemic ICI, can generate systemic immunity preventing establishment of distant tumor. Together, these results highlight the utility of these immunostimulatory NPs in generating potent anti-cancer responses in vivo. References Tzeng SY, Patel KK, Wilson DR, Meyer RA, Rhodes KR, Green JJ. In situ genetic engineering of tumors for long-lasting and systemic immunotherapy. Proc Natl Acad Sci U S A. 2020;117(8):4043–52. Luly KM, Green JJ, Sunshine JC, Tzeng SY. Biomaterial-mediated genetic reprogramming of merkel cell carcinoma and melanoma leads to targeted cancer cell killing in vitro and in vivo. ACS Biomater Sci Eng [Internet]. 2023 Nov 13;9(11):6438–50. Luly K, Green J, Tzeng S, Sunshine J. 222 Genetic reprogramming of merkel cell carcinoma and melanoma leads to increased MHC-I expression and antitumor immune activation in vitro and in vivo. J Immunother Cancer [Internet]. 2021 Nov;9(Suppl 2):A235–6. Ethics Approval All animal work was conducted within the guidelines of the Johns Hopkins Animal Care and Use Committee under approved protocol numbers MO18M388/MO21M384.
Authors: Kathryn M Luly, Erick E Rocher, Joanna Y Yang, Jordan J Green, Joel C Sunshine, Stephany Y Tzeng
Institution: Johns Hopkins University
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W4404064975