Abstract LB-079: Microbubble mediated focused ultrasound therapy enhances the antitumor potency and durability of anti-PD-L1 checkpoint blockade
Authors: Goertz David , Cruz William , Bulner Sharshi , Wright Alex , Kerbel Robert 
Published: September 2020

Abstract
Checkpoint inhibitor therapies (CITs) are fundamentally impacting the treatment landscape of many cancer types. Unfortunately, only limited subsets of patients show durable complete responses (CRs). While considerable efforts are therefore being made to combine CITs with other therapies, the issue of increased toxicity associated with this approach remains a challenge. Physical methods for enhancing CITs are also being investigated and may have the advantage of not adding to toxicity. One such approach is therapeutic ultrasound, or focused ultrasound (FUS), which can act through a range of mechanisms and is known to be associated with immunological effects. A prominent form of FUS uses systemically injected ‘microbubbles' (MBs) which oscillate in response to ultrasound to enhance vascular permeability or elicit vascular damage. Here we investigate the use of FUS+MBs to enhance the effects of a clinically relevant combination anti-PD-L1 plus paclitaxel (PTX) in the treatment of triple negative breast cancer.
Mammary carcinoma tumors (EMT6) were initiated in the mammary fat pads of immune competent Balb/c mice. At day 8 post implantation, experiments were conducted with 4 groups: sham, FUS+MBs, aPD-L1+PTX, FUS+MBs+aPD-L1+PTX. anti-PD-L1 (clone:6E11; 5 mg/kg; Genentech) was given i.p. every 3-4 days for a total of 10 doses. PTX was administered i.p. biweekly for 3 doses. FUS+MBs exposures consisted of a single treatment at pressures high enough to elicit vascular shutdown, as determined through histology.
The results (Table 1) demonstrated that the addition of FUS+MB treatment profoundly enhances the effects of aPD-L1+PTX (p&lt;0.02) and resulted in CR for 7/8 tumors. Re-challenge experiments in the contralateral fat pad of CR mice revealed either no re-growth or delayed growth, consistent with immune memory being engaged.
Day 10 Tumor Volumes ± SEMDay 10 Tumor Volumes (1 way-ANOVA; post-hoc: Tukey's)Kaplan-Meir Survival Analysis (Log-rank test)Animals with complete response(Sham) vs. (PTX + aPD-L1 + FUS + MBs)793.6 ± 193.4 vs. 105.6 ± 16.8p=0.0087p&lt;0.00010/7 vs. 7/8(PTX + aPD-L1) vs. (PTX + aPD-L1 + FUS + MBs)690.8 ± 217.2 vs. 105.6 ± 16.8p=0.039p=0.0222/6 vs. 7/8(FUS + MBs) vs. (PTX + aPD-L1 + FUS + MBs)255.0 ± 102.4 vs. 105.6 ± 16.8p=0.85p=0.135/9 vs. 7/8(Sham) vs. (FUS + MBs)793.6 ± 193.4 vs. 255.0 ± 102.4p=0.043p=0.0010/7 vs. 5/9(Sham) vs. (PTX + aPD-L1)793.6 ± 193.4 vs. 690.8 ± 217.2p=0.96p=0.0390/7 vs. 2/6(PTX + aPD-L1) vs. (FUS + MBs)690.8 ± 217.2 vs. 255.0 ± 102.4p=0.16p=0.342/6 vs. 5/9
As FUS is a rapidly growing treatment modality in oncology, these results may ultimately have significant implications for enhancing CITs without added toxicity. This approach warrants further investigation, including its potential impact on immune memory.
Citation Format: David Goertz, William Cruz, Sharshi Bulner, Alex Wright, Robert Kerbel. Microbubble mediated focused ultrasound therapy enhances the antitumor potency and durability of anti-PD-L1 checkpoint blockade [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-079.