Stimulating systemic antitumor immunity through local interventions is actively being investigated in solid tumors; radiologists are critical to the successful delivery of intratumoral immunotherapy in lesions where administration requires imaging guidance.

Inhibitors of the phosphatidylinositol 3-kinase/ protein kinase B/ mammalian target of rapamycin (PI3K/AKT/mTOR) pathway hold promise for the treatment of breast cancer, but resistance to these treatments can arise via feedback loops that increase surface expression of the receptor tyrosine kinases (RTK) epidermal growth factor receptor 1 (EGFR) and human epidermal growth factor receptor 3 (HER3), leading to persistent growth pathway signaling. We developed PET probes that provide a method of imaging this response in vivo, determining which tumors may use this escape pathway while avoiding the need for repeat biopsies. Methods: Anti-EGFR-F(ab′)₂ and anti-HER3-F(ab′)₂ were generated from monoclonal antibodies by enzymatic digestion, conjugated to DOTA, and labeled with ⁶⁴Cu. A panel of breast cancer cell lines was treated with increasing concentrations of the AKT inhibitor GDC-0068 or the PI3K inhibitor GDC-0941. Pre and post treatment expression of EGFR and HER3 was compared using Western blot, and correlated to probe accumulation with binding studies. Nude mice xenografts of HCC-70 or MDA-MB-468 were treated with either AKT inhibitor or PI3K inhibitor and imaged with either EGFR or HER3 PET Probe. Results: Changes in HER3 and EGFR PET probe accumulation correlate to RTK expression change as assessed by Western blot (R² of 0.85-0.98). EGFR PET Probe PET/CT imaging of HCC70 tumors shows SUV of 0.32±0.03 for vehicle vs 0.50±0.01 for GDC-0941 vs 0.62±0.01 for GDC-0068 treated tumors, respectively, p<0.01 for both comparisons to vehicle. HER3 PET Probe PET/CT imaging of MDAMB468 tumors shows SUV of 0.35±0.02 for vehicle vs 0.73±0.05 for GDC-0068 treated tumors, p<0.01. Conclusion: Our imaging studies, using PET probes specific to EGFR and HER3, show that changes in RTK expression indicative of resistance to PI3K and AKT inhibitors can be seen within days of therapy initiation, and are of sufficient magnitude as to allow reliable clinical interpretation. Noninvasive PET monitoring of these RTK feedback loops should help to rapidly assess resistance to PI3K and AKT inhibitors and guide selection of appropriate combinatorial therapeutic regimen on an individual patient basis.

Thermal ablation modalities (cryoablation, radiofrequency ablation, and microwave ablation) have long been noted to occasionally induce a systemic antitumoral response. With the widespread use of checkpoint inhibitors, there is a significant interest in whether thermal ablation can promote immune system tumor recognition and increase checkpoint inhibitor response rates. In this review, we examine the current state of preclinical and clinical evidence examining the combination of checkpoint inhibitor therapies and thermal ablation modalities as well as discuss remaining the unanswered questions and directions for future research.

Objective . To evaluate the pre-treatment and post-treatment imaging-based dosimetry of patients treated with 90Y-microspheres, including accurate estimations of dose to tumor, healthy liver and lung. To do so, the Monte Carlo (MC) TOPAS platform is in this work extended towards its utilization in radionuclide therapy. Approach . Five patients treated at the Massachusetts General Hospital were selected for this study. All patients had data for both pre-treatment SPECT-CT imaging using 99mTc-MAA as a surrogate of the 90Y-microspheres treatment and SPECT-CT imaging immediately after the 90Y activity administration. Pre- and post-treatment doses were computed with TOPAS using the SPECT images to localize the source positions and the CT images to account for tissue inhomoegeneities. We compared our results with analytical calculations following the voxel-based MIRD scheme. Main results . TOPAS results largely agreed with the MIRD-based calculations in soft tissue regions: the average difference in mean dose to the liver was 0.14 Gy GBq ⁻¹ (2.6%). However, dose distributions in the lung differed considerably: absolute differences in mean doses to the lung ranged from 1.2 to 6.3 Gy GBq ⁻¹ and relative differences from 153% to 231%. We also found large differences in the intra-hepatic dose distributions between pre- and post-treatment imaging, but only limited differences in the pulmonary dose. Significance . Doses to lung were found to be higher using TOPAS with respect to analytical calculations which may significantly underestimate dose to the lung, suggesting the use of MC methods for 90Y dosimetry. According to our results, pre-treatment imaging may still be representative of dose to lung in these treatments.