Irreversible electroporation augments checkpoint immunotherapy in prostate cancer and promotes tumor antigen-specific tissue-resident memory CD8+ T cells.

Memory CD8+ T cells populate non-lymphoid tissues (NLTs) following pathogen infection, but little is known about the establishment of endogenous tumor-specific tissue-resident memory T cells (TRM) during cancer immunotherapy. Using a transplantable mouse model of prostate carcinoma, here we report that tumor challenge leads to expansion of naïve neoantigen-specific CD8+ T cells and formation of a small population of non-recirculating TRM in several NLTs. Primary tumor destruction by irreversible electroporation (IRE), followed by anti-CTLA-4 immune checkpoint inhibitor (ICI), promotes robust expansion of tumor-specific CD8+ T cells in blood, tumor, and NLTs. Parabiosis studies confirm that TRM establishment following dual therapy is associated with tumor remission in a subset of cases and protection from subsequent tumor challenge. Addition of anti-PD-1 following dual IRE + anti-CTLA-4 treatment blocks tumor growth in non-responsive cases. This work indicates that focal tumor destruction using IRE combined with ICI is a potent in situ tumor vaccination strategy that generates protective tumor-specific TRM.

Methods for characterizing convective cryoprobe heat transfer in ultrasound gel phantoms.

While cryosurgery has proven capable in treating of a variety of conditions, it has met with some resistance among physicians, in part due to shortcomings in the ability to predict treatment outcomes. Here we attempt to address several key issues related to predictive modeling by demonstrating methods for accurately characterizing heat transfer from cryoprobes, report temperature dependent thermal properties for ultrasound gel (a convenient tissue phantom) down to cryogenic temperatures, and demonstrate the ability of convective exchange heat transfer boundary conditions to accurately describe freezing in the case of single and multiple interacting cryoprobe(s). Temperature dependent changes in the specific heat and thermal conductivity for ultrasound gel are reported down to -150 °C for the first time here and these data were used to accurately describe freezing in ultrasound gel in subsequent modeling. Freezing around a single and two interacting cryoprobe(s) was characterized in the ultrasound gel phantom by mapping the temperature in and around the "iceball" with carefully placed thermocouple arrays. These experimental data were fit with finite-element modeling in COMSOL Multiphysics, which was used to investigate the sensitivity and effectiveness of convective boundary conditions in describing heat transfer from the cryoprobes. Heat transfer at the probe tip was described in terms of a convective coefficient and the cryogen temperature. While model accuracy depended strongly on spatial (i.e., along the exchange surface) variation in the convective coefficient, it was much less sensitive to spatial and transient variations in the cryogen temperature parameter. The optimized fit, convective exchange conditions for the single-probe case also provided close agreement with the experimental data for the case of two interacting cryoprobes, suggesting that this basic characterization and modeling approach can be extended to accurately describe more complicated, multiprobe freezing geometries. Accurately characterizing cryoprobe behavior in phantoms requires detailed knowledge of the freezing medium's properties throughout the range of expected temperatures and an appropriate description of the heat transfer across the probe's exchange surfaces. Here we demonstrate that convective exchange boundary conditions provide an accurate and versatile description of heat transfer from cryoprobes, offering potential advantages over the traditional constant surface heat flux and constant surface temperature descriptions. In addition, although this study was conducted on Joule-Thomson type cryoprobes, the general methodologies should extend to any probe that is based on convective exchange with a cryogenic fluid.

Numerical simulation of a BPH thermal therapy--a case study involving TUMT.

The use of numerical simulation as a means to predict the outcome of transurethral microwave thermotherapy (TUMT) is set forth in detail. The simulation was carried out as a case study of a specific TUMT procedure. The selection of the case study was based on the availability of extensive medical records which documented an extraordinary application of TUMT. Predictions were made of the time-varying temperature patterns within the prostate, the bladder, the sphincter, the pelvic floor, and the fat and connective tissue which envelop these organs. These temperature patterns provided the basis of maps which highlighted those locations where necrosis occurred. An injury integral was used to predict the extent of the necrotic tissue produced by the therapy. It was found that, for the specific case being considered, necrosis occurred not only within the prostate but also extended to the neck of the bladder and to the fatty tissue. A special feature of the simulation was the accounting of the liquid-to-vapor phase change of the interstitial water. The vapor generated by the phase change is believed to significantly enlarge the region of necrosis. By the same token, the vapor pressure is expected to cause motion of the high-temperature liquid to deep-tissue regions. The damage predicted by the numerical simulation was compared, in detail, with post-operative medical examinations and found to be corroborated.