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Effective consolidative chemoradiation (CRT) regimens are lacking. In this phase 1 trial, we evaluated the safety and efficacy of nab-paclitaxel, capecitabine, and radiation therapy after induction chemotherapy in patients with locally advanced and borderline-resectable pancreatic cancer (LAPC and BRPC). Also, we evaluated a computed tomography (CT)-based biomarker of response.Eligible patients had pathologically confirmed pancreatic ductal adenocarcinoma, underwent computed tomography-imaging, received a diagnosis of LAPC or BRPC, and received induction chemotherapy. Standard 3 + 3 study design was used, with 3 escalating nab-paclitaxel dose levels (50, 75, and 100 mg/mTwenty-three patients started and finished on protocol (LAPC = 14, BRPC = 9). No grade 3 and 4 toxicities were reported in level 1 (n = 3) or level 2 (n = 3) initial groups. Two patients in the initial level 3 group developed dose limiting toxicity, establishing level 2 dose as the maximal tolerated dose. Level 2 group was expanded for additional 15 patients (for a total of 23 on trial), 5 of whom developed grade 3 toxicities. Seven patients underwent surgical resection. Median OS and PFS were 21.2 and 8.1 months, respectively. Type I IR was associated with better OS (P = .004) and PFS (P = .03) compared with type II IR.We established the maximum tolerated dose for nab-paclitaxel in a consolidative CRT regimen for pancreatic ductal adenocarcinoma. Preliminary efficacy results warrant phase 2 trial evaluation. IR may be used for personalized treatment.

In this commentary, we describe the potential of highly ablative doses utilizing Stereotactic Body Radiation Therapy (SBRT) in single or few fractions to enhance immune-responsiveness, how timing of this approach in combination with immune-checkpoint inhibitors may augment treatment-effect, and whether Personalized Ultrafractionated Stereotactic Adaptive Radiation Therapy (PULSAR) is an avenue for future advancement in the continued endeavor to foster a systemic effect of therapy beyond the radiation treatment field. The ablative potential of SBRT may support an increase in tumor-antigen presentation, enhancement of immune-stimulatory components, and an improvement in tumor-microenvironment immune cell infiltration. Furthermore, the latest advancement of ablative radiation delivery is PULSAR-based therapy, whereby ablative doses are delivered in pulses of treatment that may be several weeks apart, combined with adaptive treatment to tumor changes across time. The benefits of this novel approach include the ability to optimize direct tumor control by assessment of tumor size and location via dedicated imaging acquired prior to each delivered pulse, and further potentiation of immune recognition through combination with concurrent immune-checkpoint blockade.

In the past decade, the study of mechanisms of cancer immunity has seen a prominent boom, which paralleled the increased amount of research on the clinical efficacy of immune checkpoint blockade in several lethal types of cancers. This conspicuous effort has led to the development of successful immunotherapy treatment strategies, whose medical impact has been recognized by the awarding of 2018 Nobel Prize in Physiology or Medicine to the two pioneers of check point inhibitor research, Tasuku Honjo and James Allison. Despite these promising achievements, the differences in the clinical response rate in different cancer patients and the high risk of toxicity of immune-based therapies represent crucial challenges. More remarkably, the causes responsible for different outcome (success versus failure) in patients with tumor having same histotype and clinical characteristics remain mostly unknown. MicroRNAs (miRNAs), small regulatory non-coding RNA molecules representing the most studied component of the dark matter of the human genome, are involved in the regulation of many pathways of cancer and immune cells. Therefore, understanding the role of miRNAs in controlling cancer immunity is necessary, as it can contribute to reveal mechanisms that can be modulated to improve the success of immune-therapy in cancer patients. Here, we discuss the latest findings on immune pathways regulated by miRNAs in cancer, miRNA-mediated regulation of immune cells in the tumor microenvironment, and miRNAs as potential target for immunotherapies.

Summary In radiation therapy for cancer, the therapeutic ratio represents an optimal balance between tumor control and normal tissue complications. As improvements in the therapeutic arsenal against cancer extend longevity, the importance of late effects of radiation increases, particularly those caused by vascular endothelial injury. Radiation both initiates and accelerates atherosclerosis, leading to vascular events like stroke, coronary artery disease, and peripheral artery disease. Increased levels of proinflammatory cytokines in the blood of long-term survivors of the atomic bomb suggest that radiation evokes a systemic inflammatory state responsible for chronic vascular side effects. In this review, the authors offer an overview of potential mechanisms implicated in radiation-induced vascular injury., Central Illustration

Tumor hypoxia is a well-recognized driver of resistance to traditional cancer therapies such as chemotherapy and radiation therapy. We describe development of a new nanoconstruct composed of gold nanorods (GNRs) conjugated to carbonic anhydrase IX (CAIX) antibody that specifically binds to CAIX, a biomarker of hypoxia, to facilitate targeting tumor hypoxic areas for focused photothermal ablation. Physicochemical characterization studies confirmed the size, shape, monodispersity, surface charge, and serum stability of the GNRs. Enzyme-linked immunosorbent assays and cellular binding and uptake studies confirmed successful conjugation of antibody to the GNRs and specificity for CAIX. Near-infrared irradiation of CAIX-overexpressing cells treated with GNR/anti-CAIX resulted in significantly higher cell death than cells treated with control GNRs. In vivo biodistribution studies using hyperspectral imaging and inductively coupled plasma mass spectrometry confirmed intravenous administration results not only in greater accumulation of GNR/anti-CAIX in tumors than control GNRs but also greater penetration into hypoxic areas of tumors. Near-infrared ablation of these tumors showed no tumor regression in the sham-treated group, regression but recurrence in the non-targeted-GNR group, and complete tumor regression in the targeted-GNR group. GNR/anti-CAIX nanoconstructs show promise as hypoxia targeting and photothermal ablation agents for cancer treatment.

Small interfering RNA (siRNA), with its highly sequence-specific ability to modulate target gene expression, is seen as a promising therapeutic approach in cancer therapy. However, the major impediments to widespread clinical utilization are the optimal and durable targeting of target genes and safe and effective delivery of siRNA to the site of interest in the tumor niche. In this review, we will discuss gold nanocarriers with varied geometries and architecture as siRNA delivery vehicles for targeted cancer treatment. In addition, the gold nanostructures provide optical imaging functionalities as well as the ability to optically track delivery of siRNA to the cancer site, thus enabling true theranostics.

Radiotherapy is a component of the standard of care for many patients with locally advanced nonmetastatic tumors and increasingly those with oligometastatic tumors. Despite encouraging advances in local control and progression-free and overall survival outcomes, continued manifestation of tumor progression or recurrence leaves room for improvement in therapeutic efficacy. Novel combinations of radiation with immunotherapy have shown promise in improving outcomes and reducing recurrences by overcoming tumor immune tolerance and evasion mechanisms via boosting the immune system's ability to recognize and eradicate tumor cells. In this review, we discuss preclinical and early clinical evidence that radiotherapy and immunotherapy can improve treatment outcomes for locally advanced and metastatic tumors, elucidate underlying molecular mechanisms and address strategies to optimize timing and sequencing of combination therapy for maximal synergy.

Purpose Active Breathing Coordinator (Elekta AB, Crawley, UK) is a motion management strategy for radiation treatment. During setup, aligning the patient to the bony spine alone does not necessarily lead to an accurate alignment to soft tissue targets, and further adjustment is necessary. Determining a safe range of values for such adjustments is an important quality assurance measure and was the purpose of this study, with focus on stereotactic body radiation therapy in patients with pancreatic cancer. Methods and Materials The retrospective study included 19 previously treated patients. For each fraction, a free-breathing cone beam computed tomography scan was registered to a reference breath-hold computed tomography for alignment to the spine. Two perpendicular breath-hold kV projection images were then acquired and compared with corresponding reference digitally reconstructed radiographs for additional alignment with a surrogate fiducial marker. By comparing the breath-hold kV projection images from subsequent treatment fractions with those from the first fraction, we derived the 3-dimensional variability of the fiducial position with respect to the reference image. Results We observed intrafraction setup error to be within 2.0 mm. For interfraction, we observed average reproducibility of 1.7 ± 0.8 mm, 2.0 ± 1.4 mm, and 3.2 ± 2.5 mm in the left–right (LR), anterior–posterior (AP), and superior–inferior (SI) directions, respectively. The average excursion values from free breathing spine to breath-hold fiducial alignment were 1.5 ± 1.4 mm, 2.0 ± 1.9 mm, and 3.0 ± 2.0 mm in the LR, AP and SI directions, respectively. The observed ranges of average excursions among all patients were 0.2 to 5.1 mm, 0.1 to 5. 9 mm, and 0.6 to 7.8 mm in the LR, AP, and SI directions, respectively. Conclusions This study demonstrates that intrafraction targeting errors can be within 2 mm, and interfraction shifts from free-breathing spine to Active Breathing Coordinator breath-hold target can be as high as 8 mm. Values that deviate significantly would need further investigation to rule out factors such as local progression, bowel gas, or fiducial shift before treatment.

BACKGROUND AND PURPOSE: This study documents the utilization and efficacy of proton beam therapy (PBT) in western patients with localized unresectable hepatocellular carcinoma (HCC). METHODS AND METHODS: Forty-six patients with HCC, Child-Pugh class of A or B, no prior radiotherapy history, and ECOG performance status 0-2 received PBT at our institution from 2007 to 2016. Radiographic control within the PBT field (local control, LC) and overall survival (OS) were calculated from the start of PBT. RESULTS: Most (83%) patients had Child-Pugh class A. Median tumor size was 6 cm (range, 1.5-21.0 cm); 22% of patients had multiple tumors and 28% had tumor vascular thrombosis. Twenty-five (54%) patients received prior treatment. Median biologically effective dose (BED) was 97.7 GyE (range, 33.6-144 GyE) administered in 15 fractions. Actuarial 2-year LC and OS rates were 81% and 62%; median OS was 30.7 months. Out-of-field intrahepatic failure was the most common site of disease progression. Patients receiving BED ≥90 GyE had a significantly better OS than those receiving BED

An ever-increasing body of literature affirms the physical and biological basis for sensitisation of tumours to conventional therapies such as chemotherapy and radiation therapy by mild temperature hyperthermia. This knowledge has fuelled the efforts to attain, maintain, measure and monitor temperature via technological advances. A relatively new entrant in the field of hyperthermia is nanotechnology which capitalises on locally injected or systemically administered nanoparticles that are activated by extrinsic energy sources to generate heat. This review describes the kinds of nanoparticles available for hyperthermia generation, their activation sources, their characteristics, and the unique opportunities and challenges with nanoparticle-mediated hyperthermia.

Theoretical investigations suggest that gold nanoparticle (GNP)-mediated radiation dose enhancement and radiosensitization can be maximized when photons interact with gold, predominantly via photoelectric absorption. This makes ytterbium (Yb)-169, which emits photons with an average energy of 93 keV (just above the K-edge of gold), an ideal radioisotope for such purposes. This investigation tests the feasibility of tumor-specific prostate brachytherapy achievable with Yb-169 and actively targeted GNPs, using an external beam surrogate of Yb-169 created from an exotic filter material - erbium (Er) and a standard copper-filtered 250 kVp beam. The current in vitro study shows that treatment of prostate cancer cells with goserelin-conjugated gold nanorods (gGNRs) promotes gonadotropin releasing hormone receptor-mediated internalization and enhances radiosensitivity to both Er-filtered and standard 250 kVp beams, 14 and 10%, respectively. While the degree of GNP-mediated radiosensitization as seen from the in vitro study may be considered moderate, the current in vivo study shows that gGNR treatment plus Er-filtered x-ray irradiation is considerably more effective than radiation treatment alone (p

Purpose Intracellular localization of gold nanoparticles has been shown to enhance the effects of radiation. However, few studies have investigated the effect of subcellular localization of these particles on enhancing the radiosensitization effect in cells treated with radiation of varying energies and linear energy transfer (LET) levels. Herein, we evaluate the radiosensitization potential of nuclear-targeted gold nanoparticles across a spectrum of energies and LETs. Methods Gold nanospheres (AuNSs) were functionalized with a nuclear localization sequence (NLS) peptide to enhance the nuclear accumulation of these particles. Internalization of the particles into the cells was achieved using a cell penetrating peptide (CPP). Cellular and nuclear internalization were assessed in Panc-1 human pancreatic adenocarcinoma cancer cells using western blot (WB), transmission electron microscopy, dark field microscopy and inductively-coupled plasma mass spectrometry (ICP-MS). DNA damage due to radiation was evaluated through γH2AX and 53BP1 foci staining. Clonogenic cell survival assay was performed to evaluate the radiosensitization effect after irradiation with 250-kVp X-rays, Cs-137, Co-60, 6 MV and 100 MeV protons (LET 2.5 and 7.7 keV/µm). Results Nuclear-targeted particles (nAuNS) and non-targeted particles (PEGylated, pAuNS) demonstrated similar cellular internalization. However, enhanced uptake of nuclear-targeted particles was observed in the nucleus when compared to non-targeted particles. This was confirmed using dark field microscopy, WB and ICP-MS analysis. DNA double strand breaks through γH2AX and 53BP1 foci staining revealed significantly higher numbers of foci at early (1 hour) and late (24 hour) time points following radiation and nAuNS compared to radiation and pAuNS treatment. Clonogenic cell survival assay revealed significantly higher radiosensitization enhancement factor (REF) at 10% survival fraction for nAuNS compared to pAuNS for all beams assessed. Protons with higher LETs resulted in greater clonogenic cell death and nAuNS further increased radiosensitization whereas pAuNS did not. Conclusion Our data demonstrates that, across a spectrum of radiation energies and LETs, nuclear-targeted gold nanoparticles enhance radiosensitization beyond that achievable with strictly intracytoplasmic gold nanoparticles. Citation Format: Sunil Krishnan, Maureen Aliru. Nuclear-targeted gold nanoparticles as radiosensitizers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3212.

Abstract 4683 Natural killer (NK) cells can kill malignant or virus-infected cells through the interaction of activating and inhibitory receptors without needing specific antigen recognition of target cells, and therefor have broad therapeutic applications for treatment of human malignancies. However, due to their limited life-span in vivo and poor expansion in vitro, production of sufficient numbers of NK cells for effective adoptive immunotherapy poses an obstacle. Genetically engineered artificial antigen presenting cells (aAPCs) consisting of K562 modified 4-1BBL and membrane bound IL-15 or IL-21 have been reported for their ability to support ex vivo NK cell proliferation. aAPCs with mbIL-21 were shown to promote increased proliferation of NK cells with shorter telomeres, but differences in in vivo survival or tumor or tissue migration have not been assessed. Tumor and/or tissue migration is primarily mediated by the expression of chemokine receptors. Using aAPCs bearing mbIL15 or mbIL21, we expanded NK cells for 3 weeks and assessed their expression of chemokine receptors, organ migration, and in vivo survival in a xenograft model. Propagated NK cells showed relatively similar levels of low to modest expression of CCR2, CCR7, CXCR4 and CXCR5, and high expression levels of CXCR3. Mean CCR5 expression levels were similar on cells that were positive, but CCR5 was expressed on a higher percentage of NK cells expanded with mbIL-15 than those expanded with mbIL-21. In contrast, about 20% of mbIL-21 expanded NK cells expressed CX3CR1 expression whereas mbIL-15 NK cells showed almost no expression of this receptor. Results from ongoing migration and survival experiments will also be presented. Disclosures: No relevant conflicts of interest to declare.