Hybridizing mechanistic mathematical modeling with deep learning methods to predict individual cancer patient survival after immune checkpoint inhibitor therapy.

We present a study where predictive mechanistic modeling is used in combination with deep learning methods to predict individual patient survival probabilities under immune checkpoint inhibitor (ICI) therapy. This hybrid approach enables prediction based on both measures that are calculable from mechanistic models (but may not be directly measurable in the clinic) and easily measurable quantities or characteristics (that are not always readily incorporated into predictive mechanistic models). The mechanistic model we have applied here can predict tumor response from CT or MRI imaging based on key mechanisms underlying checkpoint inhibitor therapy, and in the present work, its parameters were combined with readily-available clinical measures from 93 patients into a hybrid training set for a deep learning time-to-event predictive model. Analysis revealed that training an artificial neural network with both mechanistic modeling-derived and clinical measures achieved higher per-patient predictive accuracy based on event-time concordance, Brier score, and negative binomial log-likelihood-based criteria than when only mechanistic model-derived values or only clinical data were used. Feature importance analysis revealed that both clinical and model-derived parameters play prominent roles in neural network decision making, and in increasing prediction accuracy, further supporting the advantage of our hybrid approach. We anticipate that many existing mechanistic models may be hybridized with deep learning methods in a similar manner to improve predictive accuracy through addition of additional data that may not be readily implemented in mechanistic descriptions.

Digital Screen Time and the Risk of Female Breast Cancer: A Retrospective Matched Case-Control Study.

Background: As the use of electronic devices such as mobile phones, tablets, and computers continues to rise globally, concerns have been raised about their potential impact on human health. Exposure to high energy visible (HEV) blue light, emitted from digital screens, particularly the so-called artificial light at night (ALAN), has been associated with adverse health effects, ranging from disruption of circadian rhythms to cancer. Breast cancer incidence rates are also increasing worldwide. Objective: This study aimed at finding a correlation between breast cancer and exposure to blue light from mobile phone. Material and Methods: In this retrospective matched case-control study, we aimed to investigate whether exposure to blue light from mobile phone screens is associated with an increased risk of female breast cancer. We interviewed 301 breast cancer patients (cases) and 294 controls using a standard questionnaire and performed multivariate analysis, chi-square, and Fisher's exact tests for data analysis. Results: Although heavy users in the case group of our study had a statistically significant higher mean 10-year cumulative exposure to digital screens compared to the control group (7089±14985 vs 4052±12515 hours, respectively, P=0.038), our study did not find a strong relationship between exposure to HEV and development of breast cancer. Conclusion: Our findings suggest that heavy exposure to HEV blue light emitted from mobile phone screens at night might constitute a risk factor for promoting the development of breast cancer, but further large-scale cohort studies are warranted.

Inhibition of MER proto-oncogene tyrosine kinase by an antisense oligonucleotide enhances treatment efficacy of immunoradiotherapy.

BACKGROUND: The combination of radiotherapy and immunotherapy (immunoradiotherapy) has been increasingly used for treating a wide range of cancers. However, some tumors are resistant to immunoradiotherapy. We have previously shown that MER proto-oncogene tyrosine kinase (MerTK) expressed on macrophages mediates resistance to immunoradiotherapy. We therefore sought to develop therapeutics that can mitigate the negative impact of MerTK. We designed and developed a MerTK specific antisense oligonucleotide (ASO) and characterized its effects on eliciting an anti-tumor immune response in mice. METHODS: 344SQR cells were injected into the right legs on day 0 and the left legs on day 4 of 8-12 weeks old female 129sv/ev mice to establish primary and secondary tumors, respectively. Radiation at a dose of 12 Gy was given to the primary tumors on days 8, 9, and 10. Mice received either anti-PD-1, anti-CTLA-4 or/and MerTK ASO starting from day 1 post tumor implantation. The composition of the tumor microenvironment and the level of MerTK on macrophages in the tumor were evaluted by flow cytometry. The expression of immune-related genes was investigated with NanoString. Lastly, the impact of MerTK ASO on the structure of the eye was histologically evaluated. RESULTS: Remarkably, the addition of MerTK ASO to XRT+anti-PD1 and XRT+anti-CTLA4 profoundly slowed the growth of both primary and secondary tumors and significantly extended survival. The ASO significantly reduced the expression of MerTK in tumor-associated macrophages (TAMs), reprograming their phenotype from M2 to M1. In addition, MerTK ASO increased the percentage of Granzyme B+ CD8+ T cells in the secondary tumors when combined with XRT+anti-CTLA4. NanoString results demonstrated that the MerTK ASO favorably modulated immune-related genes for promoting antitumor immune response in secondary tumors. Importantly, histological analysis of eye tissues demonstrated that unlike small molecules, the MerTK ASO did not produce any detectable pathology in the eyes. CONCLUSIONS: The MerTK ASO can significantly downregulate the expression of MerTK on TAMs, thereby promoting antitumor immune response. The combination of MerTK ASO with immunoradiotherapy can safely and significantly slow tumor growth and improve survival.

Consumption of Apigenin Prevents Radiation-induced Gut Dysbiosis in Male C57BL/6J Mice Exposed to Silicon Ions.

The search for medical treatments to prevent radiation-induced damage to gastrointestinal tissue is crucial as such injuries can be fatal. This study aimed to investigate the effects of apigenin (AP) on the gut microbiome of irradiated mice, as it is a promising radiation countermeasure. Male C57BL/6J mice were divided into four groups, with six mice in each group. Two groups were given food with apigenin (20 mg/kg body weight or AP 20) before and after exposure to 0 or 50 cGy of silicon (28Si) ions, while another two groups of mice received regular diet without apigenin (0 mg/kg body weight or AP 0) before and after irradiation. The duodenum, the primary site for oral AP absorption, was collected from each mouse seven days after radiation exposure. Using 16S rRNA amplicon sequencing, we found significant differences in microbial diversity among groups. Firmicutes and Bacteroidetes were the major phyla for all groups, while actinobacterial and proteobacterial sequences represented only a small percentage. Mice not given dietary apigenin had a higher Firmicutes and Bacteroidetes (F/B) ratio and an imbalanced duodenal microbiota after exposure to radiation, while irradiated mice given apigenin had maintained homeostasis of the microbiota. Additionally, irradiated mice not given apigenin had decreased probiotic bacteria abundance and increased inflammation, while apigenin-supplemented mice had reduced inflammation and restored normal histological structure. In conclusion, our results demonstrate the potential of dietary apigenin as a countermeasure against radiation-induced gut injuries due to its anti-inflammatory activity, reduction of gut microbiota dysbiosis, and increase in probiotic bacteria (e.g., Lachnospiraceae, Muribaculaceae and Bifidobacteriaceae).

Survival outcomes and toxicity of adjuvant immunotherapy after definitive concurrent chemotherapy with proton beam radiation therapy for patients with inoperable locally advanced non-small cell lung carcinoma.

INTRODUCTION: Adjuvant immunotherapy (IO) following concurrent chemotherapy and photon radiation therapy confers an overall survival (OS) benefit for patients with inoperable locally advanced non-small cell lung carcinoma (LA-NSCLC); however, outcomes of adjuvant IO after concurrent chemotherapy with proton beam therapy (CPBT) are unknown. We investigated OS and toxicity after CPBT with adjuvant IO versus CPBT alone for inoperable LA-NSCLC. MATERIALS AND METHODS: We analyzed 354 patients with LA-NSCLC who were prospectively treated with CPBT with or without adjuvant IO from 2009 to 2021. Optimal variable ratio propensity score matching (PSM) matched CPBT with CPBT + IO patients. Survival was estimated with the Kaplan-Meier method and compared with log-rank tests. Multivariable Cox proportional hazards regression evaluated the effect of IO on disease outcomes. RESULTS: Median age was 70 years; 71 (20%) received CPBT + IO and 283 (80%) received CPBT only. After PSM, 71 CPBT patients were matched with 71 CPBT + IO patients. Three-year survival rates for CPBT + IO vs CPBT were: OS 67% vs 30% (P < 0.001) and PFS 59% vs 35% (P = 0.017). Three-year LRFS (P = 0.137) and DMFS (P = 0.086) did not differ. Receipt of adjuvant IO was a strong predictor of OS (HR 0.40, P = 0.001) and PFS (HR 0.56, P = 0.030), but not LRFS (HR 0.61, P = 0.121) or DMFS (HR 0.61, P = 0.136). There was an increased incidence of grade ≥3 esophagitis in the CPBT-only group (6% CPBT + IO vs 17% CPBT, P = 0.037). CONCLUSION: This study, one of the first to investigate CPBT followed by IO for inoperable LA-NSCLC, showed that IO conferred survival benefits with no increased rates of toxicity.

Bombarding Oligoprogression: Oncologic Outcomes After Radiation to Patients With Oligoprogressive Non-Small Cell Lung Cancer on Maintenance Systemic Therapy.

OBJECTIVES: This study aims to evaluate the efficacy and toxicity of radiotherapy (RT) to oligoprogressive metastatic non-small cell lung cancer (NSCLC). METHODS: This is a retrospective analysis of 23 patients with metastatic NSCLC on maintenance systemic therapy, developed oligoprogression (1 to 5 sites), and all oligoprogressive sites amenable to and treated with RT. The primary endpoints included progression-free survival (PFS) and median time to start next-line therapy (MTT). Kaplan-Meier survival analysis and log-rank testing were performed using R-Studio software. RESULTS: Twenty-three patients met the inclusion criteria. The median overall survival for the entire cohort was 31.3 months (interquartile range [IQR]: 17.86 to 45.4). The median event-free survival for the entire cohort was 8.3 months (IQR: 2.7 to 12). Patients with no prior radiation had longer median event-free survival of 11.9 months (IQR: 8.4 to 18.2) compared with patients with a history of prior radiation at 4.1 months (IQR: 2.7 to 12; P = 0.041). The local control rate for the treated lesions was 97.5%. At 12 months follow-up, 6 (43%) of 14 living patients maintained systemic therapy without initiating next-line therapy. The median PFS for the entire cohort was 8.4 months (IQR: 4.1 to 17.5). Patients who did not receive prior radiation had longer median PFS of 11.9 months (IQR: 8.4 to 18.2) compared with patients who received prior radiation 6.2 months (IQR: 2.7 to 8.5; P = 0.018). Two patients (9%) had grade 3 chronic toxicity related to RT and were medically managed. CONCLUSION: We identified that in patients with oligoprogressive metastatic NSCLC, targeted RT to all progressive sites yielded high LC and favorable rates of PFS and MTT.

Microbiome and Abdominopelvic Radiotherapy Related Chronic Enteritis: A Microbiome-based Mechanistic Role of Probiotics and Antibiotics.

Chronic diarrhea and abdominal pain after radiotherapy continue to be a problem in cancer survivors. Gut microbiomes are essential for preventing intestinal inflammation, maintaining intestinal integrity, maintaining enterohepatic circulation, regulating bile acid metabolism, and absorption of nutrients, including fat-soluble vitamins. Gut microbiome dysbiosis is expected to cause inflammation, bile acid malabsorption, malnutrition, and associated symptoms. Postradiotherapy, Firmicutes and Bacteroidetes phylum are significantly decreased while Fusobacteria and other unclassified bacteria are increased. Available evidence suggests harmful bacteria Veillonella, Erysipelotrichaceae, and Ruminococcus are sensitive to Metronidazole or Ciprofloxacin. Beneficial bacteria lactobacillus and Bifidobacterium are relatively resistant to metronidazole. We hypothesize and provide an evidence-based review that short-course targeted antibiotics followed by specific probiotics may lead to alleviation of radiation enteritis.

The influence of mental toughness on responses to feedback in snooker: A real-time examination.

Two experiments investigated whether mental toughness (MT) is associated with the ability to respond to and/or overcome unwanted information during real-time sport performance. Participants were male snooker players ranging from club to professional level, and MT was measured using the MTQ48 (Clough et al., 2002). In experiment 1, players performed five break-off shots and received deceptive feedback (either positive or negative) from the researcher about their performance relative to other players. Then they performed another five break-offs. Results showed a significant decline in performance following feedback, but no interaction with the nature of feedback or MT variables. In experiment 2, feedback was delivered by a coach and yielded a significant effect on performance. Specifically, negative feedback improved performance while positive feedback impaired performance. The Life Control subscale of the MTQ48 was a significant covariate. The results suggest that negative feedback, delivered constructively by a respected figure, may act as a catalyst for performance enhancement in snooker and that this is moderated by MT.

The Inherited KRAS-variant as a Biomarker of Cetuximab Response in NSCLC.

PURPOSE: RTOG 0617 was a phase III randomized trial for patients with unresectable stage IIIA/IIIB non-small cell lung cancer comparing standard-dose (60 Gy) versus high-dose (74 Gy) radiotherapy and chemotherapy, plus or minus cetuximab. Although the study was negative, based on prior evidence that patients with the KRAS-variant, an inherited germline mutation, benefit from cetuximab, we evaluated KRAS-variant patients in RTOG 0617. EXPERIMENTAL DESIGN: From RTOG 0617, 328 of 496 (66%) of patients were included in this analysis. For time-to-event outcomes, stratified log-rank tests and multivariable Cox regression models were used. For binary outcomes, Cochran-Mantel-Haenzel tests and multivariable logistic regression models were used. All statistical tests were two sided, and a P value <0.05 was considered significant. RESULTS: A total of 17.1% (56/328) of patients had the KRAS-variant, and overall survival rates were similar between KRAS-variant and non-variant patients. However, there was a time-dependent effect of cetuximab seen only in KRAS-variant patients-while the hazard of death was higher in cetuximab-treated patients within year 1 [HR = 3.37, 95% confidence interval (CI): 1.13-10.10, P = 0.030], death was lower from year 1 to 4 (HR = 0.33, 95% CI: 0.11-0.97, P = 0.043). In contrast, in non-variant patients, the addition of cetuximab significantly increased local failure (HR = 1.59, 95% CI: 1.11-2.28, P = 0.012). CONCLUSIONS/DISCUSSION: Although an overall survival advantage was not achieved in KRAS-variant patients, there is potential impact of cetuximab for this genetic subset of patients. In contrast, cetuximab seems to harm non-variant patients. These findings further support the importance of genetic patient selection in trials studying the addition of systemic agents to radiotherapy. SIGNIFICANCE: The KRAS-variant is the first functional, inherited miRNA-disrupting variant identified in cancer. Our findings support that cetuximab has a potentially beneficial impact on KRAS-variant patients treated with radiation. The work confirms prior evidence that KRAS-variant patients are a subgroup who are especially sensitive to radiation. These findings further support the potential of this class of variants to enable true treatment personalization, considering the equally important endpoints of response and toxicity.

Nivolumab and ipilimumab with concurrent stereotactic radiosurgery for intracranial metastases from non-small cell lung cancer: analysis of the safety cohort for non-randomized, open-label, phase I/II trial.

BACKGROUND: Up to 20% of patients with non-small cell lung cancer (NSCLC) develop brain metastasis (BM), for which the current standard of care is radiation therapy with or without surgery. There are no prospective data on the safety of stereotactic radiosurgery (SRS) concurrent with immune checkpoint inhibitor therapy for BM. This is the safety cohort of the phase I/II investigator-initiated trial of SRS with nivolumab and ipilimumab for patients with BM from NSCLC. PATIENTS AND METHODS: This single-institution study included patients with NSCLC with active BM amenable to SRS. Brain SRS and systemic therapy with nivolumab and ipilimumab were delivered concurrently (within 7 days). The endpoints were safety and 4-month intracranial progression-free survival (PFS). RESULTS: Thirteen patients were enrolled in the safety cohort, 10 of whom were evaluable for dose-limiting toxicities (DLTs). Median follow-up was 23 months (range 9.7-24.3 months). The median interval between systemic therapy and radiation therapy was 3 days. Only one patient had a DLT; hence, predefined stopping criteria were not met. In addition to the patient with DLT, three patients had treatment-related grade ≥3 adverse events, including elevated liver function tests, fatigue, nausea, adrenal insufficiency, and myocarditis. One patient had a confirmed influenza infection 7 months after initiation of protocol treatment (outside the DLT assessment window), leading to pneumonia and subsequent death from hemophagocytic lymphohistiocytosis. The estimated 4-month intracranial PFS rate was 70.7%. CONCLUSION: Concurrent brain SRS with nivolumab/ipilimumab was safe for patients with active NSCLC BM. Preliminary analyses of treatment efficacy were encouraging for intracranial treatment response.

Stereotactic ablative radiotherapy with or without immunotherapy for early-stage or isolated lung parenchymal recurrent node-negative non-small-cell lung cancer: an open-label, randomised, phase 2 trial.

BACKGROUND: Stereotactic ablative radiotherapy (SABR) is the standard treatment for medically inoperable early-stage non-small-cell lung cancer (NSCLC), but regional or distant relapses, or both, are common. Immunotherapy reduces recurrence and improves survival in people with stage III NSCLC after chemoradiotherapy, but its utility in stage I and II cases is unclear. We therefore conducted a randomised phase 2 trial of SABR alone compared with SABR with immunotherapy (I-SABR) for people with early-stage NSCLC. METHODS: We did an open-label, randomised, phase 2 trial comparing SABR to I-SABR, conducted at three different hospitals in TX, USA. People aged 18 years or older with histologically proven treatment-naive stage IA-IB (tumour size ≤4 cm, N0M0), stage IIA (tumour size ≤5 cm, N0M0), or stage IIB (tumour size >5 cm and ≤7 cm, N0M0) as per the American Joint Committee on Cancer version 8 staging system or isolated parenchymal recurrences (tumour size ≤7 cm) NSCLC (TanyNanyM0 before definitive surgery or chemoradiotherapy) were included in this trial. Participants were randomly assigned (1:1; using the Pocock & Simon method) to receive SABR with or without four cycles of nivolumab (480 mg, once every 4 weeks, with the first dose on the same day as, or within 36 h after, the first SABR fraction). This trial was unmasked. The primary endpoint was 4-year event-free survival (local, regional, or distant recurrence; second primary lung cancer; or death). Analyses were both intention to treat (ITT) and per protocol. This trial is registered with ClinicalTrials.gov (NCT03110978) and is closed to enrolment. FINDINGS: From June 30, 2017, to March 22, 2022, 156 participants were randomly assigned, and 141 participants received assigned therapy. At a median 33 months' follow-up, I-SABR significantly improved 4-year event-free survival from 53% (95% CI 42-67%) with SABR to 77% (66-91%; per-protocol population, hazard ratio [HR] 0·38; 95% CI 0·19-0·75; p=0·0056; ITT population, HR 0·42; 95% CI 0·22-0·80; p=0·0080). There were no grade 3 or higher adverse events associated with SABR. In the I-SABR group, ten participants (15%) had grade 3 immunologial adverse events related to nivolumab; none had grade 3 pneumonitis or grade 4 or higher toxicity. INTERPRETATION: Compared with SABR alone, I-SABR significantly improved event-free survival at 4 years in people with early-stage treatment-naive or lung parenchymal recurrent node-negative NSCLC, with tolerable toxicity. I-SABR could be a treatment option in these participants, but further confirmation from a number of currently accruing phase 3 trials is required. FUNDING: Bristol-Myers Squibb and MD Anderson Cancer Center Alliance, National Cancer Institute at the National Institutes of Health through Cancer Center Core Support Grant and Clinical and Translational Science Award to The University of Texas MD Anderson Cancer Center.

Nanoparticle-enhanced proton beam immunoradiotherapy drives immune activation and durable tumor rejection.

The combination of radiation therapy (RT) and immunotherapy has emerged as a promising treatment option in oncology. Historically, x-ray radiation (XRT) has been the most commonly used form of RT. However, proton beam therapy (PBT) is gaining recognition as a viable alternative, as it has been shown to produce similar outcomes to XRT while minimizing off-target effects. The effects of PBT on the antitumor immune response have only just begun to be described, and to our knowledge no studies to date have examined the effect of PBT as part of a combinatorial immunoradiotherapeutic strategy. Here, using a 2-tumor model of lung cancer in mice, we show that PBT in tandem with an anti-PD1 antibody substantially reduced growth in both irradiated and unirradiated tumors. This was accompanied by robust activation of the immune response, as evidenced by whole-tumor and single-cell RNA sequencing showing upregulation of a multitude of immune-related transcripts. This response was further significantly enhanced by the injection of the tumor to be irradiated with NBTXR3 nanoparticles. Tumors of mice treated with the triple combination exhibited increased infiltration and activation of cytotoxic immune cells. This triple combination eradicated both tumors in 37.5% of the treated mice and showed robust long-term immunity to cancer.

How Reactivation of SARS-CoV-2 in Astronauts with Dysregulated Immune Systems Can Negatively Affect the Odds of Success in Future Space Missions.

We have previously reported that during future space missions the risk of severe COVID-19 infection will be a cardinal issue that needs careful attention. Our studies show that even with the most reliable pre-mission screening and quarantine strategies, astronauts with a latent (hidden, inactive, or dormant) SARS-CoV-2 infection might be sent to space. Given this consideration, an asymptomatic individual with dormant SARS-CoV-2 infection may successfully pass all the pre-launch medical tests. Then during a space mission such as a journey to Mars or beyond, when the immune system of these astronauts starts to weaken, the dormant infection may progress to a severe infection that possibly affects the chance of the mission's success. The effects of microgravity and the elevated space radiation are two key factors that should be evaluated. Furthermore, the limited size of the spacecraft, the proximity of crew members during flight operations, spacecraft atmospheric composition, limited exercise capability, effects of viral response to space radiation, and uncertainty in the likelihood of the virus to mutate and evolve during a space mission merit additional study.

Durable control of metastases in an HLA-A2+ patient with refractory melanoma after low-dose radiotherapy in combination with MAGE-A4 T cell therapy: a case report.

There is no currently approved adoptive cellular therapy for solid tumors. Pre-clinical and clinical studies have demonstrated that low-dose radiotherapy (LDRT) can enhance intratumoral T cell infiltration and efficacy. This case report describes a 71-year-old female patient with rectal mucosal melanoma that had developed metastases to liver, lung, mediastinum, axillary nodes, and brain. After systemic therapies had failed, she enrolled in the radiation sub-study of our phase-I clinical trial exploring the safety and efficacy of afamitresgene autoleucel (afami-cel), genetically engineered T cells with a T cell receptor (TCR) targeting the MAGE-A4 tumor antigen in patients with advanced malignancies (NCT03132922). Prior to the infusion of afami-cel, she received concurrent lymphodepleting chemotherapy and LDRT at 5.6 Gy/4 fractions to the liver. Time to partial response was 10 weeks, and duration of overall response was 18.4 weeks. Although the patient progressed at 28 weeks, the disease was well controlled after high-dose radiotherapy to liver metastases and checkpoint inhibitors. As of the last follow-up, she remains alive over two years after LDRT and afami-cel therapy. This report suggests that afami-cel in combination with LDRT safely enhanced clinical benefit. This provides evidence for further exploring the benefit of LDRT in TCR-T cell therapy.

Updates on radiotherapy-immunotherapy combinations: Proceedings of 6th annual ImmunoRad conference.

Focal radiation therapy (RT) has attracted considerable attention as a combinatorial partner for immunotherapy (IT), largely reflecting a well-defined, predictable safety profile and at least some potential for immunostimulation. However, only a few RT-IT combinations have been tested successfully in patients with cancer, highlighting the urgent need for an improved understanding of the interaction between RT and IT in both preclinical and clinical scenarios. Every year since 2016, ImmunoRad gathers experts working at the interface between RT and IT to provide a forum for education and discussion, with the ultimate goal of fostering progress in the field at both preclinical and clinical levels. Here, we summarize the key concepts and findings presented at the Sixth Annual ImmunoRad conference.

NLRP3 agonist enhances radiation-induced immune priming and promotes abscopal responses in anti-PD1 resistant model.

Radiotherapy (XRT), a well-known activator of the inflammasome and immune priming, is in part capable of reversing resistance to anti-PD1 treatment. The NLRP3 inflammasome is a pattern recognition receptor which is activated by both exogenous and endogenous stimuli, leading to a downstream inflammatory response. Although NLRP3 is typically recognized for its role in exacerbating XRT-induced tissue damage, the NLRP3 inflammasome can also yield an effective antitumor response when used in proper dosing and sequencing with XRT. However, whether NLRP3 agonist boosts radiation-induced immune priming and promote abscopal responses in anti-PD1 resistant model is still unknown. Therefore, in this study, we paired intratumoral injection of an NLRP3 agonist with XRT to stimulate the immune system in both wild type (344SQ-P) and anti-PD1 resistant (344SQ-R) murine-implanted lung adenocarcinoma models. We found that the combination of XRT + NLPR3 agonist enhanced the control of implanted lung adenocarcinoma primary as well as secondary tumors in a radiological dose-dependent manner, in which 12Gyx3 fractions of stereotactic XRT was better than 5Gyx3, while 1Gyx2 did not improve the NLRP3 effect. Survival and tumor growth data also showed significant abscopal response with the triple therapy (12Gyx3 + NLRP3 agonist + α-PD1) in both 344SQ-P and 344SQ-R aggressively growing models. Multiple pro-inflammatory cytokines (IL-1b, IL-4, IL-12, IL-17, IFN-γ and GM-CSF) were elevated in the serum of mice treated with XRT + NLRP3 or triple therapy. The Nanostring results showed that NLRP3 agonist is capable of increasing antigen presentation, innate function, and T-cell priming. This study can be of particular importance to treat patients with immunologically-cold solid tumors whom are also refractory to prior checkpoint treatments.

Lipid metabolism in tumor immunology and immunotherapy.

Lipids are a diverse class of biomolecules that have been implicated in cancer pathophysiology and in an array of immune responses, making them potential targets for improving immune responsiveness. Lipid and lipid oxidation also can affect tumor progression and response to treatment. Although their importance in cellular functions and their potential as cancer biomarkers have been explored, lipids have yet to be extensively investigated as a possible form of cancer therapy. This review explores the role of lipids in cancer pathophysiology and describes how further understanding of these macromolecules could prompt novel treatments for cancer.

The role of tumor metabolism in modulating T-Cell activity and in optimizing immunotherapy.

Immunotherapy has revolutionized cancer treatment and revitalized efforts to harness the power of the immune system to combat a variety of cancer types more effectively. However, low clinical response rates and differences in outcomes due to variations in the immune landscape among patients with cancer continue to be major limitations to immunotherapy. Recent efforts to improve responses to immunotherapy have focused on targeting cellular metabolism, as the metabolic characteristics of cancer cells can directly influence the activity and metabolism of immune cells, particularly T cells. Although the metabolic pathways of various cancer cells and T cells have been extensively reviewed, the intersections among these pathways, and their potential use as targets for improving responses to immune-checkpoint blockade therapies, are not completely understood. This review focuses on the interplay between tumor metabolites and T-cell dysfunction as well as the relationship between several T-cell metabolic patterns and T-cell activity/function in tumor immunology. Understanding these relationships could offer new avenues for improving responses to immunotherapy on a metabolic basis.

Outcome of Second Line Treatment of Recurrent High- Grade Glioma by re-Irradiation or Bevacizumab-based Chemotherapy: A Cross Sectional Study.

INTRODUCTION: Currently, there is no standard of treatment for the management of the recurrent high-grade glioma. Re-resection, re-irradiation, and chemotherapy are among main treatment options without any proven efficacy. AIM: To compare the outcome of second line treatment of recurrent high-grade glioma by re-irradiation or bevacizumab-based chemotherapy. METHODS: Retrospectively, patients with the recurrent high-grade glioma treated by re-irradiation (ReRT group) (34 patients) or bevacizumab-based chemotherapy (Bev group) (40 patients) as the first-file after the first recurrence were compared in term of first-line progression free survival (PFS), second-line PFS, and overall survival (OS). RESULTS: Both groups were similar in term of gender (p=0.859), age (=0.071), type of first-line treatment (p=0.227), and performance status (p=0.150). With a median follow-up of 31 months (m), mortality rate was 41.2% and 70% in the ReRT and Bev groups, respectively. In the Bev and ReRT groups, median OS was 27 m (95% confidence interval (CI) 20-33.9 m) vs. 132 m (95% CI 52.9-211 m) (p<0.0001), median first-line PFS was 11 m (95% CI 7.14-28.7 m) vs. 37 m (95% CI 8.42-65.75 m) (p<0.0001), and median second-line PFS was 7 m (95% CI 3.9-10 m) vs. 9 m (95% CI 5.5-12.4 m) (p=0.564), respectively. CONCLUSION: The PFS is similar after the second line treatment of recurrent primary central nervous system malignancies either by re-irradiation or bevacizumab-based chemotherapy.