Venkatesulu, Bhanu Prasad

Inadequate light penetration in tissues restricts photodynamic therapy to treating only superficial tumors. To enable x-ray–excited photodynamic therapy (XPDT) that targets deep-seated tumors, we synthesized a nanoscintillator-photosensitizer complex containing 5% Eu-doped Y 2 O 3 fluorescing at 611 nanometers and decorated with SiO 2 containing the scintillation-coupled photosensitizer methylene blue and a polyethylene glycol coating [PEGylated Y 2 O 3 :Eu@SiO 2 -methylene blue (pYSM)]. When irradiated, pYSMs generate singlet oxygen species in vitro, causing cytotoxicity with hallmarks of immunogenic cell death (calreticulin translocation to the cell membrane). Intravenously administered pYSMs home passively to pancreatic tumor xenografts and, upon 10 gray irradiation, cause significant tumor regression ( P < 0.01). On combining XPDT with anti-PD1 immunotherapy, a distant nonirradiated tumor also regresses via an increase in intratumoral activated CD8 + cytotoxic T cells. Collectively, we advance a systemically delivered XPDT strategy that mediates an antitumor effect in both irradiated and nonirradiated (abscopal) tumors when coupled with immunotherapy, converting an immunologically “cold” tumor to an immunologically “hot” tumor.

Abstract BACKGROUND The assessment of BM response to WBRT and its impact on NCF in clinical trials has been limited by lack of standardized imaging protocols. NRG-CC001 is a randomized clinical trial requiring pre-specified MRI protocols at baseline and 6-months, providing a uniform dataset to investigate if RR correlates with NCF changes. METHODS NRG-CC001 randomized patients with BM to hippocampal avoidance WBRT (HA-WBRT) or WBRT. NCF was analyzed using 6-month standardized change scores and deterioration, defined using the reliable change index. Chi-square and t-tests were used for pretreatment characteristic comparisons. Inter-rater reliability between central and institutional assessment of RR was assessed with weighted kappa, κ. Linear regression was used to test trends in NCF change scores across types of response and multivariable logistic regression was used to test the association of RR to NCF deterioration. RESULTS 149 and 135 patients were evaluable for RR and NCF assessment, respectively. Pretreatment characteristics were well-balanced, except for post-high school education (70.6% HA-WBRT vs. 52.5% WBRT, p=0.023). Inter-rater reliability between central and institutional assessment of RR was fair (κ=0.36). There was no difference between arms in RR (p=0.41) with overall rates of 14.1% CR, 42.2% PR, 17% SD, and 26.7% PD. Patients with CR had improved 6-month NCF change as measured by HVLT-R Total Recall (p=0.0005), HVLT-R Delayed Recall (p=0.0003), HVLT-R Delayed Recognition (p=0.011), TMT-B (p=0.033), COWA (p=0.016), and Clinical Trial Battery Composite score (p=0.0011). Multivariable analysis demonstrated less deterioration in HVLT-R Delayed Recall for CR (p=0.019) and PR (p=0.0086) vs. SD/PD and HVLT-R Recognition for PR (p=0.031) vs. SD/PD. CONCLUSIONS HA-WBRT and WBRT result in similar RR at 6-months. CR or PR is associated with better NCF preservation. This suggests investigation into treatment escalation for patients with SD/PD may provide further NCF benefit along with HA-WBRT and memantine.Grant support from NCI-UG1CA189867 and U24CA180803.

Radiotherapy (RT) of colorectal cancer (CRC) can prime adaptive immunity against tumor-associated antigen (TAA)–expressing CRC cells systemically. However, abscopal tumor remissions are extremely rare, and the postirradiation immune escape mechanisms in CRC remain elusive. Here, we found that irradiated CRC cells used ATR-mediated DNA repair signaling pathway to up-regulate both CD47 and PD-L1, which through engagement of SIRPα and PD-1, respectively, prevented phagocytosis by antigen-presenting cells and thereby limited TAA cross-presentation and innate immune activation. This postirradiation CD47 and PD-L1 up-regulation was observed across various human solid tumor cells. Concordantly, rectal cancer patients with poor responses to neoadjuvant RT exhibited significantly elevated postirradiation CD47 levels. The combination of RT, anti-SIRPα, and anti–PD-1 reversed adaptive immune resistance and drove efficient TAA cross-presentation, resulting in robust TAA-specific CD8 T cell priming, functional activation of T effectors, and increased T cell clonality and clonal diversity. We observed significantly higher complete response rates to RT/anti-SIRPα/anti–PD-1 in both irradiated and abscopal tumors and prolonged survival in three distinct murine CRC models, including a cecal orthotopic model. The efficacy of triple combination therapy was STING dependent as knockout animals lost most benefit of adding anti-SIRPα and anti–PD-1 to RT. Despite activation across the myeloid stroma, the enhanced dendritic cell function accounts for most improvements in CD8 T cell priming. These data suggest ATR-mediated CD47 and PD-L1 up-regulation as a key mechanism restraining radiation-induced immune priming. RT combined with SIRPα and PD-1 blockade promotes robust antitumor immune priming, leading to systemic tumor regressions.

CXC chemokine receptor 4 (CXCR4) is overexpressed on most breast cancer cell surfaces including triple negative breast cancer (TNBC) which lacks traditional receptor overexpression.

Abstract Background Cancer patients with coronavirus disease 2019 (COVID-19) have been reported to have double the case fatality rate of the general population. Methods A systematic search of PubMed, Embase, and Cochrane Central was done for studies on cancer patients with COVID-19. Pooled proportions were calculated for categorical variables. Odds ratio (OR) and forest plots (random-effects model) were constructed for both primary and secondary outcomes. Results This systematic review of 38 studies and meta-analysis of 181 323 patients from 26 studies included 23 736 cancer patients. Our meta-analysis shows that cancer patients with COVID-19 have a higher likelihood of death (n = 165 980, OR = 2.54, 95% confidence interval [CI] = 1.47 to 4.42), which was largely driven by mortality among patients in China. Cancer patients were more likely to be intubated. Among cancer subtypes, the mortality was highest in hematological malignancies (n = 878, OR = 2.39, 95% CI = 1.17 to 4.87) followed by lung cancer (n = 646, OR = 1.83, 95% CI = 1.00 to 3.37). There was no association between receipt of a particular type of oncologic therapy and mortality. Our study showed that cancer patients affected by COVID-19 are a decade older than the normal population and have a higher proportion of comorbidities. There was insufficient data to assess the association of COVID-19–directed therapy and survival outcomes in cancer patients. Conclusion Cancer patients with COVID-19 disease are at increased risk of mortality and morbidity. A more nuanced understanding of the interaction between cancer-directed therapies and COVID-19–directed therapies is needed. This will require uniform prospective recording of data, possibly in multi-institutional registry databases.

Abstract The coronavirus disease-2019 (COVID-19) pandemic caused by SARS-CoV-2 has exacted an enormous toll on healthcare systems worldwide. The cytokine storm that follows pulmonary infection is causally linked to respiratory compromise and mortality in the majority of patients. The sparsity of viable treatment options for this viral infection and the sequelae of pulmonary complications have fueled the quest for new therapeutic considerations. One such option, the long-forgotten idea of using low-dose radiation therapy, has recently found renewed interest in many academic centers. We outline the scientific and logistical rationale for consideration of this option and the mechanistic underpinnings of any potential therapeutic value, particularly as viewed from an immunological perspective. We also discuss the preliminary and/or published results of prospective trials examining low-dose radiation therapy for COVID-19.

Proton minibeam therapy (PMBT) is a form of spatially fractionated radiotherapy wherein broad beam radiation is replaced with segmented minibeams—either parallel, planar minibeam arrays generated by a multislit collimator or scanned pencil beams that converge laterally at depth to create a uniform dose layer at the tumor. By doing so, the spatial pattern of entrance dose is considerably modified while still maintaining tumor dose and efficacy. Recent studies using computational modeling, phantom experiments, in vitro and in vivo preclinical models, and early clinical feasibility assessments suggest that unique physical and biological attributes of PMBT can be exploited for future clinical benefit. We outline some of the guiding principle of PMBT in this concise overview of this emerging area of preclinical and clinical research inquiry.