Enhancement of Radiation Therapy through Blockade of the Immune Checkpoint, V-domain Ig Suppressor of T Cell Activation (VISTA), in Melanoma and Adenocarcinoma Murine Models.

Radiation therapy (RT) has recently demonstrated promise at stimulating an enhanced immune response. The recent success of immunotherapies, such as checkpoint inhibitors, CART cells, and other immune modulators, affords new opportunities for combination with radiation. The aim of this study is to evaluate whether and to what extent blockade of VISTA, an immune checkpoint, can potentiate the tumor control ability of radiation therapy. Our study is novel in that it is the first comparison of two VISTA-blocking methods (antibody inhibition and genetic knockout) in combination with RT. VISTA was blocked either through genetic knockout (KO) or an inhibitory antibody and combined with RT in two syngeneic murine flank tumor models (B16 and MC38). Selected mRNA, immune cell infiltration, and tumor growth delay were used to assess the biological effects. When combined with a single 15Gy radiation dose, VISTA blockade via genetic knockout in the B16 model and via anti-VISTA antibodies in the MC38 model significantly improved survival compared to RT alone by an average of 5.5 days and 6.3 days, respectively (p < 0.05). The gene expression data suggest that the mechanism behind the enhanced tumor control is primarily a result of increased apoptosis and immune-mediated cytotoxicity. VISTA blockade significantly enhances the anti-tumor effect of a single dose of 15Gy radiation through increased expression and stimulation of cell-mediated apoptosis pathways. These results suggest that VISTA is a biologically relevant immune promoter that has the potential to enhance the efficacy of a large single radiation dose in a synergic manner.

Toxicity Induced by a Bispecific T Cell-Redirecting Protein Is Mediated by Both T Cells and Myeloid Cells in Immunocompetent Mice.

Bispecific T cell engagers have demonstrated clinical efficacy; however, their use can be accompanied by severe toxicity. Mechanistic understanding of these toxicities is limited by a lack of suitable immunocompetent preclinical models. In this study, we describe an immunocompetent mouse tumor model that exhibits bispecific T cell engager-induced toxicity and recapitulates key features similar to those in human cytokine release syndrome. In this study, toxicity occurred between the second and fourth injections of an NK Group 2D bispecific T cell engager protein. Symptoms were transient, peaking 3-4 h after treatment and resolving by 8 h. Mice developed weight loss, elevated plasma cytokines, a significant reduction in spleen white pulp, and lymphocyte infiltration in the liver. Systemic cellular immune changes also occurred; notably, an increase in CD8+ T cell activation, an increase in myeloid cells in the blood, and a population of Ly-6Cint monocytes (CD11b+Ly-6G-F4/80-) emerged in the liver and spleens of bispecific protein-treated mice. IFN-γ was primarily produced by CD8+ T cells in the spleen and was required for the observed changes in both T cell and myeloid populations. Rag deficiency, IFN-γ deficiency, or depletion of either CD4+ or CD8+ T cells prevented toxicity, whereas perforin deficiency, GM-CSF deficiency, or modulation of the myeloid population through clodronate-mediated depletion showed a partial abrogation of toxicity. Together, these findings reveal that T cell activation by a bispecific T cell engager leads to changes in the host myeloid cell population, both of which contribute to treatment induced toxicity in immunocompetent mice.

Feasibility of Left Anterior Descending Coronary Artery Sparing Radiotherapy for Locally Advanced Lung Cancer.

PURPOSE: Efforts to mitigate radiotherapy (RT) associated cardiotoxicity have focused on constraining mean heart dose (MHD). However, recent studies have shown greater predictive power with cardiac substructure dose metrics such as the left anterior descending (LAD) coronary artery volume (V) receiving 15Gy (V15Gy) ≥10%. Herein, we investigated the feasibility of LAD radiation sparing in contemporary IMRT/VMAT lung cancer plans. METHODS AND MATERIALS: Single institution retrospective analysis of 54 locally advanced lung cancer patients treated with thoracic RT between February 2018-August 2021. After excluding 33 (5=non-IMRT/VMAT or intentionally LAD-optimized; 28=LAD V15Gy<10%), 21 plans with LAD V15Gy ≥10% were identified for LAD re-optimization with intent to meet LAD V15Gy <10% while maintaining meeting organ-at-risk (OAR) metrics and target coverage with original plan parameters. Dosimetric variables were compared using paired t tests. RESULTS: Most (57.1%, 12/21) were treated with definitive RT, 8/21 (38.1%) with post-operative RT, and one with neoadjuvant RT. The median prescribed RT dose was 60Gy (range 50.4-66Gy) in 30 fractions (range 28-33). LAD re-optimized plans (vs original) led to significant reductions in mean LAD V15Gy (39.4% ±13.9% vs 9.4% ±13.0%; p<0.001) and mean LAD dose (12.9Gy ± 4.6Gy vs 7.6Gy ±2.8Gy; p<0.001). Most (85.7%; 18/21) LAD re-optimized plans achieved LAD V15Gy <10%. There were no statistically significant differences in overall lung, esophageal, or spinal cord dose metrics. Only one re-optimization (1/21) exceeded an OAR constraint that was initially met in the original plan. CONCLUSIONS: To our knowledge, this is the first report describing the feasibility of LAD-optimized lung cancer RT planning using the newly identified LAD V15 Gy constraint. We observed that LAD V15Gy <10% is achievable in more than 85% of plans initially exceeding this constraint, with minimal dosimetric tradeoffs. Our results support the feasibility of routine incorporation of the LAD as an OAR in modern thoracic IMRT/VMAT planning.

Feasibility and acceptability of ChatGPT generated radiology report summaries for cancer patients.

Objective: Patients now have direct access to their radiology reports, which can include complex terminology and be difficult to understand. We assessed ChatGPT's ability to generate summarized MRI reports for patients with prostate cancer and evaluated physician satisfaction with the artificial intelligence (AI)-summarized report. Methods: We used ChatGPT to summarize five full MRI reports for patients with prostate cancer performed at a single institution from 2021 to 2022. Three summarized reports were generated for each full MRI report. Full MRI and summarized reports were assessed for readability using Flesch-Kincaid Grade Level (FK) score. Radiation oncologists were asked to evaluate the AI-summarized reports via an anonymous questionnaire. Qualitative responses were given on a 1-5 Likert-type scale. Fifty newly diagnosed prostate cancer patient MRIs performed at a single institution were additionally assessed for physician online portal response rates. Results: Fifteen summarized reports were generated from five full MRI reports using ChatGPT. The median FK score for the full MRI reports and summarized reports was 9.6 vs. 5.0, (p < 0.05), respectively. Twelve radiation oncologists responded to our questionnaire. The mean [SD] ratings for summarized reports were factual correctness (4.0 [0.6], understanding 4.0 [0.7]), completeness (4.1 [0.5]), potential for harm (3.5 [0.9]), overall quality (3.4 [0.9]), and likelihood to send to patient (3.1 [1.1]). Current physician online portal response rates were 14/50 (28%) at our institution. Conclusions: We demonstrate a novel application of ChatGPT to summarize MRI reports at a reading level appropriate for patients. Physicians were likely to be satisfied with the summarized reports with respect to factual correctness, ease of understanding, and completeness. Physicians were less likely to be satisfied with respect to potential for harm, overall quality, and likelihood to send to patients. Further research is needed to optimize ChatGPT's ability to summarize radiology reports and understand what factors influence physician trust in AI-summarized reports.

Association of Parental Status and Gender With Burden of Multidisciplinary Tumor Boards Among Oncology Physicians.

Importance: Tumor boards are integral to the care of patients with cancer. However, data investigating the burden of tumor boards on physicians are limited. Objective: To investigate what physician-related and tumor board-related factors are associated with higher tumor board burden among oncology physicians. Design, Setting, and Participants: Tumor board burden was assessed by a cross-sectional convenience survey posted on social media and by email to Cedars-Sinai Medical Center cancer physicians between March 3 and April 3, 2022. Tumor board start times were independently collected by email from 22 top cancer centers. Main Outcomes and Measures: Tumor board burden was measured on a 4-point scale (1, not at all burdensome; 2, slightly burdensome; 3, moderately burdensome; and 4, very burdensome). Univariable and multivariable probabilistic index (PI) models were performed. Results: Surveys were completed by 111 physicians (median age, 42 years [IQR, 36-50 years]; 58 women [52.3%]; 60 non-Hispanic White [54.1%]). On multivariable analysis, factors associated with higher probability of tumor board burden included radiology or pathology specialty (PI, 0.68; 95% CI, 0.54-0.79; P = .02), attending 3 or more hours per week of tumor boards (PI, 0.68; 95% CI, 0.58-0.76; P < .001), and having 2 or more children (PI, 0.65; 95% CI, 0.52-0.77; P = .03). Early or late tumor boards (before 8 am or at 5 pm or after) were considered very burdensome by 33 respondents (29.7%). Parents frequently reported a negative burden on childcare (43 of 77 [55.8%]) and family dynamics (49 of 77 [63.6%]). On multivariable analysis, a higher level of burden from early or late tumor boards was independently associated with identifying as a woman (PI, 0.69; 95% CI, 0.57-0.78; P = .003) and having children (PI, 0.75; 95% CI, 0.62-0.84; P < .001). Independent assessment of 358 tumor boards from 22 institutions revealed the most common start time was before 8 am (88 [24.6%]). Conclusions and Relevance: This survey study of tumor board burden suggests that identifying as a woman or parent was independently associated with a higher level of burden from early or late tumor boards. The burden of early or late tumor boards on childcare and family dynamics was commonly reported by parents. Having 2 or more children, attending 3 or more hours per week of tumor boards, and radiology or pathology specialty were associated with a significantly higher tumor board burden overall. Future strategies should aim to decrease the disparate burden on parents and women.