Preclinical study and phase II trial of adapting low-dose radiotherapy to immunotherapy in small cell lung cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) provide modest but unsatisfactory benefits for extensive-stage small cell lung cancer (ES-SCLC). Developing strategies for treating ES-SCLC is critical. METHODS: We preliminarily explored the outcomes of salvage low-dose radiotherapy (LDRT) plus ICI on refractory SCLC patients. Next, we evaluated the combinational efficacy in murine SCLC. The tumor immune microenvironment (TIME) was analyzed for mechanistic study. Subsequently, we conducted a multicenter, prospective phase II trial that administered concurrent thoracic LDRT plus chemoimmunotherapy to treatment-naive ES-SCLC patients (MATCH trial, NCT04622228). The primary endpoint was confirmed objective response rate (ORR), and the key secondary endpoints included progression-free survival (PFS) and safety. FINDINGS: Fifteen refractory SCLC patients treated with LDRT plus ICI were retrospectively reviewed. The ORR was 73.3% (95% confidence interval [CI], 44.9-92.2). We identified a specific dose of LDRT (15 Gy/5 fractions) that exhibited growth retardation and improved survival in murine SCLC when combined with ICIs. This combination recruited a special T cell population, TCF1+ PD-1+ CD8+ stem-like T cells, from tumor-draining lymph nodes into the TIME. The MATCH trial showed a confirmed ORR of 87.5% (95% CI, 75.9-94.8). The median PFS was 6.9 months (95% CI, 5.4-9.3). CONCLUSIONS: These findings verified that LDRT plus chemoimmunotherapy was safe, feasible, and effective for ES-SCLC, warranting further investigation. FUNDING: This research was funded by West China Hospital (no. ZYJC21003), the National Natural Science Foundation of China (no. 82073336), and the MATCH trial was fully funded by Roche (China) Holding Ltd. (RCHL) and Shanghai Roche Pharmaceuticals Ltd. (SRPL).

Safety and Tolerability of Low-Dose Radiation and Stereotactic Body Radiotherapy + Sintilimab for Treatment-Naïve Stage IV PD-L1+ Non-Small Cell Lung Cancer Patients.

PURPOSE: Low-dose radiotherapy (LDRT) may enhance the synergistic antitumor effect of combined immunotherapy and stereotactic body radiotherapy (SBRT). The safety and efficacy of this novel triple-combination therapy were evaluated for the first time as first-line treatment for patients with metastatic non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: This prospective phase I study enrolled 29 patients and included a dose-escalation and dose-expansion phase. Patients received SBRT [30 Gray (Gy)/3f] to small lesions and LDRT (2 Gy/1f, 4 Gy/2f, or 10 Gy/5f) to a large lesion concurrently, followed by sintilimab (a programmed death-1 inhibitor). The primary endpoint was safety and tolerability; secondary endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: No dose-limiting toxicities were observed during the dose-escalation phase; 4 Gy/2f was the recommended LDRT dose. Median follow-up was 15.6 months. Treatment-related adverse events (TRAE) occurred in 96.6% (28/29) of patients [grade ≥ 3; 20.7% (6/29)]; 2 patients (6.9%) discontinued due to TRAEs. Seven patients experienced pneumonitis (grade 2, n = 6; grade 3, n = 1). Immune-related adverse events were noted in 58.6% (17/29) of patients. In patients with tumor assessment (n = 28), ORR and confirmed ORR were 60.7% and 57.1%, respectively. Median PFS was 8.6 months (95% confidence interval, 3.7-16.5), and median OS was not reached. Exploratory analyses suggested both expanded and newly emerging T-cell receptor clonotypes were associated with better PFS. CONCLUSIONS: The findings indicate that the novel SBRT + LDRT + sintilimab therapy is safe and promising in patients with programmed death ligand-1-positive, driver gene-negative primary metastatic NSCLC.

Immune-related mechanisms and immunotherapy in extragonadal germ cell tumors.

Purpose of review: Extragonadal germ cell tumors (EGCTs) are relatively rare tumors, accounting for 1%-5% of all GCTs. In this review, we summarize the current research progress regarding the pathogenesis, diagnosis, and treatment of EGCTs from an immunology perspective. Recent findings: The histological origin of EGCTs is related to a gonadal origin, but they are located outside the gonad. They show great variation in morphology and can occur in the cranium, mediastinum, sacrococcygeal bone, and other areas. The pathogenesis of EGCTs is poorly understood, and their differential diagnosis is extensive and challenging. EGCT behavior varies greatly according to patient age, histological subtype, and clinical stage. Summary: This review provides ideas for the future application of immunology in the fight against such diseases, which is a hot topic currently.

Application of Artificial Intelligence in the Diagnosis, Treatment, and Prognostic Evaluation of Mediastinal Malignant Tumors.

Artificial intelligence (AI), also known as machine intelligence, is widely utilized in the medical field, promoting medical advances. Malignant tumors are the critical focus of medical research and improvement of clinical diagnosis and treatment. Mediastinal malignancy is an important tumor that attracts increasing attention today due to the difficulties in treatment. Combined with artificial intelligence, challenges from drug discovery to survival improvement are constantly being overcome. This article reviews the progress of the use of AI in the diagnosis, treatment, and prognostic prospects of mediastinal malignant tumors based on current literature findings.

A nomogram for the prediction of the survival of patients with advanced non-small cell lung cancer and interstitial lung disease.

BACKGROUND: Lung cancer is frequently accompanied by interstitial lung disease (ILD), and the overall survival (OS) of patients with these comorbidities is poor. Thus, we developed a nomogram for the prediction of the OS of patients with advanced non-small cell lung cancer (NSCLC) and ILD. PATIENTS AND METHODS: Patients with wild-type gene advanced NSCLC with and without ILD who underwent chemotherapy between 2014 and 2019 were enrolled in the present study. The 0.5- and 1-year progression-free survival (PFS) and overall survival (OS) times of patients with and without ILD were determined using the Kaplan-Meier method. Cox regression was used to assess the prognostic value of clinical factors for patients with ILD. Based on the multivariate regression results, a nomogram for survival prediction was developed. The nomogram was validated using calibration curve. RESULTS: Data from 155 patients with lung cancer and ILD and 118 matched patients with lung cancer alone who were receiving first-line chemotherapy were analyzed. The first-line chemotherapy regimens were paclitaxel + carboplatin, pemetrexed + carboplatin, gemcitabine + carboplatin, and other. The median PFS and OS were significantly shorter in patients with than in those without ILD (3.0 vs. 7.0 months [p < 0.001] and 7.0 vs. 15.0 months (p < 0.001), respectively). Multivariate analysis showed that the lymphocyte count (hazard ratio [HR] 2.38; 95% confidence interval [CI], 1.44-3.94; p = 0.01), partial pressure of oxygen (PaO2 ; HR, 1.37; 95% CI, 1.03-1.82; p = 0.03), and chemotherapy regimen were independently associated with prognosis. The nomogram showed good discriminatory ability [C-index = 0.69 (95% CI, 0.49-0.82)]. Calibration curves showed that predicted and actual prognoses were consistent. CONCLUSION: This nomogram can aid the prediction of the OS of patients with advanced NSCLC and ILD.

Uncertain resection of highest mediastinal lymph node positive among pN2 non-small cell lung cancer patients: survival analysis of postoperative radiotherapy and driver gene mutations.

BACKGROUND AND PURPOSE: The role of postoperative radiotherapy (PORT) in uncertain resection of pN2 non-small cell lung cancer (NSCLC) with highest mediastinal lymph node positive has not been determined. We aim to evaluate the effect of PORT and driver gene mutation status (DGMS) on survival in such patients. METHODS: 140 selected patients were grouped according to whether they received PORT and their DGMS. Locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) of each group were evaluated by Kaplan-Meier analyses. COX regression was used to evaluate the effects of various factors on DFS and OS. RESULTS: Of 140 patients, thirty-four patients (24.3%) received PORT, and forty (28.6%) had positive driver gene mutation status (DGp). PORT significantly prolonged LRFS (p = 0.002), DFS (p = 0.019) and OS (p = 0.02), but not DMFS (p = 0.062). By subgroup analysis, in patients with negative driver gene mutation status (DGn), those receiving PORT had notably longer LRFS (p = 0.022) and DFS (p = 0.033), but not DMFS (p = 0.060) or OS (p = 0.215), compared to those not receiving PORT. Cox analysis showed that the number of positive lymph nodes (PLNs) and administration of PORT were independent prognostic factors of DFS, and pathology, PLNs, and DGMS may be prognostic factors of OS (all p < 0.05). CONCLUSION: Postoperative radiotherapy may improve locoregional recurrence-free and disease-free survival in patients with pN2 NSCLC with positive highest mediastinal lymph nodes, while driver gene mutation status impacted OS significantly. Only patients with positive driver gene mutations experienced significant overall survival benefits from postoperative radiotherapy.

Response to Pralsetinib Observed in Meningeal-Metastatic EGFR-Mutant NSCLC With Acquired RET Fusion: A Brief Report.

Introduction: RET is well known as an important driver gene in NSCLC. Moreover, RET is a rare acquired resistance mechanism to EGFR-mutant NSCLC. Only 36 NSCLC cases of coexistence of EGFR and RET were reported previously worldwide. So far, there have been no reports on the following: (1) whether combination of EGFR tyrosine kinase inhibitor (TKI) and RET TKI works for meningeal metastasis; (2) the concentrations of EGFR TKI and RET TKI in the cerebrospinal fluid (CSF) and plasma; and (3) whether RET fusions and EGFR mutation happened in the same clone or not. Methods: We reported a patient with an EGFR-mutant NSCLC with acquired RET fusions and meningeal metastasis treated with pralsetinib and osimertinib; the specimen was analyzed by next-generation sequencing (Illumina NovaSeq 6000 platform). Symptom improvement and magnetic resonance imaging scan were used for effect evaluation. Furthermore, we determined the concentrations of pralsetinib and osimertinib in CSF and plasma by means of liquid chromatography tandem mass spectrometry. We also detected RET fusion and EGFR L858R mutation by methods of fluorescence in situ hybridization and immunohistochemistry with continuous sections to analyze whether RET fusions coexist with EGFR mutation in the same clone or not. Results: The allele frequency of the RET fusion was detected to be 12.88%. This patient achieved a partial response, indicating pralsetinib combined with osimertinib may be clinically beneficial for meningeal metastasis in patients harboring acquired coexistent RET fusions. The concentrations of pralsetinib in the CSF and plasma were 704.76 nM and 91.31 µM, whereas those of osimertinib in the CSF and plasma were 23.70 nM and 2148.94 nM, respectively. RET fusion was found in the same clone of EGFR L858R mutation. Conclusions: Our finding of this case indicated that RET fusion and EGFR mutation occur in the same population of cell clones, rather than in different cell clones. Combined pralsetinib may be an effective way to overcome the resistance, even for meningeal metastasis, owing to high CSF distribution of pralsetinib.

Combination of Palliative Thoracic Radiotherapy With Bevacizumab for Stage IV Nonsquamous NSCLC: Is There Any Impact of Time Interval on Survival?

Background: The time interval between palliative thoracic radiotherapy and bevacizumab treatment strongly influences the frequency of adverse events (AEs) when both are concurrently applied to patients with advanced lung cancer. Herein, we aimed to elucidate the optimal time interval between the treatments in these patients. Methods: The medical records of patients with stage IV nonsquamous non-small-cell lung cancer (NSCLC) without epidermal growth factor receptor and anaplastic lymphoma kinase alteration who underwent palliative thoracic radiotherapy and bevacizumab treatment from January 2008 to January 2020 were collected and analyzed. Patients were divided into 2 groups based on the time interval between treatments: <3 weeks (⩽3W group) and >3 weeks (>3W group). The progression-free survival (PFS) and overall survival (OS) for the time intervals were evaluated using the Kaplan-Meier method and Cox proportional hazard models. Adverse events were assessed by the fifth version of the Common Terminology Criteria for Adverse Events. Results: In total, 72 patients with stage IV NSCLC (⩽3W group, 37 patients; >3W group, 35 patients) who concurrently or sequentially received palliative thoracic radiotherapy and bevacizumab treatment were included in this study. In the >3W and ⩽3W groups, the median PFS (8 vs 6 months, respectively) and OS (15 vs 12 months, respectively) differed significantly. Multivariate analyses findings revealed significantly shorter OS in the latter group. In addition, the frequency of most AEs was marginally higher in the latter group (P > .05). Conclusions: The time interval between palliative thoracic radiotherapy and bevacizumab treatment that offers optimal safety is >3 weeks.

Knowledge Difference of Tumor Nutrition Risk Among Thoracic Cancer Patients, Their Family Members, Physicians, and Nurses.

To investigate the difference among patients, family members, physicians, and nurses in their ability to identify malnutrition risk in patients with thoracic cancer. The enrolled patients were evaluated by the NRS2002 nutritional risk scale. The patient-centered groups, including the patient, the primary caretaker, the physician, and the nurse, were given a questionnaire on their knowledge and understanding of nutrition therapy in cancer treatment. The incidence rate of nutritional risk in hospitalized patients with thoracic cancer was 13.8%. There were significant differences in the accuracy rate of nutritional risk assessment among the four groups (P < 0.001), in which the nurses' was 70.3%, 55.1% for the physician, 38.7% for family members, and 33.0% for patients, which was the poorest accuracy rate. No significant correlation was found between the accuracy of nutritional risk assessment and the education level and personal monthly income of each population (P > 0.05). Nearly all four groups considered it necessary to learn more about cancer nutrition therapy. For patients and their families, the main way to understand the knowledge of tumor nutrition was consultation with medical staff and information exchange between patients; for doctors, new media; and for nurses, classroom training. Nurses' assessment of nutritional risk in cancer patients achieved the highest accuracy, while the poorest accuracy originated from the patients.

Comorbidities and mortality risk among extensive-stage small-cell lung cancer patients in mainland China: impacts of hypertension, type 2 diabetes mellitus, and chronic hepatitis B virus infection.

The present study investigated the impact of major comorbidities, including hypertension, type 2 diabetes mellitus (T2DM), and chronic hepatitis B virus (HBV) infection, on the progression-free survival (PFS) and overall survival (OS) of extensive-stage small-cell lung cancer (ES-SCLC) patients in China. Patients having a pathologic diagnosis of ES-SCLC between 2009 and 2017 were enrolled and grouped according to their specific comorbidities. The PFS and OS for each group were evaluated using the Kaplan-Meier method and Cox proportional hazard models. In total, 632 patients were analyzed. The median PFS (mPFS) of these patients was 9 months [95% confidence interval (CI), 6-12 months]. The mPFS of patients without hypertension or T2DM was 9 months; conversely, it was significantly reduced for patients with hypertension [7 months (P < 0.0001)] or T2DM [5 months (P < 0.0001)]. However, mPFS was not significantly different between patients with and without HBV infection (P = 0.2936). A similar trend was observed for OS as well. Further multivariate analyses showed that the OS of patients with hypertension [hazard ratio (HR), 1.344; 95% CI, 1.073-1.683; P = 0.010] or T2DM (HR, 1.455; 95% CI, 1.134-1.868; P = 0.003) was significantly shorter than that of patients without these comorbidities. Accordingly, mortality risk was the highest in patients with concurrent hypertension and T2DM (HR, 1.665; 95% CI, 1.037-2.672; P = 0.00058). Our study found that hypertension and T2DM may be associated with a worse prognosis in ES-SCLC patients. Considerable attention should be paid to the accompanying anti-comorbidity therapies available for patients with ES-SCLC.

Case Report: Outcome of Osimertinib Treatment in Lung Adenocarcinoma Patients With Acquired KRAS Mutations.

BACKGROUND: Osimertinib belongs to the third-generation epidermal growth factor receptor tyrosine kinase inhibitor that has shown positive effects in treating lung adenocarcinoma cancer. However, the subsequent resistance to Osimertinib has become a clinical challenge. CASE PRESENTATION: We present two lung adenocarcinoma cases that developed a resistance to Osimertinib. Among them, one patient attained both KRAS exon 2 and exon 3 mutations and was given paclitaxel (albumin-bound) plus carboplatin. The other patient exhibited a KRAS exon 3 mutation, so the paclitaxel (albumin-bound) plus nivolumab was administered. Eventually, the second patient manifested a better clinical outcome than the first. CONCLUSION: These results provide supporting evidence that KRAS exon 3 (R68S) mutations may be associated with Osimertinib resistance in lung adenocarcinoma patients. This further reveals the relationship between subtypes of acquired KRAS mutations and the effect of therapeutic approaches. Moreover, the combination of chemotherapy and immune checkpoint inhibitors may generate a satisfying disease control.

Development and validation of a nomogram for assessing survival in extensive-stage small-cell lung cancer patients with superior vena cava syndrome referred for thoracic radiotherapy: a comparison of upfront vs. consolidative approaches.

PURPOSE: This study sought to design and validate a nomogram capable of predicting outcomes in extensive-stage small-cell lung cancer (ES-SCLC) patients with superior vena cava syndrome (SVCS) based upon the timing of their radiotherapy treatment. METHODS: We retrospectively analyzed data from 175 ES-SCLC patients with SCVS, comparing outcomes between those that underwent upfront thoracic radiotherapy (initial radiotherapy with simultaneous chemotherapy) and those that underwent consolidative thoracic radiotherapy (following 4-6 cycles of chemotherapy). Significant predictors of patient outcomes were identified using a Cox proportional hazard model and were used to construct our nomogram. This model was subsequently validated using receiver operating characteristic (ROC) curves, concordance index (C-index) values, and a risk classification system in order to evaluate its discriminative and predictive accuracy. RESULTS: The overall survival (OS) of ES-SCLC patients with SVCS that underwent chemotherapy (CT), consolidative thoracic radiotherapy (cc-TRT), and upfront thoracic radiotherapy (cu-TRT) was 8.2, 11.7, and 14.9 months, respectively (p < 0.001), with respective progression-free survival (PFS) durations of 3.3, 5.0, and 7.3 months (p < 0.001). A multivariate regression analysis revealed age, gender, ECOG performance status, sites of tumor metastasis, and treatment approach to all be independent predictors of survival outcomes. A nomogram was therefore developed incorporating these factors. C­index values upon internal and external validation of this nomogram were 0.7625 and 0.7959, respectively, and ROC and calibration curves revealed this model to be accurate and consistent. CONCLUSIONS: We found that upfront thoracic radiotherapy in combination with chemotherapy may be associated with a positive impact on outcomes in ES-SCLC patients with SVCS.

CXCL9 secreted by tumor-associated dendritic cells up-regulates PD-L1 expression in bladder cancer cells by activating the CXCR3 signaling.

BACKGROUND: Tumor-associated dendritic cells (TADCs) can interact with tumor cells to suppress anti-tumor T cell immunity. However, there is no information on whether and how TADCs can modulate programmed death-ligand 1 (PD-L1) expression by cancer cells. METHODS: Human peripheral blood monocytes were induced for DCs and immature DCs were cultured alone, or co-cultured with bladder cancer T24 or control SV-HUC-1 cells, followed by stimulating with LPS for DC activation. The activation status of DCs was characterized by flow cytometry and allogenic T cell proliferation. The levels of chemokines in the supernatants of co-cultured DCs were measured by CBA-based flow cytometry. The impacts of CXCL9 on PD-L1, STAT3 and Akt expression and STAT3 and Akt phosphorylation in T24 cells were determined by flow cytometry and Western blot. RESULTS: Compared with the control DCs, TADCs exhibited immature phenotype and had significantly lower capacity to stimulate allogenic T cell proliferation, particularly in the presence of recombinant CXCL9. TADCs produced significantly higher levels of CXCL9, which enhanced PD-L1 expression in T24 cells. Pre-treatment with AMG487 abrogated the CXCL9-increased PD-L1 expression in T24 cells. Treatment with CXCL9 significantly enhanced STAT3 and Akt activation in T24 cells. CONCLUSIONS: TADCs produced high levels of CXCL9 that increased PD-L1 expression in bladder cancer T24 cells by activating the CXCR3-related signaling. Our findings may shed new lights in understanding the regulatory roles of TADCs in inhibiting antitumor T cell responses and promoting tumor growth.

A Retrospective Analysis of the Effect of Anlotinib in Patients With Lung Cancer With or Without Previous Antiangiogenic Therapy.

OBJECTIVE: The purpose of this study was to initially investigate the effect of previous antiangiogenic therapy (bevacizumab and endostatin) on the efficacy of anlotinib in patients with advanced or metastatic lung cancer (LC). METHODS: We retrospectively collected the clinical data of patients with LC treated with anlotinib and divided them into group A (treated with anlotinib after the failure of previous antiangiogenic drugs and group B (no prior use of antiangiogenic drugs). We used propensity score matching (PSM) for confounding factors between the groups. Progression-free survival (PFS) and overall survival (OS) were also recorded. RESULTS: A total of 160 patients were included in the analysis. The median OS in groups A and group B was 11.8 months and 16.1 months (P=0.120), whereas the median PFS was 3.1 months and 4.7 months (P=0.009), respectively. Moreover, the objective response rate (ORR) of the two groups was 9.6% and 10.4% (P=0.874), and the disease control rate (DCR) was 71.1% and 80.5% (P=0.165).After PSM (n=46), baseline characteristics were comparable between groups A and B. Furthermore, the median OS of the two groups was 14.6 months and 16.2 months (P=0.320), whereas the median PFS was 3.5 months and 4.5 months (P=0.040), respectively. Moreover, the ORR of the two groups were 13.0% and 10.9% (P=0.748), and the DCR were 78.3% and 82.6% (P=0.599), respectively. CONCLUSIONS: Previous antiangiogenic treatments may affect the PFS of patients who receive anlotinib later, but it might not affect the patient's ORR and OS.

Applicability of the adjusted graded prognostic assessment for lung cancer with brain metastases using molecular markers (Lung-molGPA) in a Chinese cohort: A retrospective study of multiple institutions.

BACKGROUND: In this era of precision medicine, prognostic heterogeneity is an important feature of patients with non-small cell lung cancer (NSCLC) with brain metastases (BM). This multi-institutional study is aimed to verify the applicability of the adjusted Lung-molGPA model for NSCLC with BM in a Chinese cohort. METHODS: This retrospective study included 1903 patients at three hospitals in Southwest China. The performance of the Lung-molGPA model was compared with that of the adjusted DS-GPA model in terms of estimating the survival of NSCLC with BM. RESULTS: The median OS of this patient cohort was 27.0 months, and the adenocarcinoma survived longer than the non-adenocarcinoma (28.0 months vs 18.7 months, p < 0.001). The adjusted Lung-molGPA model was more accurate in predicting survival of adenocarcinoma patients than the adjusted DS-GPA model (C-index: 0.615 vs 0.571), and it was not suitable for predicting survival of non-adenocarcinoma patients (p = 0.286, 1.5-2.0 vs 2.5-3.0; p = 0.410, 2.5-3.0 vs 3.5-4.0). CONCLUSIONS: The adjusted Lung-molGPA model is better than the DS-GPA model in predicting the prognosis of adenocarcinoma patients. However, it failed to estimate the prognosis for non-adenocarcinoma patients.

Overall survival benefit of continuing immune checkpoint inhibitors treatment post dissociated response in patients with advanced lung cancer.

PURPOSE: Dissociated response (DR, reduction at baseline or increase < 20% in target lesions compared with nadir in the presence of new lesions) was observed in 20-34% of patients treated with immune checkpoint inhibitors (ICIs). DRs were defined as progression disease (PD) per response evaluation criteria in solid tumors (RECIST v1.1), while evaluation criteria related to immunotherapy incorporated the new lesions into the total tumor burden or conducted further evaluation after 4-8 weeks rather than declaring PD immediately. The main objective of this study is to compare survival between people who continuing initial ICIs treatment and those who switched to other anticancer therapy at the time of DR. PATIENTS AND METHODS: 235 patients with advanced lung cancer (LC) treated with ICIs were evaluated. Propensity score matching (PSM) was used to minimize potential confounding factors. Post-DR OS, target lesion changes were evaluated. RESULTS: 52 patients had been estimated as DRs. After PSM, the continuing ICIs treatment Post-DR cohort still had a significantly longer median post-DR OS than discontinuing ICIs treatment Post-DR cohort, 10.63 months (95% CI 6.27-NA) versus 4.33 months (95% CI 1.77-NA), respectively (p = 0.016). CONCLUSION: Within the limitations of this single-center retrospective analysis, clinically stable patients who were judged by clinicians to be eligible for continuing ICIs treatment post-DR derived apparent OS benefit than discontinuing counterpart.

Effect of Low-Dose Radiation Therapy on Abscopal Responses to Hypofractionated Radiation Therapy and Anti-PD1 in Mice and Patients With Non-Small Cell Lung Cancer.

PURPOSE: Hypofractionated radiation therapy (HFRT) can induce antitumor T cell responses, particularly in combination with immune checkpoint inhibitors (ICI), but abscopal effects are often precluded by insufficient T cell infiltration of distant, nonirradiated tumors. Additional noncytotoxic, low-dose radiation therapy (LDRT) of distant tumors may enhance the abscopal response, but clinical evidence and preclinical studies for this scenario are lacking. METHODS AND MATERIALS: We investigated whether triple treatment consisting of HFRT, ICI, and LDRT could achieve better systemic antitumor response in bilateral mouse tumor models and in patients with stage IV non-small cell lung cancer. RESULTS: Our analyses of bilateral mouse tumor models show that HFRT treatment of the primary tumor combined with LDRT treatment of the abscopal tumor and anti-PD1 therapy enhances the abscopal response compared with HFRT/anti-PD1, HFRT/LDRT, or LDRT/anti-PD1 double treatments; complete cure was observed in more than half of the mice treated with triple therapy. The enhanced abscopal effect was associated with increased infiltration of CD8+ effector T cells and upregulated expression of T cell-attracting chemokines. Of 9 patients with metastatic non-small cell lung cancer who were treated with this triple therapy, 3 and 2 patients showed partial responses and stable disease, respectively. Among 9 relatively large (175.7 ± 42.3 cm3) LDRT lesions, 6 lesions decreased by 28% in size, on average. CONCLUSIONS: Our study demonstrates preclinically that LDRT of established metastases significantly enhances the abscopal response to HFRT plus ICI. It also shows that additional LDRT was well tolerated by patients and that this treatment profile is effective and worth further study.

AG490 reverses phenotypic alteration of dendritic cells by bladder cancer cells.

Past studies have confirmed that tumors can impair the function of dendritic cells (DCs) and promote tumor evasion. AG490, a Janus kinase 2/signal transducer and activator of transcription 3 inhibitor, has been shown to induce maturation of DCs and inhibit the growth of tumor cells. In the present study, DCs were generated from healthy human peripheral blood mononuclear cells. On day 5 of culture, the DCs were co-cultured with human bladder cancer pumc-91 cells for 24 h, and then purified using magnetic beads. The maturation of the DCs was induced by lipopolysaccharide. Subsequent to co-culture with pumc-91 cells, the expression of human leukocyte antigen-antigen D related (HLA-DR), cluster of differentiation (CD)86 and CD80 was found to be reduced in the DCs, accompanied by increased production of interleukin (IL)-10, but decreased production of IL-12p70. Furthermore, the DCs co-cultured with pumc-91 inhibited the proliferation of allogeneic T cells. Finally, AG490 restored the expression of HLA-DR, CD86 and CD80. These data identified that bladder cancer cells could inhibit the antigen-presenting function of the DCs and induce anergy in T cells. AG490 may partly reverse this inhibitory effect of bladder cancer cells on DCs, activate immunogenicity and induce the antitumor immunity response of DCs.

Targeting bladder cancer using activated T cells armed with bispecific antibodies.

In the present study, we aimed to investigate whether EGFR or HER2 may serve as a target for T cell-mediated immunotherapy against human bladder cancer. Expression of EGFR and HER2 was detected on the surface of bladder cancer cells, including Pumc-91 and T24 cells, and their chemotherapeutic drug-resistant counterparts. Activated T cells (ATCs) were generated from healthy PBMCs that were stimulated by the combination of anti-CD3 monoclonal antibody and anti­CD28 monoclonal antibody in the presence of interleukin-2 for 14 days. The ATCs were then armed with chemically hetero-conjugated anti-CD3xanti-EGFR (EGFRBi-Ab) or anti-CD3xanti-HER2 (HER2Bi-Ab). The specific cytolytic activity of ATCs armed with EGFRBi-Ab or HER2Bi-Ab against human bladder cancer cells was evaluated by lactate dehydrogenase activity assays in vitro. In contrast to unarmed ATCs, EGFRBi-Ab-armed ATCs and HER2Bi-Ab-armed ATCs showed increased cytotoxic activity against bladder cancer cells. Moreover, Bi-Ab-armed ATCs expressed higher levels of activating marker CD69 and secreted more IFN-γ, TNF-α and IL-2 than did unarmed ATCs. EGFRBi-Ab- or HER2Bi-Ab-armed ATCs may provide a promising immunotherapy for bladder cancer.