Cancer immunotherapy is a potent treatment modality, but its clinical benefit depends on the tumor's immune profile. Here, we used mJX-594 (JX), a targeted and GM-CSF-armed oncolytic vaccinia virus, ...as a strategy to remodel the tumor microenvironment (TME) and subsequently increase sensitivity to αPD-1 and/or αCTLA-4 immunotherapy.
The remodeling of the TME was determined using histologic, flow-cytometric, and NanoString immune profiling analyses. JX was intratumorally injected into implanted Renca kidney tumors or
transgenic mouse breast cancers with or without αPD-1 and/or αCTLA-4. Various combination regimens were used to evaluate immunotherapeutic anticancer responses.
Intratumoral injection of JX remodeled the TME through dynamic changes in the immune system, as shown by increased tumor-infiltrating T cells and upregulation of immune-related gene signatures. This remodeling induced conversion of a noninflamed tumor into an inflamed tumor. JX virotherapy led to enhanced abscopal effects in distant tumors, with increased intratumoral infiltration of CD8
T cells. A depletion study revealed that GM-CSF is an indispensable regulator of anticancer efficacy of JX. Dual-combination therapy with intratumoral JX and systemic αPD-1 or αCTLA-4 further enhanced the anticancer immune response, regardless of various treatment schedules. Of note, triple combination immunotherapy with JX, αPD-1, and αCTLA-4 elicited the most potent anticancer immunity and induced complete tumor regression and long-term overall survival.
Our results show that intratumoral JX treatment induces dramatic remodeling of the TME and more potently suppresses cancer progression with immune-checkpoint blockades by overcoming resistance to immunotherapy.
Background
This study evaluated the effects of body mass index (BMI) before the diagnosis of the first primary cancer on the development of secondary primary cancers (SPCs) in female cancer ...survivors.
Methods
This study population included 146 377 Korean female cancer survivors whose first primary cancer was diagnosed between 2002 and 2010. The incidence of SPCs was evaluated throughout follow‐up until December 2011. We used Cox proportional hazards models to calculate the hazard ratios of SPCs with prediagnosis BMI and compared it to those of first cancers in the general population.
Results
After 565 877 person‐years of follow‐up, 2222 patients with SPC were observed. The higher BMI was more in female cancer survivors than in general population. The age‐standardized incidence rate of cancer in cancer survivors was 2.02 times higher than that of the general population. There were positive linear trends between prediagnosis BMI and risk of overall, colorectal, ovary, thyroid, and obesity‐related SPCs. In addition, the BMI‐SPC risk association was statistically significant in female cancer survivors without smoking history (Ptrend = 0.001) and with a localized first primary cancer (Ptrend = 0.014). However, the magnitude of the BMI‐SPC risk association was similar to that for first cancers in the general population (Pheterogeneity = 0.403 in BMI ≥ 30.0 kg/m2).
Conclusions
In female cancer survivors, prediagnosis obesity was a risk factor for overall, individual, and obesity‐related SPCs. However, the magnitude of the BMI‐SPC risk association was similar to that for first cancers in the general population.
In this Korean national cohort study, which included 146 377 Korean female cancer survivors whose first primary cancer was diagnosed between 2002 and 2010, the age‐standardized incidence rate of cancer in cancer survivors was higher than that of the general population. However, the magnitude of the body mass index (BMI)‐SPC risk association was similar to that for first cancers in the general population.
Positively Charged Liposomes
Systemic delivery of positively charged fusogenic liposomes loaded with a stimulator of interferon genes (STING) agonist (PoSTING) selectively targets the tumor ...microenvironment and suppresses aberrant tumor angiogenesis. PoSTING can convert non‐inflamed cold tumors (upper) into inflamed hot tumors (lower) by normalizing tumor blood vessels (red) and promoting CD8+ T cell infiltration (green) into the tumors. More details can be found in article number 2300544 by Dong Keun Han, Hong Jae Chon, Chan Kim, and co‐workers.
Background: The increased demand for genetic testing and counseling necessitates healthcare professionals (HCPs) to improve their genetic competency through training programs. This systematic review ...identified HCPs’ learning needs and their perspectives on essential information for families with hereditary cancer. Methods: This review covered studies published from 2013 to 2024 across five databases. Data were analyzed using a content analysis. Results: Thirteen studies involving 332 HCPs were analyzed. Most studies focused on the learning needs of physicians caring for families affected by Hereditary Breast and Ovarian Cancer in North America and Europe. HCPs required training emphasizing practical counseling skills over the basics of genetics. Learning needs varied by profession: physicians needed training in assessing cancer risk and supporting decision-making in risk management; nurses required information on resources and the genetic care system; genetic counselors sought guidance on family communication and planning. Essential information identified for families included risk-reducing strategies, personalized cancer risk assessment, family implications, psychological issues, (cascade) genetic testing, and social concerns. Conclusions: The findings have implications for the development of training programs for HCPs, emphasizing the need for tailored training based on professions. Future research should explore the needs of HCPs caring for families with diverse hereditary cancers and cultural backgrounds.
Although stimulator of interferon genes (STING) agonists has shown great promise in preclinical studies, the clinical development of STING agonist therapy is challenged by its limited systemic ...delivery. Here, positively charged fusogenic liposomes loaded with a STING agonist (PoSTING) are designed for systemic delivery and to preferentially target the tumor microenvironment. When PoSTING is administered intravenously, it selectively targets not only tumor cells but also immune and tumor endothelial cells (ECs). In particular, delivery of STING agonists to tumor ECs normalizes abnormal tumor vasculatures, induces intratumoral STING activation, and elicits robust anti‐tumor T cell immunity within the tumor microenvironment. Therefore, PoSTING can be used as a systemic delivery platform to overcome the limitations of using STING agonists in clinical trials.
Systemically administering positively charged fusogenic liposomes loaded with a stimulator of interferon genes (STING) agonist (PoSTING) stably delivers a STING agonist to the tumor microenvironment. PoSTING selectively targets not only tumor cells but also immune and endothelial cells. PoSTING normalizes abnormal tumor vasculatures, induces intratumoral STING activation, and elicits robust anti‐tumor T cell immunity.
This study evaluated the association of serum HER2 (sHER2) levels at diagnosis with clinicopathologic parameters and disease free survival (DFS) in operable breast cancer patients according to ...intrinsic subtype.
The sHER2 levels were measured using a chemiluminescence immunoassay. The HER2 status in all tumor tissues was determined by immunohistochemistry, and confirmed in equivocal cases by fluorescence in situ.
There were 436 consecutive stage I-III breast cancer patients with sHER2 result at diagnosis between Nov 2004 and Dec 2011. High sHER2 levels (≥ 15 ng/ml) were reported in 52 patients (11.9%) and HER2 overexpression in tumor tissue was observed in 111 patients (25.5%). High sHER2 levels were associated significantly with advanced stage (P < 0.001), mastectomy (P = 0.012), neoadjuvant chemotherapy (P < 0.001), anti-HER2 therapy (P < 0.001) and hormone therapy (P = 0.022). The patients with high sHER2 levels had a worse DFS (P < 0.001). In multivariate analysis, high sHER2 levels were associated significantly with worse DFS (HR = 2.25, 95% CI 1.27-3.99, P = 0.005). High sHER2 levels were associated with worse DFS in the HR+/HER2-, HR+/HER2+ and HR-/HER2+ subtypes (P = 0.043, 0.003 and 0.041, respectively).
These results show that the sHER2 level at diagnosis is a useful prognostic factor in patients with operable breast cancer, especially in the HR+/HER2-, HR+/HER2+ and HR-/HER2+ subtypes.
Oncolytic viruses selectively replicate and destroy cancer cells while sparing normal cells, prompting their recognition as promising antitumor agents. Herpes simplex virus (HSV) is suitable as an ...anticancer agent, given its considerable therapeutic gene capacity and excellent safety profile in clinical trials. Interleukin (IL)-12 induces a Th1-type immune response that mediates interferon (IFN)-γ release from natural killer (NK), CD4
and CD8
T cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces the generation of antigen-presenting cells and promotes dendritic cell differentiation. We established a novel oncolytic HSV-1 (∆6/GM/IL12) co-expressing IL-12 and GM-CSF and tested its effects against a B16-F10 murine melanoma model. ∆6/GM/IL12 administration diminished tumor growth and prolonged survival compared to treatment with ∆6/GM or ∆6/IL12 expressing each individual cytokine. Flow cytometry and histological analysis showed increased activation of CD4
and CD8
T cells in ∆6/GM/IL12-treated mice. Enzyme-linked immunosorbent spot assay showed an increase in the phenotypically characterized IFN-γ-producing cell population in ∆6/GM/IL12-treated mice. Moreover, ∆6/GM/IL12 induced a B16-F10-specific cytotoxic immune response that enhanced IFN-γ production by CD3
CD8
T cells. Therefore, IL-12 and GM-CSF from an engineered oncolytic HSV have a synergistic effect, boosting the immune response to increase their antitumor effects.
Background
As the incidence of breast cancer has increased and the survival rate has improved, supporting the optimal follow‐up strategy has become an important issue. This study aimed to evaluate ...follow‐up imaging usage after breast cancer surgery and the implications on mortality in Korea.
Methods
This study included 96,575 breast cancer patients diagnosed during 2002–2010 and registered in the Korea Central Cancer Registry, Statistics Korea, and Korean National Health Insurance Service. We evaluated the frequency of breast imaging (mammography and breast MRI) and systemic imaging for evaluating the presence of distant metastasis (chest CT, bone scan, and PET‐CT), and performed analyses to determine if they had an effect on mortality.
Results
The median follow‐up period was 72.9 months (range: 12.0–133.3) and 7.5% of the patients died. Among all patients, 54.7%, 16.2%, 45.6%, and 8.5% received 3 or more mammograms, chest CTs, bone scans, and PET‐CTs within 3 years after surgery, respectively. Among patients who developed recurrence after 3 or more years, a comparison of overall mortality and breast‐cancer specific mortality according to the frequency of imaging by modality (<3 vs. ≥3) showed that only mammography had significantly reduced mortality (hazard ratio HR: 0.72, 95% CI: 0.61–0.84, p < 0.0001; HR: 0.72, 95% CI: 0.61–0.84; p < 0.0001).
Conclusions
This study showed that only frequent mammography reduced mortality and frequent imaging follow‐up with other modalities did not when compared to less frequent imaging. This finding provides supportive evidence that clinicians need to adhere to the current guidelines for surveillance after breast cancer surgery.
This study aimed to evaluate follow‐up imaging usage and the clinical implications after breast cancer surgery using Korea national cohort. We found that only frequent mammography reduced mortality and other imaging modalities did not. Therefore, clinicians need to adhere to the current guidelines for surveillance after breast cancer surgery.
BackgroundPeritoneal carcinomatosis is a fatal clinical presentation of colon cancer, characterized by unresponsiveness to conventional anticancer therapies, including immune checkpoint inhibitors. ...Here, we elucidated the immune-evasion mechanisms during the peritoneal carcinomatosis of colon cancer and developed a novel immunotherapy by activating the stimulator of interferon genes (STING) pathway.MethodsWe generated a syngeneic peritoneal carcinomatosis model of colon cancer. Mice were intraperitoneally treated with either STING agonist (MIW815, also known as ADU-S100) or PD-1 blockade or both. The tumor microenvironment was comprehensively analyzed using multiplexed immunofluorescence imaging, flow cytometry, and NanoString immune profiling.ResultsIntraperitoneal colon cancer cells induce a massive influx of immunosuppressive M2-like macrophages, upregulate immune checkpoints, and impair effector T cell functions during peritoneal dissemination; these collectively create a highly angiogenic and immunosuppressive milieu that is resistant to anti-PD-1 monotherapy. Intraperitoneal administration of a STING agonist suppressed aberrant angiogenesis, increased pericyte coverage, and normalized tumor vessels, thereby facilitating the infiltration of activated CD8+ T cells into peritoneal tumor nodules. Moreover, STING activation reprogramed tumor-associated macrophages toward the M1 phenotype. STING activation converted immunologically cold peritoneal tumors into T-cell-inflamed tumors in a type-I interferon-dependent manner. Lastly, the STING agonist synergistically cooperated with PD-1 and/or COX2 blockade to further suppress the peritoneal dissemination of colon cancer, resulting in complete eradication of tumor and ascites, and inducing durable antitumor immunity.ConclusionsSTING activation can normalize the peritoneal vascular and immune microenvironment, providing a rationale for a novel combination therapeutic strategy for peritoneal carcinomatosis in colon cancer.
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