Journal of Immunotherapy

Design of Therapeutic Vaccines Based on Antigen Epitopes of α-9 HPV E6 in Sichuan

Persistent infections with high-risk human papillomavirus (HR-HPV) are the primary cause of vaginal/cervical squamous intraepithelial neoplasia (VAIN/CIN) and cervical cancer (CC), with the prevalence of infection escalating alongside disease severity. Notably, the α-9 HPV species was responsible for 58.20% of all HR-HPV infections in our study. Given the absence of therapies to eradicate established infections, developing effective therapeutic vaccines is a critical priority. The HPV E6 oncoprotein represents an ideal target for such immunotherapies. In this study, we used a comprehensive in silico approach to identify and characterize potential T-lymphocyte epitopes from the E6 proteins of α-9 HR-HPV, which was predominant in our study cohort. Our integrated bioinformatics pipeline encompassed sequence analysis for conservation, followed by rigorous prediction of antigenicity, allergenicity, proteasomal processing, TAP transport efficiency, and immunogenicity. Through this systematic screening, we identified a panel of epitope candidates predicted to have a high potential for eliciting a robust and specific immune response. While these predictions provide a powerful theoretical foundation, it must be stressed that they constitute computational hypotheses requiring mandatory experimental validation. Our findings do not constitute functional epitopes but rather offer a prioritized, evidence-based roadmap for future laboratory investigations. This work significantly accelerates the rational design of HPV therapeutic vaccines by narrowing the focus to the most viable candidates, thereby conserving substantial time and resources in the downstream experimental verification process.

Clinical Efficacy and Safety of Cadonilimab Immunotherapy in Advanced Cervical Cancer: A Retrospective Study

This multicenter retrospective study assessed the safety and antitumor activity of cadonilimab in patients with recurrent or metastatic cervical cancer, particularly those with negative PD-L1 expression. Patients received cadonilimab, with or without additional treatments like chemotherapy, bevacizumab, or radiotherapy, and were monitored every 3 weeks until disease progression or intolerable toxicity was observed. The study included 21 patients: 18 with recurrent/metastatic cervical cancer (Figo IB1-IIIC) and 3 with newly diagnosed advanced cervical cancer (Fig IVB). The median follow-up duration was 9.7 (IQR: 2.3–23.6) months, and the median number of treatment cycles for cadonilimab was 10. Six patients had PD-L1-positive expression, and 6 had PD-L1-negative expression. Two patients with newly diagnosed advanced cervical cancer and 3 with recurrent disease achieved complete response; 10 patients had a partial response, and 1 patient had stable disease. Objective response rates were 71.4% (15 of 21 patients) overall and 66.7% (4 of 6 patients) for patients with PD-L1-negative expression. Grade 3–4 treatment-related adverse events occurred in 33.3% of patients, while immune-related adverse events were all G1-2 and occurred in 2 (9.5%) patients. No patients discontinued treatment due to intolerable toxicities. The study concluded that cadonilimab-containing therapies showed promising results in terms of responses and survival outcomes, with a favorable safety profile.

Immune Checkpoint Inhibitor–Induced Ureteritis and Cystitis in Patients With Lung Cancer and Uterine Malignancies: A Case Series and Literature Review

Immune checkpoint inhibitors (ICIs) have demonstrated significant efficacy across various cancers but can cause immune-related adverse events (irAEs). While common irAEs such as dermatitis, pneumonitis, and colitis are well-documented, rare events like cystitis and ureteritis remain underrecognized. We report 3 cases of ICI-induced cystitis and ureteritis. The first case involves a 67-year-old female with lung cancer who developed immune-related cystitis and ureteritis after 3 cycles of pembrolizumab, with recurrence 8 months after discontinuation. Both episodes presented with hematuria, urinary frequency, and dysuria, and were responsive to corticosteroid treatment. The second case involves a 37-year-old female with cervical cancer who developed a truncal rash, hematuria, urinary frequency, and dysuria after the first cycle of cadonilimab, a PD-1/CTLA-4 bispecific antibody. Her condition worsened with rising serum creatinine levels. Imaging revealed bladder wall thickening and ureteral dilation. Partial symptom relief followed oral corticosteroids, but complete resolution was achieved with intravesical corticosteroid irrigation. The third case describes a 35-year-old female with endometrial cancer who presented with similar urinary symptoms and flank pain after 4 cycles of pembrolizumab. Rapid creatinine elevation necessitated ureteral stent placement, which failed to alleviate symptoms. After exclusion of infectious etiologies, immune-related cystitis/ureteritis was diagnosed. Symptoms resolved with intravenous corticosteroids. This report underscores the importance of early recognition and management of rare urinary irAEs to avoid unnecessary interventions and prolonged interruption of anti-tumor therapy. It also highlights intravesical methylprednisolone as a potential treatment modality that warrants further investigation.

Efficacy and Safety of Immune Checkpoint Inhibitors on Advanced Cervical Cancer: A Systematic Review and Meta-analysis

This study aims to evaluate the efficacy and safety of immune checkpoint inhibitors (ICIs) in patients with histologically proven advanced cervical cancer. MEDLINE (through PubMed), Web of Science, Embase, and the Cochrane Library were comprehensively searched. Eligible studies were clinical trials investigating the efficacy and safety on ICIs in patients with confirmed advanced cervical cancer. Response rates and adverse events rates were pooled using either a random-effects model or a fixed-effects model based on the I 2 value. A total of 12 clinical trials with 523 women diagnosed with advanced cervical cancer were included. Programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors were identified. The pooled objective response (OR) rate, complete response (CR) rate, partial response (PR) rate, and stable disease (SD) rate of PD1 antibodies were 0.24 (95% CIs: 0.11–0.39; I 2=90%, P<0.01), 0.03 (95% CIs: 0.02–0.05; I 2=0%, P =0.92), 0.20 (95% CIs: 0.08–0.36; I 2=91%, P<0.01), 0.31 (95% CIs: 0.23–0.40; I 2=79%, P<0.01), respectively. Adverse events (AEs) rate of any grade was 0.81 (95% CIs: 0.72–0.88; I 2=83%, P<0.01). This study indicates that PD-1/PD-L1 inhibitors reveal acceptable clinical responses and tolerable adverse events in the treatment of advanced cervical cancer. Well-designed clinical trials investigating the efficacy and safety of immune checkpoint inhibitors (ICIs) are needed.

Integrative Multi-Omics Analysis Reveals Molecular Subtypes of Ovarian Cancer and Constructs Prognostic Models

Abstract: Ovarian cancer (OV) remains the most lethal gynecological malignancy. The aim of this study was to identify molecular subtypes of OV through integrative multi-omics analysis and construct machine learning-based prognostic models for predicting the efficacy of immunotherapy. In here, the mutation, copy number variation, RNA sequencing expression profiles, and clinical information were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Multi-omics data were stratified using the MOVICS package, identifying different molecular subtypes. Our analysis identified 2 molecular subtypes (CS1 and CS2) with significant survival differences. Transcriptional regulatory network analysis revealed differential activation of transcription factors such as FOXA1 and GATA3 in CS1, whereas AR and ESR2 were enriched in CS2. A robust prognostic signature comprising 5 key genes was developed through the integration of 10 machine learning algorithms, demonstrating high predictive power across data sets. Immune cell infiltration analysis revealed that anti-tumor immune cells were more abundant in low-risk groups, whereas pro-tumor immune cells predominated in high-risk groups. Furthermore, low-risk patients exhibited better immunotherapy responses and higher tumor mutational burden (TMB). In conclusion, our findings underscore the potential of multi-omics integration in unveiling novel OV subtypes and constructing predictive models that inform personalized treatment strategies. Future research should focus on validating these findings in larger cohorts to enhance OV management through targeted therapeutic approaches.

Tumor Microenvironment CD8 T and Treg Cells–related Genes Signature Distinguishes Distinct Prognosis and Targeted Therapies Response in Endometrial Cancer

Although most endometrial cancer (EC) patients have a favorable prognosis, the overall survival (OS) of metastatic and recurrent EC could hardly be improved by the current chemoradiotherapy. We aimed to reveal the tumor microenvironment immune infiltration characteristics to elucidate the underlying mechanism of EC progression and guide clinical decisions. In the Cancer Genome Atlas (TCGA) cohort, Kaplan-Meier survival curves confirmed Tregs and CD8 T cells were prognosis-protective factors in OS of EC (P<0.05). Weighted gene coexpression network analysis identified 2 gene modules closely correlated with Tregs and CD8 T-cell infiltration. We randomly split the TCGA EC cohort into the training and testing cohorts at a ratio of 7:3. An immune-related prognosis risk index (IRPRI), including NR3C1, E2F1, OTOG, TTK, PPP1R16B, and FOXP3, was established by univariate, Least Absolute Shrinkage and Selection Operator, and multivariate Cox regression with area under the curve >0.67. Distinct clinical, immune, and mutation characteristics existed between IRPRI groups by multiomics analysis. Cell proliferation and DNA damage repair-related pathways were activated, and immune-related pathways were inactivated in the IRPRI-high group. Furthermore, patients in the IRPRI-high group had lower tumor mutation burden, programmed death-ligand 1 expression, and Tumor Immune Dysfunction and Exclusion scores, indicating a poor response to immune checkpoint inhibitors therapy (P<0.05), which was also validated in the TCGA testing cohort and independent cohorts, GSE78200, GSE115821, and GSE168204. Also, the higher mutation frequencies of BRCA1, BRCA2, and genes enrolled in homologous recombination repair in the IRPRI-low group predicted a good response to PARP inhibitors. Finally, a nomogram integrating the IRPRI group and prognosis significant clinicopathological factors for EC OS prediction was developed and validated with good discrimination and calibration.

Topical Imiquimod Treatment of High-grade Cervical Intraepithelial Neoplasia (TOPIC-3): A Nonrandomized Multicenter Study

Topical imiquimod could be an alternative, noninvasive, treatment modality for high-grade cervical intraepithelial neoplasia (CIN). However, evidence is limited, and there are no studies that compared treatment effectiveness and side effects of topical imiquimod cream to standard large loop excision of the transformation zone (LLETZ) treatment. A multi-center, nonrandomized controlled trial was performed among women with a histologic diagnosis of CIN 2/3. Women were treated with either vaginal imiquimod (6.25 mg 3 times weekly for 8 to 16 wk) or LLETZ according to their own preference. Successful treatment was defined as the absence of high-grade dysplasia at the first follow-up interval after treatment (at 20 wk for the imiquimod group and at 26 wk for the LLETZ group). Secondary outcome measures were high-risk human papillomavirus (hrHPV) clearance, side effects, and predictive factors for successful imiquimod treatment. Imiquimod treatment was successful in 60% of women who completed imiquimod treatment and 95% of women treated with LLETZ. hrHPV clearance occurred in 69% and 67% in the imiquimod group and LLETZ group, respectively. This study provides further evidence on topical imiquimod cream as a feasible and safe treatment modality for high-grade CIN. Although the effectiveness is considerably lower than LLETZ treatment, imiquimod treatment could prevent initial surgical treatment in over 40% of women and should be offered to a selected population of women who wish to avoid (repeated) surgical treatment of high-grade CIN.

Cellular and Humoral Immune Responses Induced by an HLA Class I–restricted Peptide Cancer Vaccine Targeting WT1 Are Associated With Favorable Clinical Outcomes in Advanced Ovarian Cancer

The HLA-A*24:02–restricted peptide vaccine targeting Wilms’ tumor 1 (WT1) (WT1 vaccine) is a promising therapeutic strategy for ovarian cancer; however, its efficacy varies among patients. In this study, we analyzed WT1-specific immune responses in patients with advanced or recurrent ovarian cancer that was refractory to standard chemotherapies and their associations with clinical outcomes. In 25 patients, the WT1 vaccine was administered subcutaneously weekly for 3 months and biweekly thereafter until disease progression or severe adverse events. We assessed Wilms’ tumor 1–specific cytotoxic T lymphocytes (WT1-CTLs) and Wilms’ tumor 1 peptide-specific immunoglobulin G (WT1235-IgG). After vaccination, the percentage of tetramer high-avidity population of WT1-CTLs among CD8+ T lymphocytes (%tet-hi WT1-CTL) and the WT1235-IgG titer increased significantly, although the values were extremely low or below the limit of detection before vaccination (%tet-hi WT1-CTL: 0.003%–0.103%.; WT1235-IgG: <0.05–0.077 U/mL). Patients who had %tet-hi WT1-CTL of ≥0.25% (n=6) or WT1235-IgG of ≥0.10 U/mL (n=12) had a significantly longer progression-free survival than those of patients in the other groups. In addition, an increase in WT1235-IgG corresponded to a significantly longer progression-free survival (P=0.0496). In patients with systemic inflammation, as evidenced by elevated C-reactive protein levels, the induction of tet-hi WT1-CTL or WT1235-IgG was insufficient. Decreased serum albumin levels, multiple tumor lesions, poor performance status, and excess ascites negatively influenced the clinical effectiveness of the WT1 vaccine. In conclusion, the WT1 vaccine induced antigen-specific cellular and humoral immunity in patients with refractory ovarian cancer. Both %tet-hi WT1-CTL and WT1235-IgG levels are prognostic markers for the WT1 vaccine.