Efficacy Of Immune Checkpoint Inhibitors Research Articles

Comparative efficacy of immune checkpoint inhibitors versus chemotherapy alone in diffuse pleural mesothelioma.

This study aimed to investigate the effects of immune checkpoint inhibitors (ICIs) versus chemotherapy on the prognosis of real-world diffuse pleural mesothelioma patients in China. Clinical data of 90 patients with diffuse pleural mesothelioma from 2019 to 2022 were collected from Harbin Medical University Cancer Hospital. Patients were divided into two groups: the ICIs-treated group (n = 46) and the chemotherapy-only group (n = 44). The efficacy and safety of immunotherapy relative to chemotherapy at different treatment stages were explored. The median progression-free survival (PFS) was 10.0 and 7.0 months, and the median overall survival (OS) was 24.7 and 15.8 months in the ICIs-treated group and the chemotherapy group, respectively. The ICIs-treated group showed an 11% increase in objective response rate (ORR) (52.2% vs. 41.0%) and an 8.0% increase in disease control rate (DCR) (78.3% vs. 70.0%) compared to the chemotherapy group. The Kaplan-Meier curves demonstrated significant PFS (HR: 0.61; 95% CI: 0.38-0.98; p = 0.038) and OS (HR: 0.47; 95% CI: 0.26-0.86; p = 0.011) benefits of receiving immunotherapy over chemotherapy alone. Subgroup analysis according to treatment timing showed the same trend. In patients with nonsurgical diffuse pleural mesothelioma, immunotherapy achieved better survival benefits compared to chemotherapy in both first- and second-/third-line treatments. The early addition of immunotherapy improved survival in patients with nonsurgical diffuse pleural mesothelioma.

Concomitant use of renin-angiotensin system inhibitors augments the efficacy of immune checkpoint inhibitors: a systematic review and meta-analysis.

The impact of renin-angiotensin system inhibitors (RASIs) on the outcome of hypertensive cancer patients undergoing immune checkpoint inhibitor (ICIs) therapy remains ambiguous. This investigation sought to elucidate the consequences of RASIs use on the prognosis for this specific patient group within the context of ICIs treatment, aspiring to provide a clearer basis for rational, evidence-driven choices in the clinical prescription of these medications. A comprehensive search was conducted on PubMed, Embase, Web of Science, and the Cochrane Library for original studies published up to 6 August 2023. Studies published in English reporting hazard ratios (HRs) with 95% confidence intervals (CIs) for overall survival (OS) and/or progression-free survival (PFS) were included. All statistical analyses were executed utilizing R software (version 4.2.2). A total of 13 studies, encompassing approximately 12,595 patients, satisfied the inclusion criteria. Meta-analyses demonstrated a statistically significant association between the use of RASIs and a favorable outcome in OS (HR, 0.74; 95% CI, 0.62-0.88) and PFS (HR, 0.77; 95% CI, 0.62-0.96) among cancer patients receiving ICIs treatment. This investigation provides compelling evidence supporting the beneficial prognostic impact of RASIs on cancer patients receiving ICIs. RASIs present a viable option as antihypertensive agents for cancer patients with hypertension undergoing ICIs treatment. Further exploration and validation through prospective studies are necessary to establish definitive guidelines for the use of RASIs in managing hypertensive cancer patients undergoing immunotherapy with ICIs. https://www.crd.york.ac.uk/prospero/, identifier CRD42023454886.

PD-L1 expression as a potential predictor of immune checkpoint inhibitor efficacy and survival in patients with recurrent or metastatic nasopharyngeal cancer: a systematic review and meta-analysis of prospective trials.

The predictive value of programmed death-ligand 1 (PD-L1) expression in nasopharyngeal cancer (NPC) patients receiving immune checkpoint inhibitors (ICIs) remains controversial. This study aimed to evaluate the optimal threshold of PD-L1 expression in predicting the efficacy of ICIs in patients with recurrent or metastatic (R/M) NPC. A meta-analysis was performed by retrieving relevant literature from PubMed, EMBASE, and Cochrane Library databases. Data on the pooled risk ratio (RR), mean overall survival (OS), progression-free survival (PFS), overall response rate (ORR) with 95% confidence interval, and 1%, 10%, and 25% PD-L1 expression cutoff points were obtained to examine the role of PD-L1 as a biomarker in R/M NPC patients receiving immunotherapy. In total, 1,312 patients from 14 studies were included. An improvement in PFS was observed in both patients with PD-L1 ≥ 1% (RR = 0.76, 95% CI 0.62-0.92, P = 0.005) and those with PD-L1 < 1% (RR = 0.68, 95% CI: 0.35-1.32, P = 0.26) who received first-line treatment with immunotherapy, with no significant difference between these subgroups. The pooled ORR was significantly higher in patients with PD-L1 ≥ 1% (ORR = 0.37) than in those with PD-L1 < 1% (ORR = 0.22) (P < 0.01) undergoing subsequent-line treatment. However, when we used the PD-L1 cutoff values of 10% and 25%, there was no significant difference between the positive (PD-L1 expression ≥ the cutoff value) and negative (PD-L1 expression < the cutoff value) subgroups. PD-L1 ≥ 1% also tended to be associated with better PFS and OS. Our meta-analysis suggested that first-line immunotherapy could significantly improve PFS in R/M NPC patients, regardless of the PD-L1 expression levels. Positive PD-L1 expression (≥ 1%) might be a potential predictive biomarker for a better overall response to immunotherapy in R/M NPC patients in subsequent-line setting. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024495841 PROSPERO, identifier CRD42024495841.

Interplay of cachexia progression on the efficacy and toxicity of immune checkpoint inhibitors in patients with esophageal squamous cell cancer (ESCC): A longitudinal perspective.

e14629 Background: Immune checkpoint inhibitors (ICIs) have significantly improved the survival of patients with advanced esophageal squamous cell cancer (ESCC), however, the benefit of ICIs was limited to a few patients. It is vital to comprehend the factors influencing the response in order to identify patients who might benefit from ICIs. Cachexia, an intricate multifaceted syndrome characterized by the loss of skeletal muscle and substantial weight reduction, might impact on the immune response and efficacy of ICIs in cancer patients. The purpose of this study is to explore the impact of longitudinal dynamics of cachexia on the efficacy and adverse effect of ICIs for advanced ESCC patients. Methods: Advanced ESCC patients received at least two cycles of ICIs were enrolled from 2017 to 2021. The baseline and longitudinal changes of cachexia during ICI treatment were collected. Based on the longitudinal weight changes during ICI treatment, patients exhibiting cachexia at baseline were categorized into "reversible cachexia" and "irreversible cachexia" group, and patients without cachexia at baseline were also divided into "latent cachexia" and "cachexia-free" group. Kaplan-Meier curves and Cox regression analysis were performed to explore the impact of cachexia on the efficacy ICIs for ESCC patients. And chi-square test was used to evaluate the correlation between cachexia and immune-related adverse effects (irAEs). Results: A total of 278 individuals who had either received or were presently undergoing ICI treatment were enrolled, with the median progression free survival (PFS) of 5.8 months and overall survival (OS) of 8.3 months. Patients with cachexia before treatment had notably poorer outcomes, with median PFS of 7.9 vs 5.3 months (P=0.001), median time to progression (TTP) of 10.9 vs 6.1 months (P&lt;0.001), and median OS of 14.3 vs 9.2 months (P=0.001). In terms of the longitudinal dynamics of cachexia, significantly inferior outcomes were observed for patients in irreversible cachexia compared to reversible cachexia, with the PFS of 4.4 months and 9 months (P&lt;0.001), the TTP of 4.9 months and 9 months (P=0.006), and the OS of 7.8 months and 15 months, respectively (P=0.003). Although patients in latent cachexia group had inferior survival compared to cachexia-free group, no statistical difference was observed, with the PFS of 10.0 and 7.9 months and OS of 13.9 and 16.2 months. Besides, neither baseline nor longitudinal changes of cachexia was associated with irAEs for ESCC patients. Conclusions: This study indicated the impact of baseline and longitudinal cachexia on the efficacy of ICIs for advanced ESCC patients with ICIs. Dynamic monitoring and management of cachexia was recommended during the ICI treatment of ESCC patients.

Multimodal fully automated predictive model for therapeutic efficacy of first-line cancer immunotherapy based on clinical information and imaging modalities including brain MRI and chest CT images in advanced non-small cell lung cancer.

1555 Background: The integration of imaging and clinical data through artificial intelligence (AI) holds promise for more accurately predicting the therapeutic efficacy of immune checkpoint inhibitors (ICI) ± platinum-based chemotherapy in individual patients with advanced non-small cell lung cancer (NSCLC). However, tumor segmentation still relies entirely on radiologist evaluation and has not yet achieved fully automated tumor evaluation for image analysis. Furthermore, while central nervous system (CNS) metastasis is a critical prognostic factor in patients with advanced NSCLC, radiomics has primarily focused on chest imaging, with few studies incorporating brain MRI analysis. Methods: This study included patients with advanced NSCLC treated with ICI ± platinum-based chemotherapy as first-line therapy from March 2017 to August 2023. We developed an ensemble model combining a logistic regression model that analyzes clinical information with a deep learning model that extracts image features. Each sub-model was independent, allowing for individual adjustments and the ability to be attached or detached. Both models were trained to predict response, 12-month progression-free survival (PFS), and 12-month overall survival (OS) using cross-entropy loss. The dataset was randomly divided into training, validation, and test sets in a 5:3:2 ratio. This random assignment was repeated four times, and the average area under the curve (AUC) was calculated. The test sets were further classified into high- and low-risk groups based on the predicted results, and log-rank tests were performed on their survival curves. Results: The study included 232 patients, with 89 (38%) receiving ICI alone and 143 (62%) receiving ICI + platinum-based chemotherapy. In the entire population, the overall response rate (ORR) for ICI ± platinum-based chemotherapy was 49.5%, with a median PFS of 7.1 months (95% confidence interval [CI]: 5.8-9.1) and a median OS of 24.5 months (95% CI: 21.2-30.3). The model achieved an AUC of 0.70 (95% CI: 0.65- 0.76) for predicting response, 0.65 (95% CI: 0.59-0.71) for 12-month PFS, and 0.69 (95% CI: 0.48-0.90) for 12-month OS. Test sets were classified into high-risk (N = 55) and low-risk (N = 60) groups. The median PFS was 6.8 months in the high-risk group and 14.7 months in the low-risk group (p &lt; 0.05). The median OS was 21.5 months in the high-risk group and 34.3 months in the low-risk group (p &lt; 0.05). Conclusions: We have demonstrated that a multimodal, fully automated ensemble model has significant predictive accuracy for the efficacy and survival outcomes of ICI ± platinum-based chemotherapy in patients with advanced NSCLC.

The efficacy of immune checkpoint inhibitors as a part of multimodality treatment in soft tissue and bone sarcoma in an academic community setting.

e23564 Background: Prior studies have shown response to immune checkpoint inhibitors (ICI) in a variety of sarcoma subtypes, however, much is still unknown about ICI use in specific sarcoma subtypes due to disease rarity. Patients (pts) are often treated with these agents as part of clinical trials, and real world data in the community setting is lacking. The aim of this study is to report real world efficacy and safety of ICI in sarcoma either alone or with radiation (RT) and/or surgery. Methods: A retrospective cohort review was conducted to identify pts with soft tissue and bone sarcoma who were administered ICI at Kellogg Cancer Center at NorthShore University HealthSystem/Endeavor Health. Pts who received ICI as part of a clinical trial were excluded. Results: A total of 29 pts receiving ICI were identified. Pts had a median of 1 prior systemic therapy. ICI included pembrolizumab (n = 23), nivolumab (n = 5), and ipilimumab/nivolumab (n = 1). Treatment was discontinued in 28 pts due to disease progression (n = 18), toxicities (n = 3), death (n = 2), and maximal response (n = 5). One patient is still undergoing treatment. Median progression-free survival (PFS) was 4.9 months. Median overall survival (OS) was 14 months. Overall response rate (ORR) is 31%. Median duration of response was not reached (44+ months). Complete response (CR) (n = 5) reported in 3 pts with undifferentiated pleomorphic sarcoma (UPS), 1 pt with SMARCA4 deficient undifferentiated sarcoma, and 1 pt with dedifferentiated chondrosarcoma. Partial response (PR) (n = 4) reported in 1 pt with UPS, 1 pt with dedifferentiated liposarcoma, 1 pt with high grade spindle sarcoma of bone, and 1 pt with malignant peripheral nerve sheath tumor. Of those pts with a CR, 2 patients received only pembrolizumab, 1 pt was administered concomitant RT, and 2 pts had administered concomitant surgery. Of the pts who had PR, 3 were also treated with concomitant RT. Grade 3 immune related adverse effects were reported in 5 of the 29 patients. Of these patients, 2 had documented CR and 3 documented PR. Conclusions: This study expands on the real world efficacy of ICI in a variety of sarcoma subtypes. CR and PR rates in this setting were high, and responses were durable, although selection bias for treatment may have played a role. This data supports the treatment of metastatic sarcoma with ICI, especially with concomitant RT and surgery, in a variety of subtypes.

Real-world safety and efficacy of concurrent immunotherapy and thoracic chemoradiotherapy: A multi-institutional analysis.

e23262 Background: Despite the success of Immune checkpoint inhibitors (ICIs) as consolidation following concurrent chemoradiotherapy (CCRT), 22% to 30% of patients still cannot be treated with durvalumab due to progression or adverse events (AEs) during or after CCRT. Concurrent ICIs with CCRT would offer the opportunity to receive ICIs and may provide treatment benefit to a greater proportion of patients. In this study, we performed a multicenter investigation to evaluate the safety and efficacy of ICIs and chemotherapy with concurrent thoracic radiotherapy. Methods: All patients from three institutions who underwent ICIs and concurrent thoracic radiotherapy were included. The rate of 12-month progression-free survival (PFS) was estimated using the Kaplan-Meier method and evaluated with 95% CIs calculated using the Greenwood formula. Therapy-related pneumonitis (TRP) and esophagitis (TRE) were defined per CTCAE v5.0. Statistics utilized logistic regression modeling and receiver operating characteristic (ROC) analysis. Results: 69 patients (median [range] age, 62 [52-76]; 61 [88.4%] male; median follow-up 30.4 months) were collected, including 18 (26.1 %) cases of non-small cell lung cancer (NSCLC), 26 (37.7 %) cases of small cell lung cancer (SCLC), and 25 (36.2 %) cases of esophageal cancer (EC). The 12-month PFS rates in NSCLC, SCLC and EC were 72.2%, 69.2% and 72.0%, respectively. The median PFS in NSCLC and SCLC was 24.3 and 13.1 months, and not reached (mean 29 months) for EC. The incidences of all-grade TRP and TRE were 60.7% and 57.7%, respectively. Grades 1-5 TRP occurred in 15.9%, 30.4%, 8.6%, 1.4%, and 0, respectively. Grades 1-5 TRE occurred in 20.2%, 28.9%, 8.6%, 0, and 0, respectively. On multivariable analysis, age and MLD significantly predicted for any-grade and grade ≥2 TRP. Only age significantly predicted for grade ≥3 TRP. ROC analysis was able to pictorially model RP risk probabilities for a variety of MLD and age thresholds. Conclusions: This real-world study can be helpful for understanding the true efficacy and toxicity of ICIs and chemotherapy with concurrent thoracic radiotherapy given the lack of robust clinical data. Close monitoring should be recommended in this patient population during RT and follow-up.

Effect of common medications on immune checkpoint inhibitor efficacy.

e14710 Background: Previous studies have suggested that certain common medications could impact immune checkpoint inhibitor (ICI) efficacy and survival. These studies lacked non-ICI control groups, raising the possibility that survival differences could be explained by confounding. Methods: We developed a pan-cancer cohort of 27,998 patients who received ICIs in the national Veterans Health Administration (VHA) from 2010 to 2023. ICI patients were matched to 66,488 historical control patients treated with chemotherapy or targeted therapy before initial ICI regulatory approval in each cancer. We ascertained baseline use of drugs from 15 common medication classes within 1 year before therapy start and performed propensity-weighted Cox regression analyses to assess the impact of each medication class on overall survival (OS) and time to next treatment (TTNT). Interaction tests measured whether the impact of each medication class was significantly different in ICI versus historical control patients. Results: In the ICI cohort, the most common cancer types were NSCLC (46%) and melanoma (10%). After adjustment for multiple comparisons, only statins (adjusted hazard ratio [aHR] 0.93), PPIs (aHR 1.06), and loop diuretics (aHR 1.19) were associated with overall survival differences among ICI patients; nearly identical associations were observed in historical control patients (interaction p-values &gt; 0.4 for all; Table). Similar results were seen for TTNT and in sensitivity analyses limiting to more recent medication users. Conclusions: Common medications do not appear to impact ICI efficacy. Previously described survival effects are likely the result of confounding. [Table: see text]

Efficacy and safety of immune checkpoint inhibitors in recurrent or metastatic nasopharyngeal carcinoma: A systematic review and meta-analysis.

e14612 Background: Treatment options for recurrent or metastatic nasopharyngeal carcinoma (NPC) are limited. Recently, the introduction of Immune Checkpoint Inhibitors (ICIs), either as single agents or combined with other treatment options, has emerged as a potential treatment for NPC. Hence, we performed a systematic review and meta-analysis to evaluate the efficacy and safety of ICIs compared to standard chemotherapy. Methods: We systematically searched PubMed, EMBASE, and Cochrane databases for randomized controlled trials (RCTs) comparing ICIs versus standard chemotherapy in patients with NPC. The main outcomes were progression-free survival (PFS), overall survival (OS) and adverse events rate. All analyses used a random-effects model, with 95% confidence intervals (CIs) and were conducted on Review Manager 5.4. Results: A total of 1,188 patients from 5 RCTs were included, of which 634 (53.3%) received PD-1 inhibitors. In a pooled analysis of all studies, treatment with ICIs demonstrated a statistically significant benefit in OS (HR 0.73; 95% CI 0.61-0.87; p&lt;0.01). In trials evaluating ICI monotherapy versus chemotherapy (617 patients), PFS was not significantly different between groups (p=0.91). However, pooling two studies evaluating ICI combined with chemotherapy vs. chemotherapy (541 patients) demonstrated higher PFS for the ICI group (HR 0.53; 95% CI 0.42-0.67; p&lt;0.01). Overall pooled PFS was non-significant (HR 0.75; 95% CI 0.49-1.16; p=0.20). In all subgroup analyses, patients treated with ICI achieved greater PFS than chemotherapy: low EBV DNA level (HR 0.61; 95% CI 0.42-0.87; p=0.007) or high EBV DNA level (HR 0.44; 95% CI 0.35-0.56; p&lt;0.01), without liver metastasis (HR 0.68; 95% CI 0.47-0.98; p=0.04), and with liver metastasis (HR 0.56; 95% CI 0.38-0.83; p=0.04). Moreover, ICIs were well tolerated and not associated with an increased risk of serious adverse events (HR 0.96; 95% CI 0.82-1.11; p=0.56). The frequency of hypothyroidism increased in the ICI group (HR 2.07; 95% CI 1.63-2.63; p&lt;0.01). Other adverse events had similar rates in both groups, such as AST and ALT levels, diarrhea, pruritus, rash, stomatitis, and vomiting. Conclusions: This meta-analysis demonstrated that immune checkpoint inhibitors significantly enhanced overall survival without substantially increasing serious adverse events in patients with M/R NPC. Further studies are needed to identify the patients who benefit the most from ICI monotherapy or combination therapies. [Table: see text]

Effect of tobacco use on response to immunotherapy in patients with cancer.

e14537 Background: Evidence from existing literature suggests that it remains unclear if tobacco usage affects the efficacy of immune checkpoint inhibitors (ICI). This research aims to evaluate the connection between smoking and the effectiveness of immune checkpoint inhibitor (ICI) therapy in specific cancer types treated at our institution. Methods: This is a retrospective cohort study where cancer patients &gt;18 years old who received immunotherapy from 2017 to 2023 were identified through our center’s Cancer Registry. This study focuses on three major cancer types: lung, head and neck, and melanoma. 458 patients with their demographics, staging, duration of treatment and last contact have been assessed. SAS 9.4 was used for analysis with Chi-square/Fisher’s Exact testing, Student’s T-test, life tests and the Cox proportional hazards model to discern the effects of tobacco use and overall survival. Results: Among 458 patients, 48 (10.48%) are never-smokers, and 410 (89.52%) are smokers (current or former). Overall, 211 (46.06%) have stage 0-IIIA, while 247 (53.93%) have IIIB-IVB tumors. The mean age is 66.08 years. Additionally, 330 patients (72.05%) received chemotherapy as part of their treatment regimen in addition to immunotherapy. Non-tobacco users exhibit a higher survival probability compared to tobacco users. At five years, non-tobacco users showed a survival rate of 41%, whereas tobacco users had a survival rate of 28% (p=0.01) and hazard ratio [HR] of 1.55 (95% confidence interval, 1.00–2.39). The median survival for all patients is 40 months among non-tobacco users and 19 months among tobacco users. Moreover, there is no difference in the survival rates between current and former smokers. Conclusions: The study demonstrates that immunotherapy has better outcomes and increases survival probability in non-tobacco users. Also, there is no difference in survival between current or former tobacco users. However, these findings warrant future prospective studies.

The safety and efficacy of immune checkpoint inhibitor in combination with FOLFOX as neoadjuvant/adjuvant therapy in patients with locally advanced colon cancer.

e15621 Background: The recurrence rate of locally advanced colon cancer (T3-4 or N+, M0) after surgery is significantly high. Emerging data indicate that the combination of immunotherapy and chemotherapy demonstrates synergistic effects in other solid tumors. Consequently, a combination of immunotherapy and chemotherapy holds the potential to benefit patients with MSS and pMMR colon cancer. We have designed a prospective trial to investigate whether the immune checkpoint inhibitor (ICI) in combination with chemotherapy represents a safe and beneficial treatment approach for locally advanced colon cancer. Methods: Inclusive Criteria: Patients with locally advanced colon cancer (T3-4 or N+, M0) confirmed through pathological biopsy, with confirmed indications for neoadjuvant/adjuvant chemotherapy by the multidisciplinary team. Patients must be eligible for surgery, and a measurable mass must be identified according to RECIST version 1.1. All individuals aged over 18 years, with an estimated life expectancy of over one year and an ECOG score within 0-1, are eligible. The neoadjuvant chemoimmunotherapy group (NACI) includes mFOLFOX 6 (Q2W) and the anti-PD-1 monoclonal antibody (Toripalimab) (3mg/kg, Q2W), while the neoadjuvant chemotherapy group (NAC) receives only mFOLFOX 6 for neoadjuvant/adjuvant therapy (a total of 12 cycles, 6 cycles pre-surgery and 6 cycles post-surgery). The primary endpoint is the pathological complete response (pCR) rate. Results: From 2019 to 2022, a total of 22 patients were enrolled in the study, with 13 in the NACI group and 9 in the NAC group. The research findings indicate that in the NACI group, over 30% (4/13) of patients achieved a pathological complete response (pCR), whereas none of the patients in the NAC group reached pCR (0/9). Among the pCR patients, one was identified as MSI-H/dMMR, two as MSS/pMMR, and one had an unknown status. Tumor regression grade (TRG) levels also revealed that all patients in the NACI group were below grade 2, significantly outperforming the NAC group (P &lt; 0.05), with statistically significant differences. However, no significant differences were observed between the NAC and NACI groups in terms of CT regression percentage, R0 resection, vascular cancer emboli, and the level of neural invasion. Adverse reactions did not show significant differences between the two groups. Conclusions: The combination of immunotherapy and chemotherapy exhibits a synergistic effect in treating locally advanced colorectal cancer. Tolerable adverse reactions suggest that neoadjuvant chemoimmunotherapy could potentially serve as a novel therapeutic option. Clinical trial information: NCT03985891 .

Effect of AURKA targeting on nuclear PD-L1 and the efficacy of immune checkpoint inhibitors in triple-negative breast cancer.

e13153 Background: Aurora-A mitotic kinase (AURKA) plays a role in Triple Negative Breast Cancer (TNBC) progression through activation of epithelial to mesenchymal transition (EMT)-mediated cancer cell plasticity. Cancer cells that undergo EMT acquire a CD44high/CD24low and/or ALDHhigh cancer stem-like phenotype (Cancer Stem Cells) characterized by intrinsic drug resistance. Cancer Stem Cells (CSCs) shows high PD-L1 expression that induces tumor immune escape through CD8+ T-cells exhaustion. Significantly, “undraggable” nuclear PD-L1 may play a key role in induction of immune therapy resistance and cancer cell plasticity. Methods: (1) TNBC Models: MDA-MB 231, unique MDA-MB 231/LM Durvalumab resistant (DUV-R) and TNBC-M40 cells established from metastatic PDXs; (2) In Vitro Studies: TNBC cells were treated with the AURKA inhibitor alisertib (50nM). PD-L1 expression was evaluated by immunoblotting. Apoptosis was measured by immunofluorescence using Cleaved-PARP antibodies. To assess stemness capacity, TNBC cells were cultured under non-adherent conditions to form mammospheres. ALDH activity (functional stemness marker) was measured using the Aldefluor Kit. (3) In Vivo Studies: 1x106 MDA-MB 231/LM cells were injected into the mammary fat pad of humanized NSG-CD34+ female mice. Animals were treated with anti-PD-L1 ICI atezolizumab (20 mg/Kg) and alisertib (25 mg/Kg) as monotherapy or in combination. 1x106 MDA-MB 231/LM cells were also injected into the mammary fat pad of humanized NSG-CD34+ female mice and treated with durvalumab (20 mg/Kg) to develop durvalumab-resistant models. PD-L1, CD44, Vimentin expression and tumor infiltration of CD8+ T-cells were assessed by immunofluorescence. Results: Treatment of MDA-MB 231/LM xenografts with alisertib decreased the levels of CD44 and PD-L1 expression and increased CD8+ T-cells tumor infiltration. Because PD-L1 genetic targeting enhanced in vitro alisertib-induced apoptosis, MDA-MB 231/LM xenografts were treated with alisertib and the anti-PD-L1 ICI atezolizumab. Com- bination of atezolizumab and alisertib resulted in the reduced expression of the EMT marker vimentin that was linked to lack of organ metastasis. Combination of atezolizumab and alisertib also induced a significant reduction of ALDHHigh CSC in ex-vivo 3D-Organoids established from TNBC-M40 cells. MDA-MB 231/LM DUV-R cells showed increased nuclear PD-L1 compared to parental cells. The combination of alisertib with Immune Checkpoint Inhibitors (ICIs) induced apoptosis of MDA-MB 231/LM DUV-R cells through down-regulation of intra-tumoral nuclear PD-L1 expression. Conclusions: This study provides innovative pre-clinical rationale for combining AURKA inhibitors with ICIs to reduce “ undruggable” nuclear PD-L1 expression and impair cancer cell plasticity of metastatic TNBCs that currently have limited effective therapeutic options.

Immune-related adverse events in patients treated with immunotherapy according to corticosteroid exposure.

e14709 Background: Patients with cancer require treatment with corticosteroids for multiple reasons, including prevention of chemotherapy-related side effects. Although corticosteroid use has been associated with lower efficacy of immune checkpoint inhibitors (ICI) in some studies, whether corticosteroid exposure affects the presence and severity of immune-related adverse events (irAEs) remains unclear. Methods: Retrospective single-center study of patients diagnosed with solid tumors treated with ICI. Eligible patients were those who received at least one cycle of ICI and had at least 1 month of follow-up post-ICI initiation. Patient data were extracted from electronic medical records. Comparisons between groups were made based on steroid exposure (defined as the administration of &gt;10 mg of prednisone or its equivalent for &gt;10 days within a 30-day period or at any point during ICI treatment, excluding steroid treatment for irAEs). Associations between variables were assessed using independent samples T-test, Chi-square, and Fisher’s exact tests. Results: We included 135 patients (mean age 61 years, SD 13); 72 (54%) were male. Forty-two (31%) had been exposed to steroids (mean prednisone equivalent of 427 mg, SD 298). Most patients received ICI as palliative treatment for advanced disease (105/135; 78%), primarily as first-line therapy (79/105; 75%). Patients exposed to corticosteroids were more likely to have received ICI with chemotherapy (76% vs 1%, p&lt;0.001), were younger (56 vs. 63 years, p=0.009), more likely to be female (62% vs. 39, p=0.014), and had lower median Charlson Comorbidity Index scores (2 vs. 3, p=0.026). Steroid-exposed patients were more likely to have employed ICI in the neoadjuvant or adjuvant settings (36 vs. 16%, p=0.024) or as third or subsequent line therapy (26 vs. 8%, p=0.044). There were no statistically significant differences in the frequency of irAEs of any grade based on steroid exposure (31% vs 41%, p=0.252). However, patients who were exposed to steroids were significantly less likely to delay or suspend ICI (10% vs. 32%, p=0.005). No other parameters were associated with the rate or severity of irAEs. Conclusions: Our findings suggest that corticosteroid exposure does not increase the frequency of irAEs in patients treated with ICI, but it is associated with a reduced likelihood of discontinuing ICI due to irAEs. These observations suggest that corticosteroids may play a beneficial role in managing patients undergoing immunotherapy, particularly in sustaining treatment continuity despite irAEs. This study underscores the need for further investigation into optimal steroid use strategies to enhance patient outcomes with immunotherapy, especially in situations when they are commonly prescribed, such as premedication for chemotherapy.

Effect of novel autologous immune training platform on end-stage patients with cancer.

2546 Background: SUPLEXA therapeutic cells are the initial autologous and non-engineered candidate to emerge from the novel ENLIST cells training platform. Manufacturing is robust, reproducible and with an acceptable cost of goods. The method requires 35 days to produce multiple doses. Multiple mechanisms of SUPLEXA therapeutic cells have been delineated and all appear to complement that of immune checkpoint inhibitors (ICIs) with SUPLEXA cells serving to enhance the number of primed anti-tumor host T cells while ICIs serve to increase the durability of primed T cells by blocking their premature down-regulation. Methods: A 35 patient Phase 1 single-agent study survey study is currently ongoing in Australia to test the safety and clinical activity of SUPLEXA cells in end-stage patients with various tumor types. No chemo preconditioning or concomitant cytokine treatment was employed. CYTOF analysis of longitudinal peripheral blood is used to monitor changes to the host immune system. Results: To date, SUPLEXA therapeutic cells have demonstrated safety and significant clinical benefit with an observed CR, PR, and many durable SD in approximately half the patients. Several solid tumor patients remain on study beyond 1 year and doing well. Longitudinal analysis of PBMCs from SUPLEXA cell treated cancer patients demonstrated durable changes in the composition of myeloid immune cell subsets in SUPLEXA treated patients, impacting the anti-tumor bias of the host immune system. Specifically, we identified a dramatic decrease in the number of peripheral myeloid derived suppressor cells (MDSCs), within 3 weeks of SUPLEXA treatment. In patients with CR and PR, we also identified stable increases in activated classical CD14+ blood monocytes. Conclusions: SUPLEXA therapeutic cells are a highly differentiated approach to cellular therapy. The first-in-human experience demonstrated a pristine safety profile and strong clinical benefit as a single-agent. The pharmacodynamic decrease of in the number of MDSCs, known to suppress the anti-tumor immune response and limit immune checkpoint inhibitors (ICIs) efficacy, supports the further clinical testing to test the hypothesis that the multiple mechanisms of SUPLEXA cells will enhance the clinical activity of ICIs. Clinical trial information: NCT05237206 .

Comparison of tumor immune microenvironments (TIMEs) between primary and metastatic sites (Mets) in triple-negative breast cancer (TNBC).

1097 Background: The TIME is critical in determining response to immune checkpoint inhibitors (ICIs), but TIME differences across primary and mets in TNBC are not well understood. Since ICIs are standard of care for patients with TNBC, we studied the TIMEs of primary TNBC and mets to investigate how immune composition may affect ICI efficacy. Secondary analysis stratified cohorts by race and disease sites to compare TIMEs in Black or African American (B/AA) with White patients, since TNBC has a high prevalence of B/AA women who are underrepresented in studies and have a worse prognosis. Methods: We retrospectively analyzed de-identified next-generation sequencing data from TNBC patients (n=1,044) in the Tempus Database. Tumors from primary breast (PB, n=553), liver (n=153), lymph node (LN, n=174), lung (n=111), and bone (n=53) sites were sequenced with the Tempus xT DNA (648-gene panel) and xR RNA assays. Histologies included invasive ductal carcinoma (82%), lobular carcinoma (2.2%), mixed ductal and lobular carcinoma (1.7%), and other (14%). Demographics, TMB, MSI, PD-L1, and proportions of B, T (CD4+, CD8+), NK cells, and macrophages were compared across sites. LN were used as a positive control. Chi-squared/Fisher’s exact or Kruskal-Wallis tests were used to assess statistical significance (two-sided, evaluated at the 0.05 alpha level). Results: The cohort (median age=57 years, IQR 46-66) comprised a diverse population (65% White, 23% B/AA, 2.8% Asian, and 9.3% other). Liver exhibited a lower percentage of B cells and higher percentage of macrophages compared to PB (p&lt;0.0001 for both), lung (p&lt;0.0001 for both), and bone (B cells p&lt;0.0001, macrophages p&lt;0.05). Liver also exhibited lower percentages of CD8+ T cells compared to PB (p&lt;0.05) and CD4+ and NK cells compared to lung (CD4+ cells p&lt;0.01, NK cells p&lt;0.0001). Bone had lower percentages of CD8+ cells compared to PB (p&lt;0.0001), lung (p&lt;0.001), and liver (p&lt;0.01). Compared to lung, bone had a lower percentage of CD4+ cells (p&lt;0.0001) and higher percentage of macrophages (p&lt;0.01). PD-L1 positivity, TMB, and MSI exhibited no differences across sites. Secondary analysis compared the TIME between B/AA and White cohorts in PB (B/AA n=85 vs White n=204: %B cells, 15 vs 11, p=0.017; %CD8 cells, 4.9 vs 7.3, p=0.025), liver (B/AA n=15 vs White n=48: %B cells, 8 vs 4, p=0.2; %CD4, 23 vs 14, p=0.2; %CD8, 7.2 vs 4.6, p=0.07), and lung (B/AA n=9 vs White n=33: %B cells, 22 vs 11, p=0.021; %CD8, 7.9 vs 5.2, p=0.5). Conclusions: Compared to PB and lung, liver and bone had immune cell infiltrates indicating a less immunogenic TIME in the overall TNBC population. Although limited by sample size, this is one of the first studies to assess the TIME across race and sites of disease. These findings are hypothesis generating and provide further rationale to better understand how the TIME across disease sites and race may alter the efficacy of ICIs in TNBC.

Impact of time-of-day infusion of camrelizumab combined with chemotherapy on efficacy in advanced malignant tumors.

e14634 Background: The combination of immune checkpoint inhibitors (ICIs) with chemotherapy has emerged as a standard first-line treatment strategy for advanced cancers. Camrelizumab and Tislelizumab, representative ICIs, have approval by the Chinese NMPA for first-line treatment of advanced cancers such as lung cancer and esophageal cancer. Previous studies have indicated that the timing of drug administration can influence the efficacy of ICIs. However, studies on the ICIs plus chemotherapy are lacking. Therefore, we conducted a retrospective study to explore the effect of the timing of infusion on patients with advanced cancer undergoing treatment with ICIs combined chemotherapy. Methods: We retrospectively enrolled a total of 253 patients diagnosed with advanced cancers between 2017 and 2023 in Guangdong Second Provincial General Hospital. Among these patients, 109 received camrelizumab (Cam cohort) plus chemotherapy and 65 received tislelizumab (Tis cohort) plus chemotherapy. Patients were grouped into morning (AM) and afternoon (PM) categories based on the timing of their ICIs administration (&lt; 1 times versus ≥ 1 times after 16:00). The Response Evaluation Criteria in Solid Tumors Criteria V.1.1 was used to evaluate the response to treatment. The primary endpoint was progression-free survival (PFS). Results: The results consistently showed that the PM group had a longer PFS than the AM group in the overall patients (p &lt; 0.01). In the Cam cohort, the PM group (n = 48) exhibited a longer PFS compared to the AM group (n = 61) (16.8 months vs. -, p = 0.02). However, no significant difference in PFS was observed among patients in the Tis cohort (AM vs. PM, n = 34 vs. n = 31, 16.1 months vs. -, p = 0.51). Subgroup analyses indicated that the PM group had a more favorable PFS treatment effect in most subgroups. The incidence of any Treatment Emerged Adverse Event (TEAE) (Cam cohort, AM vs. PM, 98.52% vs. 92.68%; Tis cohort, AM vs. PM, 97.05% vs. 100.00%) and grade 3 TEAEs (Cam cohort, AM vs. PM, 5.80% vs.7.30%; Tis cohort, AM vs.PM - vs. 12.90%) was similar in the Cam cohort and Tis cohort. The most common adverse events are anemia (Cam cohort vs. Tis cohort, 70.58% vs. 79.41%), thrombocytopenia (Cam cohort vs. Tis cohort, 54.41% vs. 58.82%) and lymphopenia (Cam cohort vs. Tis cohort, 44.11% vs. 44.11%). Conclusions: The findings of this study highlight a significant variation in daily rhythms among advanced cancer patients undergoing treatment with ICIs plus chemotherapy. Interestingly, a trend was observed in patients treated with camrelizumab, where those receiving treatment in the afternoon demonstrated a longer PFS. However, this trend was not observed in patients treated with tislelizumab. These results suggest that time-of-day infusion could potentially serve as a personalized strategy for patients treated with combination ICIs therapy.

Safety and efficacy outcomes of early cessation of anti-PD1 therapy in patients 80 years or older: A retrospective cohort study

Older patients have similar immune checkpoint inhibitor efficacy and rates of adverse events as younger patients, but appear to have decreased tolerability, particularly in the oldest patient cohort (>80 years), often leading to early cessation of therapy. We aimed to determine whether early discontinuation impacts efficacy of anti-PD-1 therapy in patients ≥80 years old. In this retrospective, multicenter, international cohort study, we examined 773 patients with 4 tumor types who were at least 80 years old and treated with anti-PD-1 therapy. We determined response rate, overall survival (OS), and progression-free survival (PFS) in patients who discontinued therapy early (<12 months) for reasons other than progression or death. We used descriptive statistics for demographics, response, and toxicity rates. Survival statistics were described using Kaplan Meier curves. Median (range) age at anti-PD-1 initiation was 83.0 (75.8–97.0) years. The cancer types included were melanoma (n = 286), non-small cell lung cancer (NSCLC) (n = 345), urothelial cell carcinoma (UCC) (n = 108), and renal cell carcinoma (RCC) (n = 34). Of these, 102 met the primary endpoint of <12 months to discontinuation for reasons other than death or progression. Median PFS and OS, respectively, for these patients were 34.4 months and 46.6 months for melanoma, 15.8 months and 23.4 months for NSCLC, and 10.4 months and 15.8 months for UCC. This study suggests geriatric patients who have demonstrated therapeutic benefit and discontinued anti-PD-1 therapy at less than 12 months of duration for reasons other than progression may have durable clinical benefit without additional therapy.

Linking the companion diagnostic function of cancer genome profiling to therapy: Investigation of TMB-high predictors.

e13033 Background: Based on the companion diagnostic function of the Comprehensive Cancer Genome Profiling (CGP) test in Japan, pembrolizumab is the standard treatment for patients with Tumor Mutational Burden (TMB)-high (H) solid tumors. In this report, we attempted to extract predictive factors of TMB-H from CGP test results. Methods: We carried out a retrospective cohort study of 42 patients with malignant breast tumors (excluding circulating tumor DNA in the blood) who underwent CGP testing between June 1, 2019, and November 30, 2023, at our hospital and affiliated institutions. We analyzed the association between clinicopathological factors, the number of analyzed cancer-related gene mutations (SNV, InDel), and TMB-H using univariate and multivariate statistical analysis. Results: Of the 42 cases (27 positive and 15 negative for estrogen receptor (ER), respectively), seven (16.7%) were TMB-H. Samples significantly associated with TMB-H according to univariate analysis were submitted as pathology specimens (non-primary (16.7%) vs. primary (0%), p = 0.011), ER (positive (16.7%) vs. negative (0%), p = 0.044), letrozole (LET) (yes (11.9%) vs. no (4.8%), p = 0.008), and previous treatment (after 6th line (14.3%) vs. before (2.4%), p = 0.041). Multivariate analysis showed that LET had a significant effect on TMB-H in Aromatase inhibitor agents (LET + Anastrozole + Exemestane) (LET: OR, 19.9; 95% CI, 2.2–183.5; p = 0.008) and the number of cancer-related gene mutations (PIK3CA+TP53) were significantly affected (PIK3CA: OR, 3.8; 95% CI, 1.1–13.2; p = 0.032. TP53: OR, 0.08; 95% CI, 0.01–0.66; p = 0.015). Single regression analysis showed a significant association between the number of PIK3CA mutations and LET. (β, 0.31; SE, 0.11; p = 0.008). Conclusions: ER positivity, history of LET use, prior therapy after the 6th line, and submission of pathology specimens from non-primary tumors to CGP testing are predictive factors for TMB-H. In multivariate analysis, the history of LET use and the number of PIK3CA mutations were significantly associated with TMB-H. Research shows that PIK3CA mutations are most frequent in patients who have undergone preoperative endocrine therapy with LET (Breast Cancer Res Treat. 2020 Nov;184(1):123–133.), suggesting that an increased number of PIK3CA mutations due to LET contributed to TMB-H. Although immune checkpoint inhibitors (ICIs) are not indicated for ER-positive breast cancer, TMB-H may be a predictor of ICI efficacy in such cases. The limitations of our research were the small sample size, and the study population only included Japanese. For the next steps needed to continue in this research, clinical trials should take place to test whether TMB-H is a predictor of ICIs in a wider population of ER-positive breast cancer.

Unaddressed Challenges in the Treatment of Cutaneous Melanoma?

Background and Objectives: While the management of noninvasive cutaneous melanoma (CM) is typically limited to a secondary excision to reduce recurrence risk and periodic follow-up, treating patients with advanced melanoma presents ongoing challenges. Materials and Methods: This review provides a comprehensive examination of both established and emerging pharmacologic strategies for advanced CM management, offering an up-to-date insight into the current therapeutic milieu. The dynamic landscape of advanced CM treatment is explored, highlighting the efficacy of immune checkpoint inhibitors and targeted therapies, either in monotherapy or combination regimens. Additionally, ongoing investigations into novel treatment modalities are thoroughly discussed, reflecting the evolving nature of melanoma management. Results: The therapeutic landscape for melanoma management is undergoing significant transformation. Although various treatment modalities exist, there remains a critical need for novel therapies, particularly for certain stages of melanoma or cases resistant to current options. Conclusions: Consequently, further studies are warranted to identify new treatment avenues and optimize the utilization of existing drugs.

Circadian control of tumor immunosuppression affects efficacy of immune checkpoint blockade.

The circadian clock is a critical regulator of immunity, and this circadian control of immune modulation has an essential function in host defense and tumor immunosurveillance. Here we use a single-cell RNA sequencing approach and a genetic model of colorectal cancer to identify clock-dependent changes to the immune landscape that control the abundance of immunosuppressive cells and consequent suppression of cytotoxic CD8+ T cells. Of these immunosuppressive cell types, PD-L1-expressing myeloid-derived suppressor cells (MDSCs) peak in abundance in a rhythmic manner. Disruption of the epithelial cell clock regulates the secretion of cytokines that promote heightened inflammation, recruitment of neutrophils and the subsequent development of MDSCs. We also show that time-of-day anti-PD-L1 delivery is most effective when synchronized with the abundance of immunosuppressive MDSCs. Collectively, these data indicate that circadian gating of tumor immunosuppression informs the timing and efficacy of immune checkpoint inhibitors.