Outcome Of Immunotherapy Research Articles

Examining the relationship between ECOG performance status and immunotherapy outcomes: Insights from real-world data analysis.

11131 Background: The impact of Eastern Cooperative Oncology Group Performance Score (ECOG) on immunotherapy (IO) outcomes is intricate, as historically clinical trials have primarily enrolled patients with ECOG scores of 0 or 1. The National Comprehensive Cancer Network (NCCN) advises against administering IO to patients with ECOG scores of 2 or higher. However, conflicting findings from research studies and variations in real-world clinical practice complicate this relationship. Our study aims to elucidate the association between ECOG status and the outcomes of immunotherapy. Methods: Data collected from SUNY Upstate Medical University treated cancer patients who underwent immunotherapy and chemotherapy was used for analysis. The Kaplan-Meier method and Cox regression were used to analyze survival probability based on therapy, age, and ECOG. Results: Of 813 patients included in the study, 46.99% (n=382) received immunotherapy. 51.85% (n=421) were females. The mean age was 64.1 years in IO group and 67.7 years in non-IO/chemo group. 52.5% (n=187) of patients who were ≤ 64 years received IO compared to only 42.7% (n=195) of patients who were ≥ 65 years (p=0.005). 48.6% (n=118) of patients with ECOG score 0 received IO, while only 40.5% (n=72) patients with ECOG score of ≥3 received IO (p=0.279). Patients who received IO with ECOG score of ≥3 had higher probability of survival compared to other groups (p<0.0001). While, in non-IO group, patients with ECOG 0 had higher probability of survival compared to ECOG 3 (HR 1.773, 1.209 – 2.600). There was no difference in overall survival in patients receiving IO based on age categories (p=0.2627, HR 1.148, 0.901 – 1.462). Conclusions: Our findings suggest that relying solely on ECOG status to determine eligibility for immunotherapy may be overly restrictive. Patients with significant comorbidities could still derive benefits from immunotherapy. Further investigation is warranted to comprehensively assess the influence of ECOG status on immunotherapy outcomes.

Case series: Outcomes of immunotherapy in locally advanced and metastatic cutaneous squamous cell carcinoma in Lakes and Waikato region.

e21529 Background: Cutaneous squamous cell carcinomas (CSCC) have an incidence of 425 per 100,000 in New Zealand (1). 5% progress to locally advanced or metastatic disease. Immunotherapy is unfunded for this indication despite excellent response and safety profile (2). The objective was to evaluate real world outcomes of patients who managed to access immunotherapy. Methods: Review of referrals to medical oncology in the Lakes & Waikato region between 1 August 2017 to 31 August 2022 with unresectable locally advanced or metastatic CSCC who had immunotherapy. Patients who were not referred to medical oncology, could not afford immunotherapy and/or unsuitable for a clinical trial were excluded from analysis. Results: 13/15 (86.7%) reviewed were male. Mean age was 71. 7 were locally advanced and 8 were metastatic. 14 self-funded pembrolizumab (11 first line, 3 second line). 1 accessed immunotherapy via a trial. 12 (80%) had significant responses; 3 achieved a complete response and 9 achieved a partial response. Median duration of response was not reached, with a median number of 18 cycles delivered. Median follow up was 23.8 months. 9 (60%) remain alive with ongoing response. 6 died on treatment; 3 from non-malignancy and non-treatment related causes. No Grade IV toxicities were observed. Grade III transaminitis was seen in one patient. Grade I-II toxicities seen in 11 (73.3%), including arthralgia (26.7%), fatigue (20%), transaminitis (13.3%), rash (20%), hypothyroidism (6.7%), diarrhoea (6.7%) and dyspnoea (6.7%). Conclusions: Despite an elderly & comorbid cohort, immunotherapy resulted in durable responses and excellent safety profile, highlighting the unmet need for immunotherapy funding in New Zealand. More understanding is required around the different responses to anti-PD1 therapies for the same malignancy type. (1) Pondicherry A, et al. The burden of non-melanoma skin cancers in Auckland, New Zealand. Australas J Dermatol. 2018 Aug; 59(3):210-213 (2) Hughes B, et al. Pembrolizumab for locally advanced and recurrent/metastatic cutaneous squamous cell carcinoma (KEYNOTE-629 study): an open-label, nonrandomized, multicentre, phase II trial. Ann Oncol. 2021;32(10):1276-1285.

Individual HLAs affect survival after allogeneic stem cell transplantation in adult T-cell leukaemia/lymphoma.

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for adult T-cell leukaemia/lymphoma (ATL). Specific HLAs are associated with outcomes of immunotherapy and allo-HSCT. We hypothesised that individual HLAs would affect the clinical outcomes of ATL patients after allo-HSCT. Using data from a Japanese registry, we retrospectively analysed 829 patients with ATL who received transplants from HLA-identical sibling donors or HLA-A, -B, -C or -DRB1 allele-matched unrelated donors between 1996 and 2015. We evaluated the overall mortality risk of HLA-A, -B and -DR antigens with frequencies exceeding 3%. Outcomes were compared between transplants with or without specific HLA antigens. Of the 25 HLAs, two candidates were identified but showed no statistically significant differences by multiple comparison. HLA-B62 was associated with a lower risk of mortality (hazard ratio [HR], 0.68; 95% confidence interval [CI]: 0.51-0.90; p = 0.008), whereas HLA-B60 was associated with a higher risk of mortality (HR, 1.64; 95% CI: 1.19-2.27; p = 0.003). In addition, HLA-B62 was associated with a lower risk of transplant-related mortality (TRM) (HR, 0.52; 95% CI: 0.32-0.85, p = 0.009), whereas HLA-B60 was associated with a higher risk of grades III-IV acute graft-versus-host disease (HR, 2.63; 95% CI: 1.62-4.27; p < 0.001). Neither HLA influenced relapse. The higher risk of acute GVHD in HLA-B60-positive patients and the lower risk of TRM in HLA-B62-positive patients were consistent with previously obtained results from patients with other haematological malignancies. Consideration of HLA in ATL patients may help to predict risk and outcomes after allo-HSCT.

Effect of intrinsic STING of CD8+T cells on self-metabolic reprogramming and anti-tumor effects.

e20062 Background: Many preclinical studies have demonstrated that STING agonists have effective anti-tumor effects, but their adverse effects prevent practical use. Previous research by our team has demonstrated that STING has a more significant anti-tumor role in host immune cells than tumor cells, and the level of STING mRNA is associated with the outcome of immunotherapy in non-small cell lung cancer. Although STING is necessary for CD8+T cells to exert immunological activity, its effect on CD8+T cells is debatable. Therefore, we will concentrate on the particular roles of STING in CD8+T cells. Methods: We used in vitro and in vivo models to confirm the influence of STING on CD8+T cell function. We examined the impact of STING on CD8+T cell metabolic function using RNA-seq, Seahorse, flow, electron microscopy, and other techniques. STING knockout mice were used to study the effect of competitive inhibition of glycolytic products during immunotherapy. In addition, we collected peripheral blood immune cells from 30 immunotherapy patients to examine the correlation between immune cell glycolysis levels and immunotherapy efficacy. Results: RNA-seq showed significant changes in signaling pathways such as glycolysis/glycogen synthesis, oxidative phosphorylation, tricarboxylic acid cycle, and one carbon unit in STING-/- CD8+T cells. In vitro experiments revealed that the inactivation of the STING gene reduced the number of mitochondria, altered the choice of metabolic pathways, and impaired the anti-tumor ability. Flow results showed that the mean fluorescence intensity of mitochondria in STING-/- CD8+T decreased. Seahorse experiment showed that STING-/- CD8+T glycolysis was enhanced, and oxidative phosphorylation was decreased. Meanwhile, the content of lactic acid in the culture supernatant of STING-/- CD8+ T increased dramatically, the high level of lactic acid further inhibited the proliferation of CD8+ T and the secretion of IFN-γ. Competitive inhibition of the glycolysis process or lactic acid formation can save the function of STING-/- CD8+ T cells and the secretion of IFN-γ, save the immunotherapy effect of STING-/- mice. This provides a new therapeutic idea for patients with low STING expression and poor immunotherapy response. In the peripheral blood immune cells of immunotherapy patients, we observed a negative correlation between the mRNA levels of glycolysis-associated molecules and STING. Additionally, we found a correlation between the levels of glycolysis-associated molecules in immune cells and immunotherapy efficacy outcomes. Conclusions: Our study is the first to explore the effect of STING on the metabolic process in CD8+ T cells. Intervening in the metabolic process of STING-deficient CD8+ T can save the efficacy of immunotherapy.

Clinical characteristics, prognosis, and immunotherapy outcome in pediatric melanoma: Analysis from a large Chinese cohort.

10050 Background: Malignant melanoma in children and adolescents is rare, with limited data on Chinese populations.To assess the clinical characteristics, survival, prognostic factors, and the efficacy of immunotherapy in a real-world cohort of Chinese pediatric patients with melanoma. Methods: This is a retrospective, cohort study included pediatric melanoma patients between February, 2005 and May, 2021, with a median follow-up time of 76.7 months. Data analyses were conducted in May, 2023. This study enrolled patients from Sun Yat-sen University Cancer Center, the biggest cancer institution in South China for cancer prevention, diagnosis and treatment. Inclusion criteria for this study were as follows: 1) histopathologically confirmed diagnosis of melanoma; 2) Age ≤18 year; 3) with complete clinical data on sex, age, histopathological features, etc. The exclusion criteria was secondary malignant melanoma. Main outcomes and measures were patient’s OS and EFS. Results: 43 patients were enrolled, with median age of 138.9 (range 13.1-215.0) months, including 30 cutaneous melanoma, 7 meningeal melanoma, 5 mucosal melanoma, and 1 uveal melanoma. The frequency of BRAF V600E mutation was 16.7% (4/24). Mismatch repair proteins were normally expressed (7/7), and the positive rate of programmed cell death ligand 1 expression was 55.6% (5/9). The event-free survival and overall survival of cutaneous, mucosal and meningeal melanoma were 46.7±9.1% vs 75.0±21.7% vs 16.7±15.2% ( P = 0.010), 65.5±8.9% vs 75.0±21.7% vs 16.7±15.2% (P&lt; 0.001), respectively. Survival of cutaneous melanoma were associated with pathological type, ulceration, Clark level, disease spread, sentinel lymph node status, tumor stage and Ki-67 expression. 5 of 9 patients who were treated with PD-1 inhibitors (5 with PD-1 inhibitors alone, 3 with PD-1 inhibitors plus angiogenesis inhibitors, 1 with combination of anti-PD1, anti-angiogenic inhibitors plus chemotherapy) were evaluable with the overall response rate of 20%. The most common immune-related adverse event was hypothyroidism. Conclusions: This is the largest real-world study in pediatric melanoma patients in Asia. The prognosis of mucosal melanoma was favorable, followed by cutaneous melanoma, and meningeal melanoma had the worst prognosis. PD-1 antibody combined with angiogenesis inhibitors maybe a promising choice in pediatric melanoma.

Multi-index comprehensive evaluation of the efficacy and response mechanism of immunotherapy in non-small cell lung cancer.

This research conducted multi-index comprehensive evaluations of the immunotherapeutic efficacy and response in non-small cell lung cancer (NSCLC). Forty-five patients with epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) wild-type advanced NSCLC who received immunotherapy were included. Immunohistochemistry was adopted to detect the expression levels of programmed death ligand 1 (PD-L1) with X-ray cross-complementing protein 1 (XRCC1) and excision repair cross-complementing group 1 (ERCC1) proteins in tumor tissues. Flow cytometry was utilized to measure the levels of T-cell subsets in peripheral blood before and after treatment. PCR-RELP method was employed to evaluate XRCC1 and ERCC1 gene polymorphisms in peripheral blood. According to the treatment effect, patients evaluated as complete response (CR), partial response (PR), and stable disease (SD) were categorized into the immune response group, and patients evaluated as progressive disease (PD) were categorized into the immune unresponsive group. The correlation between PD-L1 protein expression, XRCC1 and ERCC1 protein expression, gene polymorphisms, T-cell subpopulation levels, and treatment efficacy was analyzed. The therapeutic efficacy of patients with positive PD-L1 expression was better than that of patients with negative PD-L1 expression (P < 0.05). After treatment, peripheral blood CD3+ and CD4+ cell levels and Thl/Th2 cell levels were higher and CD8+ T cells were lower in the immune response group than in the immune unresponsive group (P < 0.05). Among the patients in the immune response group, peripheral blood CD3+ and CD4+ cell levels were higher and CD8+ T cells were lower in patients with positive PD-L1 expression than in patients with negative PD-L1 expression (P < 0.05). In the XRCC1 gene, the proportion of patients in the immune response group carrying the Arg/Trp + Trp/Trp genotype was higher than that of patients in the immune unresponsive group (P < 0.05). In the ERCC1 gene, the proportion of patients in the immune response group carrying the C/T + T/T genotype was higher than that of patients in the immune unresponsive group (P < 0.05). The positive expression rates of XRCC1 and ERCC1 in patients in the immune unresponsive group were higher than those in the immune response group (P < 0.05). PD-L1 protein expression, XRCC1 and ERCC1 protein expression, and gene polymorphisms are associated with immunotherapy outcome in EGFR/ALK wild-type advanced NSCLC patients, and may be biological indicators for predicting immunotherapy outcome in EGFR/ALK wild-type advanced NSCLC patients.

Effect of probiotics on quality of life for patients with cancer undergoing immunotherapy.

e24148 Background: Probiotics are crucial in oncology for enhancing gut health, boosting immune response, potentially improving immunotherapy efficacy, and reducing side effects of cancer treatments. Research links a healthy gut microbiome with better immunotherapy outcomes, however, more studies in this area are required to validate this hypothesis. Methods: Oncological patients at Hospital Ángeles Puebla's Comprehensive Cancer Center undergoing immunotherapy were invited to participate and provided their consent to receive a daily probiotic and prebiotic mix (including Lactobacillus rhamnosus, Bifidobacterium longum, Pediococcus pentosaceus, and others) for three months. Their health was closely monitored, and quality of life assessed using the EORTC-QLQ-C30 questionnaire at the start, day 45, and day 90. A Kruskal-Wallis H-test was conducted to correlate the EORTC-QLQ-C30 scores with their diagnosis, clinical stage, presence of comorbidities, and use of ancillary treatments, as well as a Spearman's test to associate these scores with their age. Results: 22 patients were included. Average age was 64.5 years, with 77% being male and 23% female. 68.18% were in stage IV, 4.55% in stage III, 18.18% in stage II, and 9.09% in stage I. Comorbidities included: diabetes in 31.82%, hypertension in 40.91%, and other diseases in 22.73%. Treatment regimens involved 81.81% receiving Anti-PD-L1 and 18.18% receiving Anti-PD-1. Additionally, 40.91% were on corticosteroids and another 40.91% on proton pump inhibitors as ancillary treatments. Median follow-up was 3.13 months, during which 23% of the patients experienced adverse events. Of these, 9.09% were grade 4 according to the CTCAE v.5, and 13.63% were grade 1. Significant differences were found between patients with hepatocellular carcinoma versus renal carcinoma in the overall score on day 1 (KW: 4.47, p-value: 0.0344), with no differences in the rest of the scores. Significant differences were also identified between patients with advanced-stage versus early or locally advanced-stage cancer in terms of pain (KWS: 4.091, p-value: 0.043), dyspnea (KWS: 4.355, p-value: 0.037), loss of appetite (KWS: 4.091, p-value: 0.043), constipation (KWS: 3.971, p-value: 0.046), and diarrhea (KWS: 4.355, p-value: 0.037). A negative correlation was found between age and social functioning (Spearman: -0.73, p-value: 0.03), as well as with the presence of pain (Spearman: -0.73, p-value: 0.04). Conclusions: In this study, we observed a decrease in symptoms and an increase in functionality and overall quality of life scores among the patients. This suggests that patients undergoing active immunotherapy treatment may benefit from the use of probiotics and prebiotics as an ancillary treatment. However, further extended studies with larger populations are necessary to corroborate our findings.

Time restricted eating (TRE) and immunotherapy outcomes in head and neck squamous cell carcinoma (HNSCC) via modulation of microbial butyrate and tryptophan metabolic pathways.

e18028 Background: Metastatic HNSCC continues to have very poor prognosis. Only a fraction of patients respond to immune checkpoint blocker therapy (ICB), with no effective treatment options for non-responders. Gut microbial composition and diversity have been associated with response to ICB in many cancers including HNSCC. We have previously demonstrated that TRE significantly improved progression free survival via modulation of gut microbiota. We herein report our mechanistic data demonstrating critical role of microbially mediated butyric and tryptophan metabolic pathways in augmenting antitumor immune response to ICB. Methods: Paired blood and stool samples, at baseline and at first response assessment, from 43 HNSCC patients enrolled in the TRE study (NCT05083416) was collected and analyzed using untargeted and targeted metabolomics, focusing on tryptophan and short chain fatty acid pathway. Further shot gun metagenomic sequencing was conducted on stool samples. Finally, we performed an in vitro luciferase cytotoxicity assay using SCC-4 human cancer cells to demonstrate TRE mediated antitumor immune response. We co-cultured MHC-I and NY-ESO-1, and NY-ESO-1-specific TCR-transduced T cells. tumor cells and the T cells under different conditions of butyrate concentration and T cell-to-tumor cell ratio (1:5, 1:10) and evaluated T cell mediated tumors killing. Results: We noted significantly higher abundance of clostridium butyricum (OR-1004, p-0.0002) with corresponding higher expression of butyrate kinase enzyme in stool of patients who observed TRE (OR-1.9, p-0.0003) vs those who did not, leading to higher concentration of fecal butyric acid and hydroxy indole acetic acid (HIAA) (OR-4.2, p-0.003), both of which were independently associated with longer progression free survival (HR-0.9, p&lt;0.01). Higher abundance of butyric acid in gut is known to enhance the gut barrier function with consequent decrease in plasma butyrate and HIAA, lower systemic levels of which, was found to be associated with longer progression free survival in our cohort (OR-0.9, p-0.05). Both butyrate and 5HIAA are known activators of immunosuppressive aryl hydrocarbon receptor (AhR) expressed on cytotoxic CD8T cells, inhibiting CD8 mediated antitumor response. In line with our hypothesis, we observed that butyrate and 5HIAA impaired CD8 T mediated T cell killing of tumor cells in a dose-dependent manner. Conclusions: These results suggest that TRE favorably modulates ICB response via enrichment of gut microbiota with butyrate producing microbial organism, leading to increased abundance of gut butyrate and microbial tryptophan metabolites and their consequent reduction in systemic circulation, ultimately enhancing antitumor immune response.

Immunotherapy outcomes and profile in lung cancer brain metastases.

8646 Background: Brain metastasis (BM) in NSCLCs have a unique tumor micro-environment (TME) characterized by distinct immune-constituents and the presence of blood-brain barrier, differentiating them from primary NSCLC tumors (PT). Despite the high incidence of BM, earlier trials indicated that less than 15% of BM patients benefit from immune checkpoint inhibitors (ICIs). We characterized the TME of BM to potentially identify a subset of patients who may respond favorably to ICIs. Methods: 36,726 NSCLC samples were analyzed by NGS of DNA (592-gene) and RNA (whole transcriptome) at Caris Life Sciences (Phoenix, AZ). TMB-high was defined as &gt;=10mt/MB, PD-L1 was tested by IHC (22c3), and TME by RNA expression (quanTIseq). Real-world overall survival was obtained from insurance claims data and calculated from treatment start on six common ICIs to last contact (IO-OS), while time-on-treatment (TOT) was from first to last of treatment. Hazard ratios (HRs) were calculated using the Cox proportional hazards model and p values (log-rank test). Fisher’s exact tests and Mann-Whiney U were used and adjusted for multiple comparisons (q&lt;0.05). Results: Samples were comprised of 63.5%, PT 4.9% BM, and 31.6% extracranial metastases. High TMB and loss of heterozygosity (LOH) rates were higher in BM vs. PT (55% vs. 35.7%) and (28.0% vs. 14.3%), q&lt;0.05, respectively, while PD-L1+ rate was similar (53.3% BM vs. 55.6% PT). Significant mutational differences in BM vs. PT included TP53 (77.7% vs 65.1%), KEAP1 (19.4% vs. 12.1%), and STK11 (17.5% vs. 12.0%), q&lt;0.05. Immune deconvolution demonstrated the abundance of neutrophils, Tregs, monocytes, and B cells was higher in PT vs. BM (fold-change: 1.35-1.73, q&lt;0.05), while dendritic cells were higher in BM vs. PT (fold-change: 13, q&lt;0.05). BM had significantly longer IO-OS (24.4 vs. 19.7 mo: HR = 0.83, 95% CI 0.76-0.90, p&lt;0.05) and TOT (7.7 vs. 6.0 mo; HR = 0.83, 95% CI 0.77-0.89, p&lt;0.05) compared to PT. PD-L1+ and TMB High were associated with longer IO-OS in BM vs. PT (HR = 0.71, 95% CI 0.63-0.81, p&lt;0.05) and (HR = 0.83, 95% CI 0.74 – 0.93, p&lt;0.05), respectively. By histology, squamous cell carcinoma (SC) was significantly more prevalent in PT compared to BM (25.9% vs. 8.5%, q&lt;0.05). In adenocarcinoma (AD), BM was associated with longer IO-OS (HR = 0.78, 95% CI 0.70-0.87, p&lt;0.05) compared to PT, while in SC, the survival association was not significant. The longer survival seen in AD was still significant after multivariate analysis with TP53, STK11 and KEAP1 (HR = 0.76, 95% CI 0.68-0.86, q&lt;0.05). In BM, PD-L1+ and TMB High were associated with longer IO-OS in AD and may be considered first line treatment in this population, if asymptomatic. Conclusions: Historically BM have been associated with poor outcomes. We demonstrate that BM has higher TMB, increased infiltration of dendritic cells, and higher LOH than PT. After stratifying patients based on PD-L1 and TMB, patients with BM adenocarcinoma histology had improved post ICI survival.

Seasonal patterns in immunotherapy outcomes.

e14684 Background: Immune checkpoint inhibitors (ICIs) allow the immune system to target cancer cells. The immune system is affected by seasonal factors e.g. viruses, allergens, vaccines and ultraviolet exposure. There is evidence that some immune-related adverse events are more common in winter and that higher vitamin D (VD) levels and VD supplementation are associated with longer overall survival (OS). This study aimed to determine if season of ICI initiation was associated with OS. Methods: We evaluated patients who received ICI treatment at The Christie Hospital, UK, between 2017 and 2022. Season of ICI initiation was categorised as: (i) Nov-Apr vs May-Oct and (ii) Dec-Feb vs Jun-Aug (i.e. winter vs summer). For each category, median OS (mOS) was estimated using the Kaplan-Meier method. Adjusted Cox models were used to estimate hazard ratios (HR) and 95% confidence intervals for associations of season of ICI initiation with OS and to test for interactions with ICI and diagnosis. Where data were available, associations of baseline VD levels and VD supplements with OS were estimated along with the association between season of ICI initiation and OS in patients with normal VD and/or receiving VD supplements. Results: 3010 patients were included and 1804 OS events occurred during 36.4 months [m] median follow-up. ICI indications included pembrolizumab or atezolizumab for advanced non-small cell lung cancer (NSCLC, 1st line n 304, median OS [mOS] 17.0 m; 2nd line n 197, mOS 10.7 m), pembrolizumab plus chemotherapy for advanced NSCLC (n 288, mOS 16.3 m), pembrolizumab or nivolumab for melanoma (advanced n 211, mOS 25.2 m; adjuvant n 226, mOS not reached), and ipilimumab + nivolumab for melanoma (n 203, mOS 45.4 m) or renal cancer (n 129, mOS 38.6 m). Confounders were balanced across seasons of ICI initiation, including sex (48% Nov-Apr vs 52% May-Oct), age (median 66.7 vs 67.2 years), PS 0/1 (83% vs 84%), body mass index (median 26.0 vs 25.7 kg/m2) and setting (adjuvant 13.0% vs advanced 12.4%). Season of ICI initiation was not associated with OS (Nov to Apr vs May to Oct mOS 20.8 vs 20.5 m, HR 1.01, 0.92-1.11; Dec-Feb vs Jun-Aug mOS 20.0 vs 21.3 m, HR 0.97, 0.85-1.10). Interactions with ICI and diagnosis were not significant. 214 patients had baseline VD levels and 96 received VD supplements before ICI initiation. VD deficiency was highest in February (23.6%) and lowest in August (1.1%). Among 209 patients with normal VD levels or receiving VD supplements, season of initiation was not associated with OS (Nov to Apr vs May to Oct mOS 45.4 vs 43.4 m; HR 0.98, 0.63-1.53). However, VD deficiency (n 37) was associated with shorter OS (HR 2.06, 1.21-3.52) and VD supplementation with longer OS (HR 0.69, 0.52-0.92). Conclusions: While VD deficiency and VD supplementation were associated with OS, season of ICI initiation was not. These results provide reassurance the OS benefits of ICIs remain similar irrespective of time of year of initiation despite seasonal factors that may influence the immune system.

Insights into the heterogeneity of the tumor microenvironment in lung adenocarcinoma and squamous carcinoma through single‐cell transcriptomic analysis: Implications for distinct immunotherapy outcomes

AbstractBackgroundImmune checkpoint blockade has emerged as a key strategy to the therapy landscape of non‐small cell lung cancer (NSCLC). However, notable differences in immunotherapeutic outcomes exist between the two primary NSCLC subtypes: lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). This disparity may stem from the tumor immune microenvironment's heterogeneity at the transcriptome level.MethodsBy integrative analysis of transcriptomic characterization of 38 NSCLC patients by single‐cell RNA sequencing, the present study revealed a distinct tumor microenvironment (TME) between LUAD and LUSC, with relevant results further confirmed in bulk transcriptomic and multiplex immunofluorescence (mIF) validation cohort of neoadjuvant immunotherapy patients.ResultsLUAD exhibited a more active immune microenvironment compared to LUSC. This included highly expression of HLA I/II in cancer cells, reinforced antigen presentation potential of dendritic cells and enhanced cytotoxic activity observed in T/NK cells. In LUSC, cancer cells highly expressed genes belonging to the aldo‐keto reductases, glutathione S‐transferases and aldehyde dehydrogenase family, negatively correlating with immunotherapy outcomes in the validation cohort of our center. Further analysis revealed elevated infiltrated cancer‐associated fibroblasts (CAFs) in LUSC, which was corroborated in The Cancer Genome Atlas cohort. Corresponding increased infiltration of ADH1B+ CAFs in major pathologic response (MPR) patients and the higher presence of FAP+ CAFs in non‐MPR patients were demonstrated by multiplex mIF. Moreover, upregulating immunosuppressive extracellular matrix remodeling was identified in LUSC.ConclusionsThese comprehensive analyses advance the understanding of the differences in TME between LUAD and LUSC, offering insights for patient selection and developing subtype‐specific treatment strategies.

Sex influence on cancer immunotherapy efficacy and safety in advanced non-small cell lung cancer (NSCLC): A Canadian institution real-world experience.

e20618 Background: Males and females differ in innate and adaptive immune responses. This difference may also be reflected in their response to cancer immunotherapies. Immune checkpoint inhibitors (ICIs) have revolutionized the treatment for advanced NSCLC, however the impact of sex on treatment outcomes in these patients remains unclear. The aim of this retrospective cohort study was to evaluate sex-related differences in immunotherapy outcome in a real-world population of NSCLC patients treated with ICIs. Methods: Demographics, clinical, pathological and treatment characteristics were assessed. Treatment-related variables were analyzed to understand the differences in efficacy and safety outcomes including response rates, PFS, OS and all-cause treatment discontinuation (TD) in relation to sex. Results: 152 advanced NSCLC patients receiving first-line immunotherapy, either alone or in conjunction with chemotherapy, were included in the study cohort. Females were younger age, were more likely to be non-smokers, have non-squamous tumors and had a higher prevalence of pre-existing autoimmune diseases compared to males. Disease control (CR/PR/SD) was achieved in 65.8% of patients. Median PFS was 12.0 mo in females and 14.1 mo in males. Median OS for all patients was 15.8 mo; 16.1 and 15.7 mo in females and males respectively. No statistical differences based on gender were observed in PFS and OS (P = 0.767 and P = 0.657). In regression analysis older age and presence of liver metastases were independent poor prognostic factors. Gender was not an independent prognostic factor in PFS and OS. Notably, 44 or 28.9% patients developed symptomatic immune-related adverse events (ir-AEs) that led to TD (Table 1). ir-AE-related TD occurred at a significantly higher rate in females compared with males (Table 1; 38.2% vs 19.7%, RR = 1.90; 95% CI: 1.12 to 3.26; p = 0.018). GI toxicity, including hepatitis and colitis was predominantly observed in females, whereas pneumonitis was the most frequent ir-AE leading to TD in males. Conclusions: Despite no significant differences based on gender were observed in PFS and OS, our study showed that female patients with advanced NSCLC receiving ICIs are at a substantially greater risk of severe symptomatic ir-AEs and TD. This finding indicates that broad-based sex differences in this context could potentially exist and emphasizes the need for further investigations into the role played by gender in immunity and cancer immunotherapy treatment.[Table: see text]

Neoadjuvant toripalimab plus chemotherapy for resectable stage II-IIIB non-squamous non-small cell lung cancer with EGFR mutations: A multi-center, multi-cohort, exploratory study.

TPS8120 Background: Neoadjuvant immunotherapy has been widely applied in the treatment of resectable stage II-IIIB NSCLC patients without driver gene mutation. However, as for the EGFR-positive patients, the therapeutic effect of neoadjuvant treatment, either TKI or chemotherapy, is far from satisfied and the outcome of neoadjuvant immunotherapy plus chemotherapy in these patients remains an unanswered but crucial question. Herein, we conducted a phase 2 prospective trial (NCT05962021). Methods: This is a multicenter, multi-cohort prospective phase 2 study in the treatment-naïve patients with resectable stage II-IIIB (N2) (AJCC 8th edition) non-squamous NSCLC harboring EGFR mutations (19DEL or L858R). Enrolled patients will be divided into two cohorts according to EGFR status and receive neoadjuvant toripalimab (240mg, q3w) plus platinum-based doublet chemotherapy (pemetrexed 500mg/m2 plus carboplatin AUC 5, q3w) for 3 cycles. Surgery will be performed after completion of neoadjuvant therapy based on the multidisciplinary discussion, while local radiotherapy will be considered if the patient cannot undergo surgery due to disease progression. Key inclusion criteria: non-squamous NSCLC, resectable stage II-IIIB (N2), EGFR mutations (19DEL or L858R), age≥18 years, ECOG PS 0-1 and adequate cardiopulmonary function. Exclusion criteria: prior systemic anticancer treatment, contraindication to immunotherapy, active autoimmune disease. Adequate pre-treatment tissue samples are required for RT-PCR or next-generation sequencing to determine the EGFR mutation status and PD-L1 expression immunohistochemical detection. The primary study endpoint is complete pathological response (pCR) rate, per blinded independent pathologist review. Simon's optimal two-stage design will be used to test the null hypothesis of pCR rate ≤5% and alternative hypothesis of pCR rate ≥15%, and 5 or more pCRs among 56 patients per arm are needed for the primary endpoint to be met. Secondary endpoints include major pathological response (MPR) rate, pCR/MPR rate in different EGFR mutation subgroups (19DEL or L858R) and different PD-L1 expression subgroups (TPS &lt; 1% and ≥ 1%), event-free survival and safety and tolerability. Peripheral blood, stool and tissue samples will be obtained longitudinally at baseline, during perioperation and at follow-ups for exploratory analysis. Clinical trial information: NCT05962021 .

Outcomes of combined immunotherapy and palliative radiotherapy in patients with recurrent/metastatic head and neck cancers.

e18002 Background: Immunotherapy has revolutionized the treatment for recurrent/metastatic head and neck cancers (R/M HNC). It is uncertain whether the combination of immunotherapy and radiotherapy can provide survival benefits for R/M HNC. Methods: This study included patients with R/M HNC who underwent immunotherapy in our institute from November 2018 to October 2022. All patients received intravenous PD-1 inhibitors every 3 weeks. Palliative radiotherapy was administered to localized lesions for symptomatic treatment purposes in addition to systemic therapies. Tumor response was evaluated using RECIST1.1 criteria. The primary outcome measures were progression-free survival (PFS) and overall survival (OS). Other outcome measures were disease control rate (DCR) and objective response rate (ORR). The Kaplan-Meier method was utilized for survival analysis, and univariate and multivariate Cox regression analysis was conducted to identify prognostic factors associated with PFS and OS. Results: We included 129 R/M HNC patients. The median follow-up time was 14.0 months. The median number of immunotherapy courses received was 4 (range: 1-60). During immunotherapy, 43 patients received palliative radiotherapy, targeting primary tumors, lymph nodes, metastasis in liver, lung, bone, and other sites. Following the treatments, 16 (12.4%) patients achieved complete response (CR), 44 (34.1%) achieved partial response (PR), 35 (27.1%) had stable disease (SD), and 34 (26.4%) had progressive disease (PD). The ORR was 46.5% and the DCR was 73.6%. The group receiving immunotherapy combined with palliative radiotherapy had higher ORR (65.1% vs 37.2%, p = 0.005) and DCR (90.7% vs 65.1%, p = 0.004) than those without palliative radiotherapy. The PFS (15.0 months vs 4.0 months, p = 0.0027) and OS (not reached vs 26.0 months, p = 0.036) were improved in patients receiving palliative radiotherapy compared to those not. Patients who had received prior radiotherapy (n = 81) had a shorter PFS (4.0 months vs 14.0 months, p = 0.014), while there was no difference in OS (p = 0.16). We further showed that patients had better PFS (20.0 months vs 2.0 months; p &lt; 0.0001) and OS (43 months vs 17 months; p = 0.0043) when they received more than 4 cycles of immunotherapy. At the same time, our findings demonstrated that immunotherapy combined with nanoparticle albumin‐bound (nab-) paclitaxel-based regimens may prolong PFS (14.0 months vs 4.0months vs 2.5months, p = 0.0055) than gemcitabine-based regimens and other regimens. Conclusions: In patients with R/M HNC, the combination of immunotherapy and palliative radiotherapy demonstrates a synergistic effect, resulting in survival benefits. Prior radiotherapy might compromise patients’ PFS. Increasing the number of immunotherapy cycles and combining with nab-paclitaxel chemotherapy may improve patient survival.

Molecular residual disease (MRD) interception in locoregionally advanced head and neck squamous cell carcinoma (LA-HNSCC): MERIDIAN study.

TPS6122 Background: The detection of circulating tumor DNA (ctDNA) after definitive treatment or MRD is associated with recurrence across different tumor types. We previously showed that ctDNA detection using a bespoke tumor-informed assay (RaDaR), in LA-HNSCC patients (pts) after surgery, definitive radiation (RT) or chemoRT (CRT), is associated with recurrence within a year (Sanz-Garcia et al, ASCO 2023). To date, the impact of intercepting MRD prior to progression in HNSCC has not been explored. Anti-PD-1 blockade has shown benefit in recurrent/metastatic HNSCC but the efficacy in LA-HNSCC is still uncertain. TIGIT is overexpressed in HNSCC and could be a potential target to improve immunotherapy (IO) outcomes. Rilvegostomig (AZD2936) is a monovalent bispecific TIGIT/PD-1 antibody that has shown acceptable safety in phase I studies, currently in phase III studies. We hypothesize that IO (AZD2936) could induce ctDNA clearance post-definitive treatment and avoid, or delay recurrence. Methods: This study will recruit 200 pts with high-risk LA-HNSCC treated with curative intent: surgery ± adjuvant therapy, definitive RT or CRT; stage III Human Papilloma virus (HPV) positive or III-IVB HPV negative. Archival tissue must be available for whole exome sequencing (WES). Pts will be enrolled in part A (definitive therapy) and part B (follow up – FU - post-definitive therapy). Plasma samples will be collected in part A (pre-treatment and post-surgery prior to adjuvant therapy) and part B (at 4-6 weeks: FU1 and 8-12 weeks: FU2). These FU samples will be analyzed in real time for ctDNA using RaDaR, an assay that targets patient specific somatic variants identified by WES of matched tumor tissue. MRD+ pts (defined as having ctDNA detected at FU2) will be enrolled to part C (interception) and randomized 3:1 to receive AZD2936 750mg IV q3w for 6 cycles or observation. 30% of pts (N=60) will be enrolled in part C. Tumor must be positive for PD-L1 (CPS≥1) and there should not be residual primary tumor or distant metastases at FU2; residual lymph nodes are allowed if neck dissection is performed. Part D will consist of long term FU of MRD+ pts; RaDaR will be performed at week 2 (W2) and week 10 (W10), and radiological assessments will be performed at W2. MRD- pts will be enrolled in part E (long term FU). The primary endpoint of MERIDIAN is ctDNA clearance in MRD+ pts, defined as no detection of ctDNA at Part D W2 and W10. We will have 87% power to identify a significant improvement in ctDNA clearance rate from 10% (observation) to 40% (AZD2936) given a significance level of 0.1. Secondary objectives include survival and safety. Exploratory analyses include: ctDNA detection using other assays (HPV DNA, methylated ctDNA), ctDNA detection in part E and beyond W10 in part D, quality of life assessments (FACT-ICM, EORTC-HN43), health economics and radiomics. As of February 2024, 19 patients are recruited. Clinical trial information: 05414032.

PD-L1 and alternative immune checkpoints (AICs) in non-small cell lung cancer (NSCLC): Insights into the tumor immune microenvironment (TIME) and immunotherapy (IO) outcomes.

8531 Background: PD-L1 and recently identified AICs (B7x, B7-H3, and HHLA2) may function as key immune evasion mechanisms in NSCLC and influence IO efficacy. This study explores the expression patterns of PD-L1 and AICs within the TIME and their impact on IO outcomes in NSCLC, including key molecular subtypes. Methods: NSCLC samples (n=27,629) were analyzed (Caris Life Sciences) with NextGen Sequencing on DNA (592 genes or whole exome)/RNA (whole transcriptome). Tumor cell PD-L1 expression (22c3) was assessed by IHC. Gene expression profiles were analyzed for IFN-γ score and QuantiSEQ was used to assess immune cell infiltration in the TIME. Real-world overall survival (rwOS: from time of biopsy to last contact), time on treatment [TOT: from the first pembrolizumab (pembro) treatment to the last], and OS on pembro (OSpem: from pembro start to last contact) were calculated. Mann-Whitney U, X2/Fisher-Exact, and log-rank tests were applied where appropriate. Results: PD-L1 IHC+ NSCLC and cases with high PD-L1 RNA expression had higher IFN-γ score and immune cell fractions (p&lt;0.0001 for both) vs PD-L1 IHC- and low expression, respectively. Additionally, PD-L1 IHC+ NSCLC was associated with (a/w) higher median transcript levels (TPM) of PD-L1 and B7-H3, while PD-L1 IHC- NSCLC was a/w higher TPM of HHLA2 and B7x (p&lt;0.0001 for all). AICs expression varied by molecular subtype, e.g., higher HHLA2/B7x RNA in EGFR mutant vs wild-type (WT) NSCLC. Moreover, PD-L1 IHC+ NSCLC and cases with high PD-L1 RNA and low B7H3 RNA were a/w longer rwOS, OSpem, and TOT; high HHLA2 RNA was a/w longer rwOS and OSpem with similar TOT; and low B7x RNA expression was a/w longer OSpem and TOT with similar rwOS (Table). Conclusions: Both PD-L1 IHC+ NSCLC and cases with high PD-L1 RNA expression are a/w a more inflammatory TIME, and superior survival and IO outcomes. Moreover, consistent with our prior HHLA2 IHC work (PMIDs: 27553831, 29374053), HHLA2 RNA expression was significantly higher in PD-L1 IHC- and EGFR mutant cases. These findings support the potential utility of transcriptomics along with protein expression for assessing novel predictive biomarkers for IO. Furthermore, the distinct expression profiles of AICs identified in our study may represent key subtypes mediating IO response in WT and EGFR mutant NSCLC. [Table: see text]

A single institution review of immunotherapy use, adverse events, and outcomes in early-onset cancer.

e23320 Background: A significant portion of cancer patients are treated with immune checkpoint inhibitors (ICI) and many experience immune related adverse events (irAE) which impact treatment and outcomes. A paucity of data exists related to use of ICIs in Early Onset Cancers (EOC), their irAE, and its correlation to outcomes. Methods: A single institution database of immunotherapy use from an NCI-designated cancer center (NCI-CC) was reviewed with patients treated from 2010-2019. Two cohorts were examined: EOC (age ≤50 at diagnosis), and age &gt; 50. Clinically significant irAEs were defined as those requiring hospitalization (≥grade 3). Pearson's Chi-squared test and Fisher's exact test were used for analysis. Significance was defined as p &lt; 0.05. Results: A total of 1067 patients were identified, 173 were EOC. Race and ethnicity were similar between groups, the EOC group had significantly higher proportion of females, private insurance, working, single, treated at main campus, and ECOG 0. Main cancer types in EOCs were skin cancers (38.2%), lung (16.2%), and heme malignancies (11.6%); those &gt; 50 were lung (46.6%), skin cancer (21.6%), and GU malignancies (11.2%). Stages of cancer were not statistically different nor was type or doses of ICI. EOCs were more likely to get a greater number of ICIs. IrAE requiring hospitalization were similar between groups; 20 (11.6%) in EOC vs 95 (10.6%) in &gt; 50. There was no difference in the incidence of specific irAEs. Further stratification of EOC cohort by age group 13-30, 31-40, and 41-50 demonstrated no difference in experience of an irAE. Ipilimumab had the highest incidence of irAE in EOC; 12 (75.0%) vs 52 (33.1%), as did receiving 2+ ICIs: 11 (68.8%). The number of doses of a specific ICI was not correlated to irAE in EOC. EOC patients without an irAE were more likely to have a disease response; either stable disease, partial response, or a complete response: 21 (70.0%) vs 1 (12.5%); there was no difference in mortality. Conclusions: In a single NCI-CC review of ICI use, EOC had no difference in ≥grade 3 irAEs or in specific irAEs relative to older adults. Within EOCs, those who experienced a significant irAE were more likely to have received Ipilimumab or 2+ ICIs and were less likely to obtain a response to treatment, although mortality was not different. [Table: see text]

Complex immune microenvironment of chordoma: a road map for future treatment

BackgroundChordoma, a rare bone tumor, presents limited treatment options and patients typically exhibit poor survival outcomes. While immunotherapy has shown promising results in treating various tumors, research on the immune...

Single-cell analysis reveals cellular and molecular factors counteracting HPV-positive oropharyngeal cancer immunotherapy outcomes

BackgroundOropharyngeal squamous cell carcinoma (OPSCC) induced by human papillomavirus (HPV-positive) is associated with better clinical outcomes than HPV-negative OPSCC. However, the clinical benefits of immunotherapy in patients with HPV-positive OPSCC...

Comprehensive Analysis of angiogenesis associated genes and tumor microenvironment infiltration characterization in cervical cancer

BackgroundCervical cancer is among the most prevalent malignancies worldwide. This study explores the relationships between angiogenesis-related genes (ARGs) and immune infiltration, and assesses their implications for the prognosis and treatment of cervical cancer. Additionally, it develops a diagnostic model based on angiogenesis-related differentially expressed genes (ARDEGs). MethodsWe systematically evaluated 15 ARDEGs using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA), and Gene Set Variation Analysis (GSVA). Immune cell infiltration was assessed using a single-sample gene-set enrichment analysis (ssGSEA) algorithm. We then constructed a diagnostic model for ARDEGs using Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis and evaluated the diagnostic value of this model and the hub genes in predicting clinical outcomes and immunotherapy responses in cervical cancer. ResultsA set of ARDEGs was identified from the Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and UCSC Xena database. We performed KEGG, GO, and GSEA analyses on these genes, revealing significant involvement in cell proliferation, differentiation, and apoptosis. The ARDEGs diagnostic model, constructed using LASSO regression analysis, showed high predictive accuracy in cervical cancer patients. We developed a reliable nomogram and decision curve analysis to evaluate the clinical utility of the ARDEG diagnostic model. The 15 ARDEGs in the model were associated with clinicopathological features, prognosis, and immune cell infiltration. Notably, ITGA5 expression and the abundance of immune cell infiltration (specifically mast cell activation) were highly correlated. ConclusionThis study identifies the prognostic characteristics of ARGs in cervical cancer patients, elucidating aspects of the tumor microenvironment. It enhances the predictive accuracy of immunotherapy outcomes and establishes new strategies for immunotherapeutic interventions.