Combination Chemoimmunotherapy Research Articles

XPO1-Mediated mRNA Export of Genome Maintenance Regulators Drives Chemotherapy Resistance in Aggressive Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy and displays vast genetic and transcriptomic heterogeneity. Current treatment guidelines recommend first-line chemoimmunotherapy consisting of an anthracycline backbone, which produces cure rates of approximately 65%. However, the remaining patients will face relapsed or refractory disease, which, even in the era of chimeric antigen receptor T cells, is difficult to treat. In this issue of Cancer Research, Marullo and colleagues investigate the biological underpinnings of the tumor-suppressive activity of the newly approved XPO1 inhibitor selinexor in the treatment of lymphoma. In a translational effort covering genomic and biochemical approaches, combined with in vivo validation experiments and a phase I clinical trial, they demonstrate that upon DNA damage, XPO1 selectively exports transcripts encoding proteins involved in genome maintenance via the RNA-binding proteins THOC4 and eIF4E. Pharmacologic interception of this export process enhances chemosensitivity in various lymphoma models, and combined selinexor plus chemoimmunotherapy displays a favorable toxicity profile and early evidence of efficacy in patients. See related article by Marullo et al., p. 101.

CD24hiCD27+ Bregs within Metastatic Lymph Nodes Promote Multidrug Resistance in Breast Cancer.

Axillary lymph nodes (LN) are the primary and dominant metastatic sites in breast cancer. However, the interaction between tumor cells and immune cells within metastatic LNs (mLN) remains poorly understood. In our study, we explored the effect of CD24hiCD27+ regulatory B cells (Breg) within mLNs on orchestrating drug resistance of breast cancer cells. We collected mLN samples from patients with breast cancer who had received standard neoadjuvant therapy (NAT) and analyzed the spatial features of CD24hiCD27+ Bregs through multicolor immunofluorescence staining. The effect of CD24hiCD27+ Bregs on drug resistance of breast cancer cells was evaluated via in vitro experiments. A mouse model with mLNs was used to evaluate the strategies with blocking the interactions between Bregs and breast cancer for improving tumor regression within mLNs. In patients with breast cancer who had received NAT, there is a close spatial correlation between activated CD24hiCD27+ Bregs and residual tumor cells within mLNs. Mechanistically, CD24hiCD27+ Bregs greatly enhance the acquisition of multidrug resistance and stem-like features of breast cancer cells by secreting IL6 and TNFα. More importantly, breast cancer cells further promote the activation of CD24hiCD27+ Bregs via CD40L-dependent and PD-L1-dependent proximal signals, forming a positive feedback pattern. PD-L1 blockade significantly attenuates the drug resistance of breast cancer cells induced by CD24hiCD27+ Bregs, and addition of anti-PD-L1 antibody to chemotherapy improves tumor cell remission in mLNs. Our study reveals the pivotal role of CD24hiCD27+ Bregs in promoting drug resistance by interacting with breast cancer cells in mLNs, providing novel evidence for an improved strategy of chemoimmunotherapy combination for patients with breast cancer with mLNs.

1428P Clinical benefit of combination chemo-immunotherapy in first-line treatment for patients over the age of 65 or 75 with metastatic NSCLC

1428P Clinical benefit of combination chemo-immunotherapy in first-line treatment for patients over the age of 65 or 75 with metastatic NSCLC

2010P Non-invasive radiomics signature predicts response to combination chemoimmunotherapy in extensive-stage small cell lung cancer (ES SCLC)

2010P Non-invasive radiomics signature predicts response to combination chemoimmunotherapy in extensive-stage small cell lung cancer (ES SCLC)

Evaluation of Real-Life Chemoimmunotherapy Combination in Patients with Metastatic Small Cell Lung Carcinoma (SCLC): A Multicentric Case-Control Study.

The current first-line standard treatment for advanced small cell lung cancer (SCLC) is a combination of chemotherapy and immunotherapy. However, few efficacy data are available in a real-life settings, including frail patients. The aim of this study is to describe the real-life efficacy of chemoimmunotherapy in an unselected SCLC population. We conducted a retrospective multicenter study, which compared two cohorts of patients with treatment-naive metastatic SCLC treated in six academic centers in the Greater Paris area. Cohort 1 included patients treated with chemotherapy between January 2017 and December 2018, and cohort 2 included patients treated with chemoimmunotherapy between January 2019 and December 2020. A total of 153 consecutive patients were included (cohort 1: n = 96; cohort 2: n = 57). Clinical characteristics were similar between the two cohorts. Overall survival (OS) was statistically higher in cohort 2 (median survival 15.47 months) than in cohort 1 (median survival 9.5 months) (p = 0.0001). OS for patients with a performance status ≥2 and for patients ≥70 years old was not statistically different between the two cohorts. Chemoimmunotherapy efficacy was better compared to chemotherapy alone in case of brain or liver metastases. In conclusion, the combination of chemoimmunotherapy in metastatic SCLC appears to provide a real-life OS benefit. Dedicated clinical trials are needed to test this strategy in patients with impaired performance status or advanced age.

Assessing treatment outcomes of chemoimmunotherapy in extensive-stage small cell lung cancer: an integrated clinical and radiomics approach

BackgroundSmall cell lung cancer (SCLC) is a highly malignant cancer characterized by metastasis and an extremely poor prognosis. Although combined chemoimmunotherapy improves the prognosis of extensive-stage (ES)-SCLC, the survival benefits...

Meta-Analysis on the Combination of Chemotherapy With Programmed Death-Ligand 1 and Programmed Cell Death Protein 1 Blockade as First-Line Treatment for Unresectable Pleural Mesothelioma

IntroductionDual immune checkpoint blockers regimen represents a standard first-line therapy in unresectable pleural mesothelioma (PM). Novel combination strategies, including immune checkpoint blockers and antiangiogenic drugs, are currently under investigation in this setting. We aimed to assess the efficacy of the chemoimmunotherapy combination by reference to literature evidence. MethodsA systematic review and meta-analysis of trials with first-line platinum-based chemotherapy associated with programmed death-ligand 1 and programmed cell death protein 1 agent in unresectable PM. We estimated the weighted summary proportion of disease response, along with the landmark probability of survival outcomes. ResultsA total of 349 patients with unresectable PM from four trials (DREAM, PrE0505, JME-001, and IND.227) were included, 79% (n = 274) with epithelioid and 21% (n = 75) with nonepithelioid histologic type. In aggregate, the objective response rate was 59.2% (95% confidence interval [CI]: 50.3%–67.9%) and disease control rate was 92.2% (95% CI: 89.2%–94.8%). Comparing epithelioid versus nonepithelioid tumors, the objective response rate was 64.5% versus 46.4%, (p < 0.001) and the disease control rate was 92.3% versus 80.0%, (p = 0.043), with an OR of 2.56 (95% CI: 1.51–4.32) for disease response and of 3.37 (95% CI: 0.99–11.47) for disease control. The aggregated estimated probability of progression-free survival was 63% (95% CI: 53%–71%) at 6 months and 25% (95% CI: 21%–31%) at 12 months, whereas the 6-, 12- and 24-month overall survival rates were 88% (95% CI: 81%–93%), 71% (95% CI: 61%–79%) and 39% (95% CI: 34%–45%), respectively. ConclusionsAccording to our analysis, first-line chemoimmunotherapy holds promise as a new treatment approach for PM, exhibiting encouraging survival outcomes and an enhanced response rate, including for the epithelioid subtype. Ongoing studies are necessary to establish its precise placement within the treatment algorithm.

Hyaluronic acid-bilirubin nanomedicine-based combination chemoimmunotherapy

Despite significant advances in immune checkpoint blockade (ICB), immunosuppression mediated by tumor-associated myeloid cells (TAMCs) poses a major barrier to cancer immunotherapy. In addition, while immunogenic cell death (ICD) provides a viable approach to inducing anti-tumor immune response, it remains unknown how to effectively trigger ICD while addressing immunosuppressive TAMCs. Here, we show that SC144, a gp130 inhibitor that blocks the IL-6/gp130/STAT3 pathway, induces ICD of tumor cells and polarizes macrophages to M1-phenotype in vitro. However, as SC144 also induces killing of CD8+ T-cells, we sought to deliver SC144 selectively to tumor cells and TAMCs. Toward this goal, we have developed hyaluronic acid-bilirubin nanoparticles (HABN) that accumulate in CD44hi tumor cells and TAMCs. Systemic administration of SC144 loaded in HABN (SC144@HABN) induces apoptosis and ICD of tumor cells, increases the ratio of M1-like to M2-like macrophages, and decreases the frequency of myeloid-derived suppressor cells and CD4+ regulatory T-cells, while promoting anti-tumor CD8+ T-cells. Moreover, SC144@HABN combined with anti-PD-L1 ICB efficiently eliminates MC38 tumors and ICB-resistant 4T1 tumors. Overall, our work demonstrates a therapeutic strategy based on coordinated ICD induction and TAMC modulation and highlights the potential of combination chemoimmunotherapy.

Concurrent chemoradiotherapy versus radiotherapy alone after induction chemoimmunotherapy for stage III NSCLC patients who did not undergo surgery: a single institution retrospective study

BackgroundWith remarkable success and few side effects, induction chemoimmunotherapy has been used to improve the prognosis of patients with resectable or potentially resectable non-small cell lung cancer (NSCLC), even in stage III disease. However, for patients who are medically inoperable, unresectable or refuse surgery after induction chemoimmunotherapy, it is unclear whether patients should be treated with concurrent chemoradiotherapy (cCRT) or radiotherapy (RT) alone considering patient safety and tolerability. This study aimed to determine whether cCRT is safe and superior to RT alone after chemoimmunotherapy for stage III NSCLC.MethodsPatients diagnosed with stage III NSCLC who received chemoimmunotherapy followed by cCRT/RT alone without surgery at Tianjin Cancer Hospital between November 2018 to December 2021 were retrospectively collected. Patients were divided into two groups: induction chemoimmunotherapy followed by cCRT (cCRT cohort) or RT alone (RT alone cohort). Kaplan-Meier method was used to estimate survival. Univariate and multivariate Cox regression models were adopted to estimate risk factors for PFS.ResultsSixty-five patients were included, with 44 (67.7%) received RT alone and 21 (32.3%) received cCRT. Patients in the cCRT group had significantly prolonged PFS (HR = 0.155, p = 0.004), LPFS (HR = 0.225, p = 0.029) and DMFS (HR = 0.028, p = 0.006) than those in the RT alone group. Albeit nonsignificant, a trend toward improved OS (HR = 0.030, p = 0.069) was also observed in the cCRT group. The multivariate analysis further confirmed that cCRT (HR = 0.141, p = 0.008) was the independent factor for promoting a favorable PFS. Treatment-related adverse events were similar between groups (p > 0.05). Patients with consolidation immunotherapy exhibited a trend of improved PFS (HR = 0.398, p = 0.274) and numerically better OS (HR = 0.018, p = 0.209) compared with those without.ConclusionsFor patients with unresectable stage III NSCLC, cCRT following chemoimmunotherapy appears to be safe and may prolong survival compared with radiotherapy alone. Further investigations on the combination of chemoimmunotherapy and CRT are warranted.

Codelivery of afuresertib and celecoxib by IL4RPep-1-targeting nanoparticles for effective treatment against melanoma

Melanoma is one of the most aggressive and deadly forms of skin cancer, and effective treatments need to be developed. The combination of chemoimmunotherapy has emerged as a promising strategy for treating cancer. However, this strategy still has several limitations, including the inability of more than two drugs to reach tumor tissue simultaneously and the risk of serious adverse effects. The use of nanodrug delivery systems is an effective method to successfully combine these therapies, as they reduce side effects and improve bioavailability. In this study, we developed IL4RPep-1-targeting peptide nanoparticles (IPP NPs) for the codelivery of afuresertib and celecoxib for melanoma treatment by taking advantage of the high drug loading capacity and favorable pharmacokinetic profile of the poly(lactide-co-glycolide) nanoparticle platform. IPP NPs efficiently target three different types of melanoma cells in vitro and significantly accumulate at the tumor site in vivo. ​In both ectopic and pulmonary metastatic melanoma models, targeted codelivery of afuresertib and celecoxib not only promotes melanoma cell apoptosis but also reprograms M2-type macrophages into M1-type macrophages, reconstructing the tumor immune microenvironment and activating the immune response against cancer cells. In addition, this highly coordinated precise delivery of the drug to tumor cells significantly reduces adverse reactions associated with the combination of afuresertib and celecoxib. In summary, IPP NPs exhibit an accurate pH response and ideal targeted drug delivery capabilities for combination chemotherapy and immunotherapy, offering therapeutic potential for this combination in melanoma.

Phase 2 randomized trial of neoadjuvant or palliative chemotherapy with or without immunotherapy for peritoneal mesothelioma (Alliance A092001).

TPS8603 Background: Peritoneal mesothelioma is a rare and poorly studied disease with few treatment options. For patients (pts) who are not surgical candidates, treatment recommendations for systemic therapy have been extrapolated from clinical trials for pleural mesothelioma that commonly exclude pts with peritoneal mesothelioma. Recently, the combination of the PD-1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab received FDA-approval for the frontline treatment of non-resectable pleural mesothelioma. Additionally, a prospective, non-randomized phase 2 trial demonstrated activity with combined PD-L1 (atezolizumab) and VEGF (bevacizumab) blockade in peritoneal mesothelioma. In parallel, encouraging activity with combined chemo-immunotherapy has been reported in pleural mesothelioma. Given the benefits observed with immunotherapy, and the potential to improve upon those with chemotherapy and VEGF inhibition, we seek to determine whether the addition of the PD-L1 inhibitor atezolizumab improves outcomes with chemotherapy and bevacizumab in pts with newly diagnosed peritoneal mesothelioma. Methods: Alliance for Clinical Trials in Oncology A092001 is a prospective, randomized phase 2 clinical trial. All pts with newly diagnosed peritoneal mesothelioma will be randomized 1:1 using a dynamic allocation Pocock-Simon procedure to receive carboplatin, pemetrexed and bevacizumab, with or without atezolizumab, every 21 days for four cycles. Patients who are eligible to proceed with surgery after four cycles of therapy will then do so. Pts who are not eligible to proceed with surgery may receive maintenance bevacizumab and atezolizumab, or second-line atezolizumab with bevacizumab until progression of disease or toxicity. The primary objective is to determine if frontline treatment with carboplatin, pemetrexed, bevacizumab and atezolizumab results in a superior best response rate (RR) to carboplatin, pemetrexed and bevacizumab as determined by RECIST. With 31 eligible pts per arm (62 eligible total), this randomized design has 80% power to detect an improvement in the RR from 20% to 45%, with a 1-sided significance level of 0.10 where an interim futility analysis will be conducted after 32 pts are enrolled. Stratification factors include eligibility for cytoreductive surgery at diagnosis and histologic subtype. Secondary endpoints include progression-free survival, overall survival and adverse events. As integrated biomarkers, we will determine if soluble mesothelin-related peptides and megakaryocyte potentiating factor correlate with responses. This trial was recently approved by the National Cancer Institute Central IRB and is activating at sites across the country. Clinical trial information: NCT05001880 .

Chemo-Immunotherapy: A New Trend in Cancer Treatment.

Chemotherapy has been the basis of advanced cancer treatment for decades. This therapy has largely been considered immunosuppressive, yet accumulated preclinical and clinical evidence shows that certain chemotherapeutic drugs, under defined conditions, may stimulate antitumor immunity and potentiate immune checkpoint inhibitor (ICI)-based therapy. Its effectiveness has been highlighted by recent regulatory approvals of various combinations of chemotherapy with ICIs in several tumors, particularly in some difficult-to-treat cancers. This review discusses the immune modulatory properties of chemotherapy and how they may be harnessed to develop novel chemo-immunotherapy combinations. It also highlights the key determinants of the success of chemo-immunotherapy and provides an overview of the combined chemo-immunotherapies that have been clinically approved.

Advances in efficacy prediction and monitoring of neoadjuvant immunotherapy for non-small cell lung cancer.

The use of immune checkpoint inhibitors (ICIs) has become mainstream in the treatment of non-small cell lung cancer (NSCLC). The idea of harnessing the immune system to fight cancer is fast developing. Neoadjuvant treatment in NSCLC is undergoing unprecedented change. Chemo-immunotherapy combinations not only seem to achieve population-wide treating coverage irrespective of PD-L1 expression but also enable achieving a pathological complete response (pCR). Despite these recent advancements in neoadjuvant chemo-immunotherapy, not all patients respond favorably to treatment with ICIs plus chemo and may even suffer from severe immune-related adverse effects (irAEs). Similar to selection for target therapy, identifying patients most likely to benefit from chemo-immunotherapy may be valuable. Recently, several prognostic and predictive factors associated with the efficacy of neoadjuvant immunotherapy in NSCLC, such as tumor-intrinsic biomarkers, tumor microenvironment biomarkers, liquid biopsies, microbiota, metabolic profiles, and clinical characteristics, have been described. However, a specific and sensitive biomarker remains to be identified. Recently, the construction of prediction models for ICI therapy using novel tools, such as multi-omics factors, proteomic tests, host immune classifiers, and machine learning algorithms, has gained attention. In this review, we provide a comprehensive overview of the different positive prognostic and predictive factors in treating preoperative patients with ICIs, highlight the recent advances made in the efficacy prediction of neoadjuvant immunotherapy, and provide an outlook for joint predictors.

Serum immune mediators as novel predictors of response to anti-PD-1/PD-L1 therapy in non-small cell lung cancer patients with high tissue-PD-L1 expression.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related morbidity and mortality worldwide. Immune checkpoint inhibitors (ICIs) including anti-PD-1 and anti-PD-L1 antibodies, have significantly changed the treatment outcomes with better overall survival, but only 15-40% of the patients respond to ICIs therapy. The search for predictive biomarkers of responses is warranted for better clinical outcomes. We aim here to identify pre-treatment soluble immune molecules as surrogate biomarkers for tissue PD-L1 (TPD-L1) status and as predictors of response to anti-PD-1/PD-L1 therapy in NSCLC patients. Sera from 31 metastatic NSCLC patients, eligible for anti-PD-1/PD-L1 or combined chemoimmunotherapy, were collected prior to treatment. Analysis of soluble biomarkers with TPD-L1 status showed significant up/down regulation of the immune inhibitory checkpoint markers (sSiglec7, sSiglec9, sULBP4 and sPD-L2) in patients with higher TPD-L1 (TPD-L1 >50%) expression. Moreover, correlation analysis showed significant positive linear correlation of soluble PD-L1 (sPD-L1) with higher TPD-L1 expression. Interestingly, only responders in the TPD-L1 >50% group showed significant down regulation of the immune inhibitory markers (sPD-L2, sTIMD4, sNectin2 and CEA). When responders vs. non-responders were compared, significant down regulation of other immune inhibitory biomarkers (sCD80, sTIMD4 and CEA) was recorded only in responding patients. In this, the optimal cut-off values of CD80 <91.7 pg/ml and CEA <1614 pg/ml were found to be significantly associated with better progression free survival (PFS). Indeed, multivariate analysis identified the cutoff-value of CEA <1614 pg/ml as an independent predictor of response in our patients. We identified here novel immune inhibitory/stimulatory soluble mediators as potential surrogate/predictive biomarkers for TPD-L1 status, treatment response and PFS in NSCLC patients treated with anti-PD-1/PD-L1 therapy.

SOHO State of the Art Updates and Next Questions | Infections in Chronic Lymphocytic Leukemia Patients: Risks and Management.

Although chronic lymphocytic leukemia (CLL) is a malignancy characterized by accumulation of tumor cells in the blood, bone marrow, lymph nodes and secondary lymphoid tissues, the hallmark of the disease and the major cause of death for patients with CLL is actually immune dysfunction and associated infections. Despite improvement in treatment based on combination chemoimmunotherapy and targeted treatment with BTK and BCL-2 inhibitors leading to longer overall survival for patients with CLL, the mortality due to infections have not improved over the last 4 decades. Thus, infections are now the main cause of death for patients with CLL, posing threats to the patient whether during the premalignant state of monoclonal B lymphocytosis (MBL), during the watch & wait phase for treatment naïve patients, or upon treatment in terms of chemoimmunotherapy or targeted treatment. To test whether the natural history of immune dysfunction and infections in CLL can be changed, we have developed the machine learning based algorithm CLL-TIM.org to identify these patients. The CLL-TIM algorithm is currently being used for selection of patients for the clinical trial PreVent-ACaLL (NCT03868722), testing whether short-term treatment with the BTK inhibitor acalabrutinib and the BCL-2 inhibitor venetoclax can improve immune function and decrease the risk of infections for this high-risk patient population. We here review the background for and management of infectious risks in CLL.

BRCA mutations detected by tumour next-generation sequencing in non-small cell lung cancer: impact on response to therapy and disease course.

Data regarding the prevalence and clinical relevance of BRCA mutations in non-small cell lung cancer (NSCLC) is limited. Our objective was to evaluate the impact of pathogenic BRCA variants detected by tumour next-generation sequencing (NGS) on disease course and response to therapy. We performed a retrospective analysis of all consecutive NSCLC patients with available NGS reports in a single institution between 01/2015 and 08/2020. Pathogenicity of identified mutations was determined according to American College of Medical Genetics (ACMG) guidelines. Log rank and cox regression analyses were used to determine the association between BRCA mutation status, overall survival (OS) and progression-free survival (PFS) under various front-line treatment modalities for advanced disease. Out of 445 patients with NGS data (54% tissue, 46% liquid), 109 (24.5%) patients had a documented BRCA variant; 5.6% (25/445) had a pathogenic/likely pathogenic variant (pBRCA). Forty percent (10/25) of pBRCA patients had no co-occurring NSCLC driver mutations. Patients with pBRCA NSCLC had a less prominent smoking history [mean 42.6 (29.2) vs. 25.7 (24.0) pack years; P=0.024]. Median PFS with first-line chemo-immunotherapy was significantly prolonged for pBRCA patients (n=7) compared with wild-type BRCA (wtBRCA) patients (n=30) (HR =0.279; P=0.021, 95% CI: 0.094-0.825). pBRCA-mutated NSCLC can represent a specific subtype of pulmonary carcinoma. Patients whose tumours harbor pBRCA mutations present with a less prominent smoking history and exhibit prolonged PFS with chemo-immunotherapy combinations compared with wtBRCA controls. In a subset of these patients, pBRCA is the sole identifiable putative driver mutation, hinting at a significant role for BRCA loss in oncogenesis.

Combination chemo-immunotherapy in advanced oesophageal squamous cell carcinoma

Combination chemo-immunotherapy in advanced oesophageal squamous cell carcinoma

Abstract 964: Genomic and clinical predictors of early disease progression and chemoimmunotherapy benefit in advanced NSCLC

Abstract Background: Immune checkpoint inhibitors (ICIs) as monotherapy (ICI-mono) or with chemotherapy (ICI-chemo) are standard first-line treatment in NSCLC patients lacking targetable driver mutations. Biomarkers to identify patients at risk for early progression on ICI-mono or those who would maximally benefit from upfront ICI-chemo have not been defined. Methods: We queried the GEMINI database to identify metastatic NSCLC patients without targetable EGFR/ALK alterations who were treated with ICI-mono or ICI-chemo. Mutational profiling was performed on tissue or blood using targeted NGS. Outcome measures were defined as clinical progression free survival (PFS) or early progressive disease (PD) rate (defined as rate of 3-month progression), and their association with variables was assessed via Cox Proportional Hazards regression (PFS) or logistic regression (early PD). Predictive deep learning models were used to integrate clinicopathological factors and genomic profile. Results: 735 patients were included in this study, 269 treated with ICI-chemo and 466 with ICI-mono; 446 were treated in the first-line setting. TP53 was the most frequently altered gene (60%), followed by KRAS (37%), AR (21%), and STK11 (19%). In ICI-mono patients, alterations in STK11, ERBB2, ARID1A and CDK6 were associated with a higher likelihood of early PD; only STK11 was associated with early PD (29% vs 17%, P = 0.04) on ICI-chemo. In all patients, low PD-L1 expression and high disease burden (stage IVb and liver metastases) associated with early PD, but there were borderline significant treatment effects in favor of ICI-chemo in never smokers and patients with liver metastases and stage IVb. Shorter PFS was observed in the ICI-chemo group who had CDKN2A alterations vs wild type (median PFS: 5.1 vs 9.0 months; HR: 1.72; P = 0.01). A subgroup analysis of patients with CDKN2A alterations demonstrated preferentially worse outcomes in ICI-chemo compared to ICI-mono, with the best PFS achieved in the ICI-mono treated patients with CDKN2A point mutation. Integration of clinicogenomic features into a multivariate model with feature selection to predict early PD demonstrated a predictive performance of AUC 0.73 (vs PD-L1 alone, AUC 0.60) in the ICI-mono group, driven by liver metastases, stage IVb disease, PD-L1 expression, and STK11 alterations. These features were less predictive in ICI-chemo-treated patients, indicating a protective effect against early PD in these patients from combination chemoimmunotherapy. Conclusions: Low PD-L1, high disease burden, and STK11 alterations are markers of early PD on ICI-mono, and patients with these features may particularly benefit from upfront combination treatment with ICI-chemo to protect against early progression. Citation Format: Lingzhi Hong, Muhammad Aminu, Xuetao Lu, Maliazurina B. Saad, Pingjun Chen, Waree Rinsurongkawong, Amy Spelman, Yasir Y. Elamin, Marcelo V. Negrao, Ferdinandos Skoulidis, Carl M. Gay, Tina Cascone, Mara B. Antonoff, Boris Sepesi, Jeff Lewis, Don L. Gibbons, Ara A. Vaporciyan, Xiuning Le, J.Jack Lee, Sinchita Roy-Chowdhuri, Mark J. Routbort, John V. Heymach, Jia Wu, Jianjun Zhang, Natalie I. Vokes. Genomic and clinical predictors of early disease progression and chemoimmunotherapy benefit in advanced NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 964.

Abstract 5300: Mass spectrometry-based protein biomarker analysis in chemoimmunotherapy combinations identifies unique immune signatures in pancreatic cancer

Abstract Although the combination of chemotherapy with immunotherapy has led to significant improvements in the treatment of some solid tumors, metastatic pancreatic ductal adenocarcinoma (mPDAC) prognosis has remained largely unaffected by such approaches. Recently, PRINCE, a randomized phase 2 clinical study, reported significantly improved 1-year overall survival (OS) for mPDAC patients treated with nivolumab and chemotherapy (nivo/chemo) compared to historical control but not for sotigalimab and chemotherapy (sotiga/chemo) or a combination of the three. Interestingly, the study identified potential improvement to treatment outcome with patient stratification. Here, we report an unbiased mass spectrometry (MS)-based proteomics profiling of a subset of plasma samples from the PRINCE trial (n = 211, 62 individuals from nivo/chemo and sotiga/chemo longitudinal samples). Briefly, plasma samples were depleted, digested to tryptic peptides, measured by MS/MS and quantified using Spectronaut (Biognosys). Data was investigated for both protein and peptide biomarker with an emphasis on baseline biomarkers associated with clinical outcomes. Plasma profiling identified 1,662 proteins and 17,451 modified peptides across the cohorts. First, we developed a model that identified the pharmacodynamic effects of treatment in individual patients. In accordance with the PRINCE study and among the major model contributors, sotiga/chemo increased proteins associated with innate immunity and chemokines (including CCL15) while proteins aiding in T cell activation and immune cell migration increased with nivo/chemo (including CXCL7 and CD115). Second, we looked for markers in the pretreatment plasma samples that could predict OS. Overall, we found 25 predictive markers (p &amp;lt; 0.05), with only six shared among the two arms, including attractin and CD58. Among the seven predictive biomarkers specific to nivo/chemo, we found MEGF10 and GALNT1, which are suggested to play a role in neoantigen generation. For sotiga/chemo, we found 12 predictive biomarkers including IGF2, CD304, and periostin (known to support immune responses). Third, we expanded our predictive biomarker search to the identified peptides, an analysis that is currently only possible using an unbiased mass spectrometry-based approach. Using such an approach we identified predictive peptides, likely cleavage products, as well as predictive post-translational modifications. Herein we demonstrate the value of both an unbiased approach, as well as the use of peptide level data for novel biomarker identification. We identify numerous proteins and peptides that have the potential to be used for better patient treatment stratification in the case of mPDAC and immunotherapy. Citation Format: Nigel Beaton, Marco Tognetti, Kamil Sklodowski, Roland Bruderer, Lukas Reiter. Mass spectrometry-based protein biomarker analysis in chemoimmunotherapy combinations identifies unique immune signatures in pancreatic cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5300.

Treatment with decitabine induces the expression of stemness markers, PD-L1 and NY-ESO-1 in colorectal cancer: potential for combined chemoimmunotherapy

BackgroundThe mechanism of tumor immune escape and progression in colorectal cancer (CRC) is widely investigated in-vitro to help understand and identify agents that might play a crucial role in response to treatment and improve the overall survival of CRC patients. Several mechanisms of immune escape and tumor progression, including expression of stemness markers, inactivation of immunoregulatory genes by methylation, and epigenetic silencing, have been reported in CRC, indicating the potential of demethylating agents as anti-cancer drugs. Of these, a chemotherapeutic demethylating agent, Decitabine (DAC), has been reported to induce a dual effect on both DNA demethylation and histone changes leading to an increased expression of target biomarkers, thus making it an attractive anti-tumorigenic drug.MethodsWe compared the effect of DAC in primary 1076 Col and metastatic 1872 Col cell lines isolated and generated from patients’ tumor tissues. Both cell lines were treated with DAC, and the expression of the NY-ESO-1 cancer-testis antigen, the PD-L1 immunoinhibitory marker, and the CD44, Nanog, KLF-4, CD133, MSI-1 stemness markers were analyzed using different molecular and immunological assays.ResultsDAC treatment significantly upregulated stemness markers in both primary 1076 Col and meta-static 1872 Col cell lines, although a lower effect occurred on the latter: CD44 (7.85 fold; ***p = 0.0001 vs. (4.19 fold; *p = 0.0120), Nanog (4.1 fold; ***p < 0.0001 vs.1.69 fold; ***p = 0.0008), KLF-4 (4.33 fold; ***p < 0.0001 vs.2.48 fold; ***p = 0.0005), CD133 (16.77 fold; ***p = 0.0003 vs.6.36 fold; *p = 0.0166), and MSI-1 (2.33 fold; ***p = 0.0003 vs.2.3 fold; ***p = 0.0004), respectively. Interestingly, in the metastatic 1872 Col cells treated with DAC, the expression of both PD-L1 and NY-ESO-1 was increased tenfold (*p = 0.0128) and fivefold (***p < 0.0001), respectively.ConclusionsWe conclude that the upregulation of both stemness and immune checkpoint markers by DAC treatment on CRC cells might represent a mechanism of immune evasion. In addition, induction of NY-ESO-1 may represent an immuno-therapeutic option in metastatic CRC patients. Finally, the combination of DAC and anti-PD-1/anti-PD-L1 antibodies treatment should represent a potential therapeutic intervention for this group of patients.