Development Of Immune Checkpoint Inhibitors Research Articles

Clinical applications and perspectives of immune checkpoint inhibitors in oral squamous cell carcinoma

Abstract Immune checkpoint inhibitors (ICIs) promote antitumour immune responses by blocking inhibitory signals expressed by T cells and have significant clinical benefits in the treatment of oral squamous cell carcinoma (OSCC). With the advancement of immunotherapy, an increasing number of ICIs have been developed or are in clinical trial stages. However, drug resistance and immune-related adverse events (irAEs) associated with ICIs have limited the clinical application of immunotherapy in OSCC, and the optimal drug regimen for ICIs and the optimal duration of ICIs administration also deserves to be further discussed. New therapeutic regimens and drug delivery technologies are key to promoting the further development of ICIs. This article elucidates the mechanism of ICIs’ action and presents a review of their clinical applications and current development status in OSCC. Additionally, it summarizes the current challenges and outlines future research directions for ICIs therapy, with the aim of offering fresh insights to researchers.

Effectiveness and safety of first-line serplulimab in patients with metastatic/locally advanced esophageal carcinoma (EC): A real-world study.

e16044 Background: The prognosis of metastatic/locally advanced EC has significantly improved with the development of immune checkpoint inhibitors. Serplulimab has been approved in the treatment of various solid tumors (e.g. esophageal squamous cell carcinoma [ESCC], small cell lung cancer). Considering the lack of real-world evidence, this study aimed to explore the real-world effectiveness and safety of serplulimab as first-line therapy in patients with metastatic/locally advanced EC. Methods: Thismulticenterretrospective study included patients with metastatic/locally advanced EC who received first-line serplulimab-containing therapy from March 2022 to December 2023. The demographic and disease characteristics, chemotherapy regimens selected by physicians, treatment response and adverse events were collected from medical record. The outcomes included progression free survival (PFS), objective response rate (ORR), overall survival (OS), duration of response (DoR), time to treatment discontinuation (TTD) and safety. Results: A total of 57 patients were included, 45 (78.9%) were male with a mean age of 68 years. A majority of patients had ESCC (n=40, 70.2%) and metastatic disease (n=35, 61.4%). The most common chemotherapy regimens combined with serplulimab were paclitaxel plus cisplatin (n=27, 39.1%) and etoposide and platinum (n=13, 23.6%). With a median follow-up of 4.8 month (range: 0.7-19.7), the median PFS was 7.4 months (95% confidence interval [CI]: 3.7-11.1). The ORR and DCR were 22.8% and 96.5% in all patients, respectively. The median DoR and TTD were 4.7 months (95% CI: 4.3-not estimated [NE]) and 13.9 months (95% CI: 3.6-24.1), respectively, while the median OS was not reached (NR). The mPFS was 11.1 months (95% CI: 7.0-NE) in patients with ESCC, which was numerically longer than those with neuroendocrine carcinoma (6.5 months, 95% CI: 5.8-7.3, P=0.052). Other effectiveness outcomes in ESCC are presented in Table. Patients > 65 years had a significant improved mPFS compare to those ≤ 65 years (5.9 vs. 11.1 months, P=0.001). The rate of any grade adverse events (AEs) was 26.3% (n=15), while grade 3 or higher AEs was 10.5% (n=6), thrombocytopenia (7.0%, n=4), myelosuppression and pulmonary infection (both 5.3%, n=3) being the most common. Conclusions: First-line serplulimab combined with chemotherapy demonstrated promising effectiveness and favorable safety profile in patients with metastatic/locally advanced EC, especially in ESCC. The current real-world evidence indicates that serplulimab combined with chemotherapy could provide survival benefit for patients with advanced first-line EC. [Table: see text]

Impact of the tumor proportion score (TPS) and the combined positive score (CPS) on the use of immunotherapy in patients with metastatic non-small cell lung cancer.

e14611 Background: Expression of programmed cell death ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC) has often been measured by the Tumor Proportion Score (TPS) (1). Recently, the Combined Positive Score (CPS), which evaluates PD-L1 expression in tumor and inflammatory cells and applies to other types of cancer including gastric and head and neck cancers, was found to be equally predictive of the response to immunotherapy in NSCLC (1). In this study, we aimed to conduct a single center retrospective analysis to evaluate the clinical use and impact of using TPS and CPS data in patients with metastatic NSCLC. Methods: Patients with NSCLC who had TPS and CPS scores and received PD-1/PD-L1 inhibitors between 2021-2022 as a monotherapy or in combination with chemotherapy were included. Patients’ data was retrieved from the electronic medical record data and analysis included histopathological data, lung cancer surgical history, presence of EGFR mutation, ALK mutation, Ki67, use of adjuvant chemotherapy, type of immunotherapy used, and development of immune checkpoint inhibitor- related toxicity and treatment as applicable. TPS and CPS positivity was defined as >1 % and >1 respectively. Statistical methods employed included descriptive approaches such as calculated means as well as the Kaplan-Meier estimate. Results: 40 patients with NSCLC were included. Patients’ age ranged from 19 to 82 years old with an average age of 64.3 years old. Most patients had adenocarcinoma (65 %) and were at stage IV (72.5 %). TPS positivity was identified in 29 patients (72.5 %) and CPS positivity was identified in 35 patients (87.5 %). Patients received immunotherapy mostly as first or second line of treatment (90 %). Immune checkpoint inhibitors received by patients were pembrolizumab (50 %), nivolumab (35 %), atezolizumab (12.5 %), and durvalumab (2.5 %). The median overall survival was 16, 12, and 17 months in the <1 %, 1-49 % and > 49 % TPS groups respectively (p= 0.354); while the median overall survival was 11, 16 and 17 months in the <1, 1-49, and > 49 CPS groups respectively (p= 0.417). It is critical to highlight that there were 7 patients (17.5 %) with TPS of zero who had CPS positivity (score range: 1-10). Most of these patients had adenocarcinoma (71.4 %), received pembrolizumab or atezolizumab (85.7 %) and had a median survival of 16 months. Conclusions: The Combined Positive Score (CPS) has proven to be an effective method in evaluating the level of expression of PD-L1 in NSCLC (1,2). Similar to TPS, CPS provides critical information that can be applied to guide the use of immunotherapy, and which can greatly impact patients with NSCLC. 1. De Marchi et al., 2021. 2. Ulas et al., 2023.

The role of immunotherapy in urological cancers.

Immunotherapy is defined as a therapeutic approach that targets or manipulates the immune system. A deeper understanding of the cellular and molecular composition of the tumour environment, as well as the mechanisms controlling the immune system, has made possible the development and clinical investigation of many innovative cancer therapies. Historically, immunotherapy has played an essential role in treating urologic malignancies, while in the modern era, the development of immune checkpoint inhibitors (ICIs) has been critical to urology. Urothelial carcinoma is a common type of cancer in the genitourinary system, and treatment strategies in this area are constantly evolving. Intravesical and systemic immunotherapeutic agents have begun to be used increasingly frequently in treating urothelial carcinoma. These agents increase the anti-tumour response by affecting the body's defence mechanisms. Immunotherapeutic agents used in urothelial carcinoma include various options such as BCG, interferon, anti-PD-1 (pembrolizumab, nivolumab) and anti-PD-L1 (atezolizumab, avelumab, durvalumab). Renal cell carcinoma (RCC) has been known for many years as a tumour with unique sensitivity to immunotherapies. The recent emergence of ICIs that block PD-1/PD-L1 (pembrolizumab, nivolumab, atezolizumab) or CTLA4 (ipilimumab) signalling pathways has reestablished systemic immunotherapy as central to the treatment of advanced RCC. In light of randomized clinical trials conducted with increasing interest in the application of immunotherapies in the adjuvant setting, combination therapies (nivolumab/ipilimumab, nivolumab/cabozantinib, pembrolizumab/ axitinib, pembrolizumab/lenvantinib) have become the standard first-line treatment of metastatic RCC. Prostate cancer is in the immunologically "cold" tumour category; on the contrary, in recent years, immunotherapeutic agents have come to the fore as an essential area in the treatment of this disease. Especially in the treatment of castration-resistant prostate cancer, immunotherapeutic agents constitute an alternative treatment method besides androgen deprivation therapy and chemotherapy. Ipilimumab, nivolumab, pembrolizumab, atezolizumab, and Sipuleucel T (Vaccine-based) are promising alternative treatment options. Considering ongoing randomized clinical trials, immunotherapeutic agents promise to transform the uro-oncology field significantly. In this review, we aimed to summarize the role of immunotherapy in urothelial, renal and prostate cancer in the light of randomized clinical trials.

How Immunotherapy Has Redefined the Treatment Paradigm of Metastatic or Locally Advanced Muscle-Invasive Urothelial Bladder Carcinoma.

In the past decade, the therapeutic arsenal for metastatic bladder cancer has expanded considerably, with the development of immune checkpoint inhibitors (ICIs), antibody-drug conjugates such as enfortumab vedotin, and anti-fibroblast growth factor receptor agents. Clinical trials evaluating ICIs as neoadjuvants, adjuvants, or first- or second-line treatments have produced conflicting results. However, first-line therapeutic strategies have been redefined by the recent publication of results from two clinical trials: CheckMate-901, which demonstrated the superiority of combined treatment with nivolumab and chemotherapy in extending overall survival, and EV-302, which demonstrated that combined treatment with pembrolizumab and enfortumab vedotin reduced the risk of death by 53%. In this review, we discuss the role of ICIs, alone or in combination, in bladder cancer management in the metastatic and adjuvant settings in 2024, considering the latest published trials. The potential role of ICIs as neoadjuvants is also discussed.

Recent Advances in Cancer Immunotherapy: Clinical Implications and Future Directions

Cancer immunotherapy has transformed cancer treatment by harnessing the immune system to recognize and eliminate cancer cells. Recent years have witnessed significant advancements in this field, including the development of immune checkpoint inhibitors, chimeric antigen receptor (CAR) T-cell therapy, cancer vaccines, and adoptive cell therapy. These approaches have shown promising results in clinical trials, leading to improved outcomes for cancer patients. This paper provides an in-depth overview of recent advances in cancer immunotherapy, their clinical implications, challenges, and future directions.

Side Effects and Research Progress of Immune Checkpoint Inhibitors

Immune checkpoint inhibitor (ICI) is a new type of tumor treatment drug, also known as immunotherapy drug. They target "checkpoint" molecules in the body's immune system that prevent immune cells from attacking cancer cells. They target "checkpoint" molecules in the body's immune system that prevent immune cells from attacking cancer cells. The use of immune checkpoint inhibitors can help control or treat certain types of cancer by promoting the restoration of inactivated immune cells and enhancing the immune system's ability to attack. -This article focuses on skin reactions, immune pneumonitis, and adverse reactions in the thyroid and digestive tract. Through the analysis of recent relevant research, this question summarizes several different side effects, their causes and treatments. Although there are many treatments to deal with the side effects of this drug, it is important to note that the side effects of this drug are not always well understood. There are many treatments to deal with the related side effects, these side effects are still a barrier to the current use of ICIs. Future development directions should focus more on the development of ICIs. directions should focus more on the development of new targets, optimization of drug pharmacokinetics, and alleviation of side effects caused by ICIs.

Abstract 5079: Comparative studies of chemotherapy and immuno-oncology combinations in multiple mouse syngeneic tumor models

Abstract The development of immune checkpoint inhibitors (ICIs) and combinations of immuno-oncology therapies with standard-of-care (SoC) chemotherapeutic agents has shifted therapeutic paradigms for patients with multiple cancer indications. For many patients, these combinations have shown a beneficial effect on clinical outcomes and disease management. However, additional combination therapies are still needed. Preclinically, a comparison of responses from SoC chemotherapies and ICI combinations in multiple disease models may be helpful in identifying optimal treatment combinations in the clinic. Here we report the results of multiple SoC/ICI in vivo combination efficacy studies in a large panel of mouse syngeneic models spanning seven tissue origins: 1) Colon: CT26, MC38; 2) Breast: EMT6, 4T1; 3) Kidney: Renca; 4) Bladder: MB49, MBT2; 5) Skin: B16F10, CM3; 6) Lung: TC1, LL/2, M109; 7) Brain: GL261. The advantage of using syngeneic models is not limited to the rapid and reproducible tumor growth, but importantly that the animals also have an intact immune system and clinically relevant tumor microenvironment, which are required for ICI combination studies. We tested > 10 chemo SoC combinations with a murinized anti-PD-1 antibody (DX400) in 14 syngeneic mouse models. We found that multiple SoC regimens combined well with DX400 treatment, including FOLFIRI, FOLFOX (colon), Carboplatin/Paclitaxel, Carboplatin/Pemetrexed (lung), Capecitabine/Docetaxel, Cisplatin/Gemcitabine (bladder), Cisplatin/5-FU/or capecitabine, and Oxaliplatin/5-FU/or capecitabine (gastric). Specifically, we observed that the SOC/ICI combinations resulted in enhanced antitumor activities compared to single-agent treatments in many of the models. These data, particularly specific SoC combination regimens that combine well with ICIs in each disease, are useful for optimizing promising combination approaches for clinical development and will be presented here. Citation Format: Eunsil Park, Marlene Hinton, Mingmei Cai, Malgorzata A. Gil, Gustave Hebert, Long Cui, Doug Linn, Brian J. Long, Evan R. Barry. Comparative studies of chemotherapy and immuno-oncology combinations in multiple mouse syngeneic tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5079.

Abstract 4066: Generation of tumor targeted self-assembling split IL-12 subunits for the treatment of cancer

Abstract A major milestone in immuno-oncology was the development of immune checkpoint inhibitors, resulting in significant benefits for numerous patients. However, many patients are not responsive, become refractory, or cannot tolerate the treatment due to toxicity or side effects, demonstrating the need for additional immunotherapies. Cytokines are a class of promising immunomodulatory proteins being explored as therapeutics, but their success has been limited due to their rapid clearance or pleiotropic properties. Classically known as ‘signal 3’ of an endogenous immune response, IL-12p70 is a heterodimeric cytokine comprising p35 and p40 subunits. When administered exogenously, IL-12 is a potent stimulator of the immune system and can have profound anti-tumor activity; however, the clinical use of IL-12 has been limited due to poor systemic tolerability. Therefore, developing an immunotherapy that can be systemically administered and improve the therapeutic index could capitalize on the potential clinical benefit of IL-12. Mural Oncology has developed an innovative approach to mitigate the toxicity of IL-12 by splitting the heterodimer into inactive p35 and p40 monomers. The individual subunits are separately fused to two non-competitive antibody fragments targeting a highly expressed tumor-associated antigen. The goal of this approach is to conditionally activate IL-12 preferentially in the tumor microenvironment (TME). This is achieved by sequential administration of the targeted subunits, which will drive assembly and activity of the IL-12 heterodimer primarily at the tumor site, reducing systemic exposure and thereby potentially reducing associated toxicities. To engineer the split IL-12 subunits, a structure-based rational design approach was used to remove the natural intra-molecular disulfide bond and generate variants that maintained affinity between the p35 and p40 monomers. The engineered subunits were characterized using analytical methods and screened for the pair with the strongest affinity. Additionally, the candidate pair was assessed for receptor binding and functional activity on human T cells through phosphorylation of STAT4 and secretion of IFN-γ. Pharmacokinetics and pharmacodynamics were evaluated in mouse models with and without tumors demonstrating that dual targeting led to an increase in tumor retention, rapid clearance from circulation, and dose dependent release of IFN-γ. The results thus far demonstrate that the innovative approach of tumor targeted self-assembling split IL-12 has the potential to enhance the overall therapeutic potential of this cytokine. A development candidate will be identified and moved into clinical testing in cancer patients to enable us to fully understand if this design approach holds true in the clinical setting. Citation Format: Joshua Heiber, Pinar Gurel, Robert G. Newman, Kristiana Dreaden, Yanchun Zhao, Chunhua Wang, Su-Ping Pearson, Jean Chamoun. Generation of tumor targeted self-assembling split IL-12 subunits for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4066.

Abstract 4107: Evaluating the efficacy of personalized neoantigen cancer vaccine in preclinical model: A promising step towards precision immunotherapy

Abstract Background: In the past decade, immunotherapy has transformed cancer treatment, with the development of immune-checkpoint inhibitors and adoptive cell therapies. A novel frontier is personalized vaccines targeting neoantigens unique to tumor cells. Vaccines based on neoantigens have several advantages. First, neoantigens are exclusively expressed by tumor cells and can, therefore, elicit truly tumor-specific T cell responses, thereby preventing ‘off-target’ damage to nonmalignant tissues. Second, neoantigens are de novo epitopes derived from somatic mutations, which presents the possibility to circumvent T cell central tolerance of self-epitopes and thus induce immune responses to tumors. One of the major challenges is the optimal neoantigen discovery/selection. Our study combines in silico HLA binding models with the 'MHC-PepSeq' platform to enhance neoantigen prediction, creating a personalized neoantigen peptide vaccine. We aim to demonstrate its efficacy in a mouse CT26 colon cancer model. Methods: Our method involved whole exome sequencing of tumor and normal DNA to identify neoantigens expressed in CT26 tumors, generating a peptide library. The peptides were further filtered using an in-silico prediction algorithm and our proprietary peptide-MHC binding assay (PepSeq assay), to determine those exhibiting the highest binding affinity with mice HLAs. Vaccines were prepared by dissolving these peptides in sterile PBS. Mice (BALB/C) were subcutaneously implanted with CT26 tumors, then immunized with the vaccine via IV injection in combination with a TLR7/8 agonist. Mice received a second vaccine dose on Day 14, and some groups were treated with an anti-PD-1 agent. Tumors and spleens from the mice were collected, processed into single-cell suspensions, and analyzed by single-cell sequencing, TCR analysis, IHC, and flow cytometry assays. Peripheral blood mononuclear cells (PBMCs) were collected and utilized in MHC tetramer assays. Results: Preliminary in vivo studies demonstrated significant tumor growth restrictions (TGI around 70%) and prolonged tumor-free survival in some mice. Our data showed the generation of neoantigen-specific T cells in vaccinated mice. Remarkably, vaccinated, tumor-free mice, when re-challenged with the same tumor cells, maintained their tumor-free status, suggesting the vaccine induced post-treatment immunological memory. Combining the vaccine with checkpoint inhibition resulted in better tumor growth restriction in mice (TGI around 93%). Conclusion: Overall, our data suggests that our personalized neoantigen vaccine platform has the potential to evoke robust and durable immune responses and, when paired with suitable complementary therapies and immune adjuvants, may serve as an effective cancer treatment. Citation Format: Tithi Ghosh Halder, Kate Gutowsky, Serina Ng, Trason Thode, Alexis Weston, Erin Kelley, Jorge Soria-Bustos, Jorge A. Giron, Taylor Bargenquast, Mohan Kaadige, Sanjana Tripuraneni, Brian Durbin, Shelby Rheinschmidt, Sydney Adamson, Michael Gordon, Justin Moser, John Altin, Raffaella Soldi, Sunil Sharma. Evaluating the efficacy of personalized neoantigen cancer vaccine in preclinical model: A promising step towards precision immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4107.

What Is the Timing and Role of Targeted Therapy in Metastatic Melanoma?

Melanoma is the most lethal cutaneous malignancy worldwide. The last 15 years have ushered in several regulatory approvals that have dramatically altered the landscape of treatment options for patients with melanoma. Many patients with melanoma harbor activating mutations in the BRAF proto-oncogene, a key component of the mitogen-activated protein kinase (MAPK) intracellular signaling pathway. Therapies targeting BRAF have led to remarkable improvements in both response rates and survival in patients with metastatic disease. In parallel with these developments in MAPK-targeted therapy has been the clinical development of immune checkpoint inhibitors, which also have improved response rates and survival in patients with metastatic disease including randomized trials compared with MAPK-targeted therapy in patients with advanced, BRAF-mutant melanoma. Immune checkpoint inhibitors have become the preferred first-line standard-of-care treatment for patients with newly diagnosed metastatic disease in patients irrespective of BRAF mutational status. Given these developments, it is now less clear how to optimize the use of MAPK-targeted therapy regarding treatment setting and in sequence with immune checkpoint inhibitor.

Synergistic role of activated CD4+ memory T cells and CXCL13 in augmenting cancer immunotherapy efficacy

The development of immune checkpoint inhibitors (ICIs) has significantly advanced cancer treatment. However, their efficacy is not consistent across all patients, underscoring the need for personalized approaches. In this study, we examined the relationship between activated CD4+ memory T cell expression and ICI responsiveness. A notable correlation was observed between increased activated CD4+ memory T cell expression and better patient survival in various cohorts. Additionally, the chemokine CXCL13 was identified as a potential prognostic biomarker, with higher expression levels associated with improved outcomes. Further analysis highlighted CXCL13's role in influencing the Tumor Microenvironment, emphasizing its relevance in tumor immunity. Using these findings, we developed a deep learning model by the Multi-Layer Aggregation Graph Neural Network method. This model exhibited promise in predicting ICI treatment efficacy, suggesting its potential application in clinical practice.

Exploring histological predictive biomarkers for immune checkpoint inhibitor therapy response in non-small cell lung cancer.

Treatment challenges persist in advanced lung cancer despite the development of therapies beyond the traditional platinum-based chemotherapy. The early 2000s marked a shift to tyrosine kinase inhibitors targeting epidermal growth factor receptor, ushering in personalized genetic-based treatment. A further significant advance was the development of immune checkpoint inhibitors (ICIs), especially for non-small cell lung cancer. These target programmed death-ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4, which enhanced the immune response against tumor cells. However, not all patients respond, and immune-related toxicities arise. This review emphasizes identifying biomarkers for ICI response prediction. While PD-L1 is a widely used, validated biomarker, its predictive accuracy is imperfect. Investigating tumor-infiltrating lymphocytes, tertiary lymphoid structure, and emerging biomarkers such as high endothelial venule, Human leukocyte antigen class I, T-cell immunoreceptors with Ig and ITIM domains, and lymphocyte activation gene-3 counts is promising. Understanding and exploring additional predictive biomarkers for ICI response are crucial for enhancing patient stratification and overall care in lung cancer treatment.

Real world prevalence of biomarkers for treatment of advanced gastric cancer or gastroesophageal junction cancer in a cohort of Colombian patients.

402 Background: Gastric cancer (GC) is the leading cause of cancer-related deaths in Colombia, GLOBOCAN estimated 6.451 deaths in 2022. Development of immune checkpoint inhibitors and HER2 target therapy with chemotherapy had improved overall survival in advanced setting, but we do not have data about the prevalence of biomarkers used for selection of these patients in Colombia or Latin-America. Our aim is to describe the prevalence of biomarkers used currently for selection of treatment in a real-world multicenter cohort of advanced gastric and gastroesophageal junction (GEJ) cancer. Methods: We did a retrospective observational multicenter study of patients with advanced GC/GEJ cancer treated at three reference cancer centers in Bogota, Colombia between January 1, 2023 and July 31, 2023. We reviewed medical history and pathology reports looking for the prevalence of biomarkers used for selection of first line systemic therapy. Ventana 4B5 for HER2 IHQ evaluation and Dako 22C3 for PDL1 expression by CPS were used. MMR proteins were evaluated by IHQ nuclear expression. Results: 101 patients with advanced GC/GEJ were included. The median age was 61 years (range 18-83), 53,5% of patients were men, 92.1% were gastric cancer and 87,1% were de novo stage IV. Signet ring cells were found in 40%, peritoneal carcinomatosis was documented in 59% and 75,2% were distal tumors (no cardias or GEJ involvement). PDL1 positivity, defined as CPS ≥1 was found in 30.6%, using CPS ≥ 5 cutoff just 22.7% of them were positive. HER2 positivity and MMR deficiency were found in the same proportion of patients 5%. Among young patients (< 50 years) 80% had diffuse histology, 30% were CPS ≥5. HER2 status and PDL1 testing was unknown in 21% and 29% respectively. Conclusions: Among these real-world patients, both HER2 and PDL1 positivity was lower than reported in other regions. Higher incidence of distal tumors, signet ring cells and diffuse histology could explain this difference. Correlation of PDL1 positivity between 22C3 and 28.8 was unknown in our population. Our study remarks the high medical need for investigation of biomarkers and developing of prospective studies for correlation and other targets like Claudins and FGFR2b.[Table: see text]

Structural basis for the activity and specificity of the immune checkpoint inhibitor lirilumab

The clinical success of immune checkpoint inhibitors has underscored the key role of the immune system in controlling cancer. Current FDA-approved immune checkpoint inhibitors target the regulatory receptor pathways of cytotoxic T-cells to enhance their anticancer responses. Despite an abundance of evidence that natural killer (NK) cells can also mediate potent anticancer activities, there are no FDA-approved inhibitors targeting NK cell specific checkpoint pathways. Lirilumab, the most clinically advanced NK cell checkpoint inhibitor, targets inhibitory killer immunoglobulin-like receptors (KIRs), however it has yet to conclusively demonstrate clinical efficacy. Here we describe the crystal structure of lirilumab in complex with the inhibitory KIR2DL3, revealing the precise epitope of lirilumab and the molecular mechanisms underlying KIR checkpoint blockade. Notably, the epitope includes several key amino acids that vary across the human population, and binding studies demonstrate the importance of these amino acids for lirilumab binding. These studies reveal how KIR variations in patients could influence the clinical efficacy of lirilumab and reveal general concepts for the development of immune checkpoint inhibitors targeting NK cells.

Lower frequencies of circulating suppressive regulatory T cells and higher frequencies of CD4+ naïve T cells at baseline are associated with severe immune-related adverse events in immune checkpoint inhibitor-treated melanoma

BackgroundImmune-related adverse events (irAEs) are major barriers of clinical management and further development of immune checkpoint inhibitors (ICIs) for cancer therapy. Therefore, biomarkers associated with the onset of severe irAEs...

Addition of immune checkpoint inhibitors to chemotherapy versus chemotherapy alone in patients with triple-negative breast cancer: A systematic review and meta-analysis.

Triple-negative breast cancer (TNBC) is a relatively common malignant tumor with high mortality rates. There are limited treatment options and current therapy regimens often fall short of providing positive outcomes. The development of immune checkpoint inhibitors (ICIs) have provided a vital treatment option although efficacy has varied. Here, we review patient response to current TNBC treatment with and without the addition of ICIs. A systematic search of PubMed, Cochrane, and EMBASE library databases was done to search eligible studies published from their inception through April 3, 2022. The primary outcome indicators used were progression-free survival (PFS), overall survival (OS), pathological complete response rate (pCR) and objective remission rate (ORR), while adverse events (AEs) were also analyzed. Publication bias and sensitivity analyses and were performed to evaluate the quality of assessment. Overall, the meta-analysis looked at seven randomized controlled trials (RCTs) that included 4631 patients with TNBC. Results showed an improvement in PFS for patients receiving ICI in addition to chemotherapy (CT) in both the intent-to-treat (ITT) population and PD-L1 positive patients. Increased pCR rates were observed in all patients irrespective of PD-L1 status as well as increased ORR in the ITT which was more notable in PD-L1 positive subjects. While significant improvement in OS was observed only in PD-L1 positive individuals, the use of ICIs plus CT resulted in severe adverse reactions, specifically immune-related. This study supports the increased efficacy of ICIs in combination with CT compared to CT alone in patients with TNBC, with the most notable benefit observed in PD-L1 positive patients. However, combination therapy increases the risk of adverse reactions which warrants further investigation.

An Innovative and Accurate Next-Generation Sequencing–Based Microsatellite Instability Detection Method for Colorectal and Endometrial Tumors

The detection of microsatellite instability (MSI) and mismatch repair (MMR) deficiency has become mandatory for most tumors in recent years, owing to the development of immune checkpoint inhibitors as a highly effective therapy for MMR deficiency/MSI tumors. The timely and efficient detection of MSI is valuable, and new methods are increasingly being developed. To date, MMR assessment has been performed using immunohistochemistry of the 4 MMR proteins and/or microsatellite stability/MSI using PCR, mostly using the pentaplex panel. The implementation of next-generation sequencing (NGS) for MSI analysis would improve the effectiveness at a lower cost and in less time. This study describes the development of 8 new microsatellites combined with a classification algorithm, termed “Octaplex CaBio-MSID” (for Cancérologie Biologique MSI Detection tool), to assess MSI using NGS. A series of 303 colorectal cancer and 88 endometrial cancer samples were assessed via MSI testing using NGS using the Octaplex CaBio-MSID algorithm. The sensitivity and specificity of Octaplex CaBio-MSID were 98.4% and 98.4% for colorectal cancers, and 89.3% and 100% for endometrial cancers, respectively. This new NGS-based MSI detection method outperforms previously published methods (ie, Idylla [Biocartis], OncoMate MSI Dx [Promega], and Foundation One CDx [Roche Foundation Medicine]). Although highly efficient, Octaplex CaBio-MSID requires validation in a larger independent series of different tumor types.

Perioperative immunotherapy in stage IB-III non-small cell lung cancer: a critical review of its rationale and considerations.

Lung cancer is a dismal disease as a leading cause of overall cancer death, but the development of immune checkpoint inhibitors (ICIs) in driver gene mutation negative metastatic non-small cell lung cancer (NSCLC) is changing the paradigm of lung cancer treatment. Recently, ICIs are expanding their treatment area to early-stage NSCLC and ICIs have also changed their treatment strategies of such patients. And it is important to appropriately select patients with resectable early-stage lung cancer through a multidisciplinary team approach and decrease the tumor relapse rate in the ICIs era. In this review article, we discuss the recently released neoadjuvant and adjuvant data of ICIs, their treatment rationale, and unmet needs in the treatment of early-stage NSCLC.

Sintilimab plus fluorouracil, leucovorin, oxaliplatin and docetaxel regimen as neoadjuvant therapy for resectable gastric cancer and biomarker exploration.

At present, preoperative chemotherapy is the standard of care for the neoadjuvant treatment of potentially resectable gastric cancer (GC). However, because the efficacy and prognosis are not ideal, curative effects for this population are unsatisfactory. With the development of immune checkpoint inhibitors, the results of a few encouraging early trials of immunotherapeutic agents as neoadjuvant therapies for resectable GC have been reported. However, markers of theefficacy ofimmune checkpoint inhibitors remain unclear. This prospective single-center, single-arm observational study was designed to evaluate the efficacy of sintilimab plus the fluorouracil, leucovorin, oxaliplatin and docetaxel regimen as a neoadjuvant treatment for localized GC. More importantly, this workassesses multiple dimensions and include ctDNA, the immune microenvironmentand intestinal microbiome to explorecorrelations between biomarkers and neoadjuvant therapeutic efficacy. Clinical trial registration: ChiCTR2200061629 (www.chictr.org.cn/index.aspx).