Combination Of PD-1 Inhibitors Research Articles

The efficacy of neoadjuvant immunotherapy and lymphocyte subset predictors in locally advanced esophageal squamous cell carcinoma: A retrospective study.

Despite the recognized therapeutic potential of programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors in advanced esophageal squamous cell carcinoma (ESCC), their role in neoadjuvant therapy and reliable efficacy biomarkers remain elusive. We retrospectively analyzed locally advanced ESCC patients who underwent surgery following a 2-cycle platinum and paclitaxel-based treatment, with or without PD-1 inhibitors (January 2020-March 2023). We assessed peripheral blood indexes and tertiary lymphoid structures (TLS) density to evaluate their impact on pathological response and prognosis, leading to a clinical prediction model for treatment efficacy and survival. Of the 157 patients recruited, 106 received immunochemotherapy (ICT) and 51 received chemotherapy (CT) alone. The ICT group demonstrated a superior pathological response rate (PRR) (47.2% vs. 29.4%, p = 0.034) with comparable adverse events and postoperative complications. The ICT group also showed a median disease-free survival (DFS) of 39.8 months, unattained by the CT group. The 1-year DFS and overall survival (OS) rates were 73% and 91% for the ICT group, and 68% and 81% for the CT group, respectively. We found higher baseline activated T cells, lower baseline Treg cells, and a decreased posttreatment total lymphocyte and CD4+/CD8+ ratio predicted an enhanced PRR. Reduced posttreatment CD4+/CD8+ ratio and increased NK cells were associated with prolonged survival, while higher TLS density indicated poorer prognosis. Among ICT group, a lower posttreatment CD4+/CD8+ ratio indicated longer DFS and reduced posttreatment B cells indicated longer OS. A nomogram integrating these predictors was developed to forecast treatment efficacy and survival. The combination of PD-1 inhibitors and chemotherapy appears promising for locally advanced ESCC. Evaluating the differentiation status and dynamic changes of peripheral blood immune cells may provide valuable predictive insights into treatment efficacy and prognosis.

The regulating properties of Sanqi that enhances PD-1 inhibitors effects in lung cancer revealed by metabolomic and microbiome analyses

Sanqi (SQ), as a health food, is clinically used as an effective complementary therapy for treating multiple cancers with the advantages of immunomodulatory potential. Nevertheless, the efficacy and the underlying mechanism of combining SQ and PD-1 inhibitors remain inconclusive. In this study, we examined the anti-lung cancer effects of SQ in combination with PD-1 inhibitors in tumor-bearing mice. We found that PD-1 inhibitors and SQ combinedtreatment significantly inhibited tumor growthin tumor-bearing mice. Following the administration of SQ combined with PD-1 inhibitors, there was an increase in the levels of Glycolaldehyde and N-Acetyl-D-glucosamine in the plasma of mice, while the levels of 1,4-Dihydro-1-methyl-4-oxo-3-pyridinecarboxamide decreased. Specifically, SQ supplementation increased the abundance of beneficial bacteria, such as Aerococcus, while reducing the levels of pathogenic bacteria, including norank_f_norank_o_Clostridia_UCG-014, Candidatus_Saccharimonas, and Bilophila. Our data suggested that a combination of PD-1 inhibitors and SQ treatment may be a novel therapeutic strategy for lung cancer patients.

Comparison of immunochemotherapy and chemotherapy alone in conversion therapy for locally advanced unresectable esophageal squamous cell carcinoma.

The clinical value of preoperative immunochemotherapy and simple chemotherapy induction regimen in the conversion therapy of locally advanced unresectable esophageal squamous cell carcinoma (ESCC) is still unclear. Retrospective analysis was conducted on patients with unresectable cT4b stage ESCC who underwent conversion surgery in our hospital from January 2020 to December 2022. According to the preoperative induction treatment plan, they were divided into induction immunochemotherapy group (iICT group) and induction chemotherapy group (iCT group). The conversion surgery rate, R0 resection rate, radiological and pathological tumor responses, safety, and short-term survival outcomes were analyzed. The results showed that a total of 199 patients with cT4b locally advanced unresectable ESCC who underwent preoperative induction therapy were included in this study. Among them, there were 64 cases (32.2%) in the iICT group, 135 cases (67.8%) in the iCT group. There was a statistically significant difference in objective response rate (73.5% vs 48.9%) and conversion surgery rate (81.3% vs 66.7%), between the iICT and iCT groups (P=0.001 and P=0.019). Among the two groups of patients who underwent surgery, there were statistically significant differences in R0 resection rate (94.2% vs 82.2%) and pathological complete remission rate (23.1% vs 6.7%) between the iICT and iCT groups (P=0.043 and P=0.004). And there was no statistically significant difference in the incidence of grade 3 and above between two groups (P=0.928). The 2-year EFS of the iICT group and iCT group were 76.4% and 42.4%, respectively, with statistically significant differences (P=0.006). Compared with simple chemotherapy, the combination of PD-1 inhibitors and chemotherapy can achieve better conversion surgery rate, tumor response and event-free survival in the conversion therapy of locally advanced unresectable ESCC.

Effectiveness of PD-1 inhibitor-based first-line therapy in Chinese patients with metastatic gastric cancer: a retrospective real-world study.

Programmed cell death protein-1 (PD-1) inhibitor-based therapy has demonstrated promising results in metastatic gastric cancer (MGC). However, the previous researches are mostly clinical trials and have reached various conclusions. Our objective is to investigate the efficacy of PD-1 inhibitor-based treatment as first-line therapy for MGC, utilizing real-world data from China, and further analyze predictive biomarkers for efficacy. This retrospective study comprised 105 patients diagnosed with MGC who underwent various PD-1 inhibitor-based treatments as first-line therapy at West China Hospital of Sichuan University from January 2018 to December 2022. Patient characteristics, treatment regimens, and tumor responses were extracted. We also conducted univariate and multivariate analyses to assess the relationship between clinical features and treatment outcomes. Additionally, we evaluated the predictive efficacy of several commonly used biomarkers for PD-1 inhibitor treatments. Overall, after 28.0 months of follow-up among the 105 patients included in our study, the objective response rate (ORR) was 30.5%, and the disease control rate (DCR) was 89.5% post-treatment, with two individuals (1.9%) achieving complete response (CR). The median progression-free survival (mPFS) was 9.0 months, and the median overall survival (mOS) was 22.0 months. According to both univariate and multivariate analyses, favorable OS was associated with patients having Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1. Additionally, normal baseline levels of carcinoembryonic antigen (CEA), as well as the combination of PD-1 inhibitors with chemotherapy and trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive MGC, independently predicted longer PFS and OS. However, microsatellite instability/mismatch repair (MSI/MMR) status and Epstein-Barr virus (EBV) infection status were not significantly correlated with PFS or OS extension. As the first-line treatment, PD-1 inhibitors, either as monotherapy or in combination therapy, are promising to prolong survival for patients with metastatic gastric cancer. Additionally, baseline level of CEA is a potential predictive biomarker for identifying patients mostly responsive to PD-1 inhibitors.

Updated results on multiple antigens stimulating cellular therapy (MASCT-I) in metastatic urothelial carcinoma: A randomized, open-label, phase I trial.

2545 Background: The appropriate treatment for mUC remains unmet medical needs. MASCT-I, an adoptive transfer of dendritic cells (DCs) presenting 15 types of tumor-associated antigens (TAAs), showed valuable treatment in solid tumors. We previously reported the efficacy and safety of MASCT-I alone, or plus camrelizumab or chemotherapy in mUC (NCT03034304). The biomarker analysis and long-term follow-up to for this promising approach was unknown. Methods: All enrolled patients were divided into in five groups (G) as previous reported. Patients in G2 receiving maintenance therapy of MASCT-I after first-line platinum based-chemotherapy were allowed to enter enrolled in G3 and receiving MASCT-I plus camrelizumab when disease progressed. We updated the exploratory endpoint of the IFN-γ ELISPOT assay, which was used to measure activation of the cytotoxic T Lymphocyte (CTL) response in eligible patients. Long-term follow-up results for safety, progression-free survival (PFS) and overall survival (OS) were reported. Results: 39 patients were enrolled. By January 31st, 2024, median follow-up time was 31.1 months. No new safety signals were updated. As previously reported, the most common adverse events (AEs) associated with MASCT-I included grade 1 and 2 flushing, pruritus, rash, muscle cramp, fever, and arthralgia. No MASCT-I-related death occurred. Median PFS and OS for all patients were 2.3 months, and 16.9 months, respectively. Patients in G2 presented superior OS of 41.2 months and duration of response (DOR) of 6.4 months. Nine patients treated with MASCT-I and camrelizumab after progression on MASCT-I in G2 presented a 24-month PFS rate of 55.6% and a 48-month DOR rate of 71.8%. Five patients had prolonged PFS for more than 20 months while two of them had PFS of more than 43 months. To identify the potentially beneficial population, IFN-γ ELISPOT data analysis revealed that patients who had positive TAAs ELISPOT response had significant prolonged PFS and OS compared to the non-responders (median PFS: 10.1 months vs 4.8 months, HR=0.30, 95% CI: 0.14-0.61, P<0.005; median OS: not reached vs 13.6 months, HR=0.16, 95% CI: 0.05-0.57, P<0.005). The Cmax value of INF-γ-positive T cells after cell infusion was also higher in patients with better PFS. In addition, we observed a significant increase in INF-γ-positive T cell activities in patients who progressed from G2 and were subsequently treated with a combination of MASCT-I and camrelizumab (Cmax mean (SD): 72 spots per million bulk PBMCs at G2 to 186 spots per million bulk PBMCs after transfer to G3, P=0.002). Conclusions: MASCT-I alone or in combination with immunotherapy or chemotherapy are safe and well tolerated, with inspiring survival benefit. The combination of PD-1 inhibitors may enhance the antitumor activity of MASCT-I. IFN-γ ELISPOT might be able to predict potentially beneficial populations. Clinical trial information: NCT03034304 .

PD-1 Inhibitor Aggravate Irradiation-Induced Myocardial Fibrosis by Regulating TGF-β1/Smads Signaling Pathway via GSDMD-Mediated Pyroptosis.

Cancer therapy has entered a new era with the use of programmed cell death protein 1 (PD-1) immune checkpoint inhibitors. When combined with thoracic radiotherapy, it demonstrates synergistic anti-tumor effects and potentially worsens radiation-induced myocardial fibrosis (RIMF). RIMF is the final stage of radiation-induced heart disease (RIHD) and a potentially fatal clinical complication of chest radiotherapy. It is characterized by decreased ventricular elasticity and distensibility, which can result in decreased ejection fraction, heart failure, and even sudden cardiac death. Pyroptosis, a type of programmed cell death, is mediated by members of the gasdermin (GSDM) family and has been associated with numerous cardiac disorders. The effect of pyroptosis on myocardial fibrosis caused by a combination of radiotherapy and PD-1 inhibitors remains uncertain. In this study, a 6MV X-ray of 20Gy for local heart irradiation was used in the RIHD mouse model. We noticed that PD-1 inhibitors aggravated radiation-induced cardiac dysfunction and RIMF, concurrently enhancing the presence of CD8+ T lymphocytes in the cardiac tissue. Additionally, our findings indicated that the combination of PD-1 inhibitor and thoracic radiation can stimulate caspase-1 to cleave GSDMD, thereby regulating pyroptosis and liberating interleukin-8 (IL-18). In the myocardium of mice, the manifestation of pyroptosis mediated by GSDMD is accompanied by the buildup of proteins associated with fibrosis, such as collagen I, transforming growth factor β1 (TGF-β1), interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and tumornecrosisfactorα (TNF-α). Moreover, it was discovered that TFG-β1 induced the phosphorylation of Smad2/Smad3 when the cardiac underwent PD-1 inhibitor in conjunction with thoracic irradiation (IR). The findings of this research indicate that PD-1 inhibitor worsen RIMF in mice by triggering GSDMD-induced pyroptosis and influencing the TGF-β1/Smads pathway. While using the caspase-1 inhibitor Z-YVAD-FMK, RIMF can be alleviated. Blocking GSDMD may be a viable strategy for managing myocardial fibrosis caused by the combination of PD-1 inhibitors and radiotherapy.

Analysis of the Treatment for Advanced Microsatellite Stable Colorectal Cancer in Middle-Aged and Elderly People

Microsatellite stabilized (MSS) rectal cancer is a highly prevalent cancer in the middle-aged and elderly population. There exists some expertise in detecting and evaluating the chemotherapy effect in advanced colorectal cancer patients. Multiple studies have combined targeted therapy, chemotherapy, and immunotherapy as a breakthrough. Programmed cell death protein 1 (PD-1) inhibitors have certain therapeutic effects in the treatment of MSS rectal cancer patients. The combination of PD-1 inhibitors and furoquinib can improve the disease control rate (DCR) and progression- free survival (PFS) in colorectal cancer (CRC) patients with advanced MSS, and the adverse reactions are controllable. The combination of erlotinib hydrochloride and Xindilizumab was more effective in treating MSS-type colorectal cancer patients than clinical standard treatment. This study analyzes the various treatment methods for MSS-type CRC in middle- aged and elderly people to provide a reference basis in clinical practice.

Abstract 88: Novel cell-based bioassays enable preclinical animal studies during immuno-oncology drug development

Abstract Translation of immuno-oncology research into novel therapies relies on animal models to advise target selection and portray mechanism of action (MoA) and pharmacokinetics of lead candidates. Mouse, monkey, and more recently, canine models of human cancers are being utilized to this end. However, one major challenge in developing and utilizing these models is the lack of technology to characterize non-human analogs of therapeutic antibodies. Herein, we report the development of novel cell-based bioassays for mouse, monkey, and canine targets to enable immuno-oncology preclinical studies. Antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) are important MoAs for antibody-based cancer immunotherapies. We have developed a suite of cell-based bioassays, each expressing a corresponding animal Fcγ receptor (FcγR) and a luciferase reporter that responds to FcγR activation. These assays exhibit sensitive and quantitative luciferase readouts of FcγR activation. Animal models are further used to provide insight into the potential efficacy of immune checkpoint (IC) inhibitors. Programmed cell death protein 1 (PD-1) is an IC receptor that negatively regulates T cell function. Blockade of PD-1 has demonstrated clinical efficacy, but there remains a significant fraction of patients unresponsive to this therapy. Combination of PD-1 inhibitors with other interventions has been a significant focus for many programs. However, tools for functional validation of non-human PD-1 inhibitors are lacking. We report here the development of two new bioassays for functional characterization of PD-1/PD-L1 inhibitors for mouse and canine targets. Each of these assays consists of two engineered cell lines: a T effector cell line that express a luciferase reporter driven by specific promoter/response elements responding to the intracellular signals mediated by the T cell receptor (TCR), with modulation from PD-1, and an artificial antigen presenting cell line (aAPC). The bioassays are sensitive, quantitative, and have demonstrated characteristics required for potency assays for validation of antibodies in preclinical combination studies. Citation Format: Jun Wang, Denise Garvin, Aileen Paguio, Elizabeth Perrin, Jim Hartnett, Mei Cong, Jamison Grailer. Novel cell-based bioassays enable preclinical animal studies during immuno-oncology drug development [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 88.

PD-1 inhibitor combined with chemotherapy for first-line treatment of esophageal squamous cell carcinoma patients with distant metastasis: a real-world retrospective study.

The aim of this study was to evaluate whether the efficacy and safety of PD-1 inhibitors combined with chemotherapy in the treatment of patients with esophageal squamous cell carcinoma (ESCC) with distant metastasis in the real world are as effective and safe as in clinical trials. From July 2019 to July 2023, a total of 422 patients with distant metastasis of ESCC were included and divided into the PD-1 inhibitor combined chemotherapy group (PC group) and the chemotherapy alone group (C group) according to the treatment regimen. There were 278 patients in the PC group and 144 patients in the C group. The primary endpoint of this study was progression-free survival (PFS), while secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. The objective response rate (ORR) and disease control rate (DCR) of the PC group were 44.60% (124/278) and 91.00% (253/278), respectively, which were 18.9% and 3.5% higher than those of the C group. The median PFS and median OS of the PC group were significantly better than those of the C group (median PFS: 6.5 vs. 5.5 months, P < 0.001; median OS: 16.6 vs. 13.9 months, P = 0.002). Further univariate and multivariate Cox analysis showed that the Eastern Cooperative Oncology Group performance status (ECOG PS) score and the number of metastatic sites were potential predictors of PFS in PC patients. The combination of PD-1 inhibitors with cisplatin and paclitaxel (TP) was more beneficial for patients with PFS compared to the combination of cisplatin and fluorouracil (PF). Furthermore, the presence of bone metastasis, body mass index (BMI), and lymphocyte-to-monocyte ratio (LWR) before treatment may be potential predictive factors for patient OS. The adverse reactions that occurred in the PC group can be tolerated or alleviated after both prevention and active treatment. The combination of PD-1 inhibitors and chemotherapy as first-line treatment for ESCC patients with distant metastasis still has good efficacy and safety compared to clinical trials in the real world.

Комбинация Nivo-DHAP с последующей высокодозной химиотерапией и трансплантацией аутологичных гемопоэтических стволовых клеток у пациентов с рецидивами и рефрактерным течением классической лимфомы Ходжкина: результаты многоцентрового проспективного клинического исследования (ClinicalTrials.gov, NCT04091490)

Background. High-dose chemotherapy (HDCT) with autologous hematopoietic stem cell transplantation (auto-HSCT) is currently regarded as a standard treatment for patients with relapsed/refractory classical Hodgkin lymphoma (cHL). The efficacy of transplantation correlates with the depth of antitumor response achieved on pre-transplantation chemotherapy. A combination of PD-1 inhibitors with chemotherapy is a new forward-looking approach ensuring a higher rate of complete responses prior to auto-HSCT as well as better outcomes of the treatment in general.&#x0D; Aim. To assess the efficacy and safety of the combined program with Nivo-DHAP and subsequent HDCT and auto-HSCT in patients with relapsed/refractory cHL.&#x0D; Materials &amp; Methods. From March 2020 to January 2022, 38 patients were enrolled in the study. The Nivo-DHAP program consisted of two stages. At stage 1 nivolumab immunotherapy was administered: two 240 mg/day IV infusions as a monoregimen 14 days apart. Stage 2, Nivo-DHAP immunochemotherapy, started in 14 days after stage 1: nivolumab 480 mg/day IV infusion on Day 1 in combination with DHAP chemotherapy, total of 4 cycles. The efficacy of this therapy was evaluated after 2 nivolumab infusions as well as after 2 and 4 Nivo-DHAP cycles. The program was fully implemented in 36 patients. HSCs were collected after remission had been reported, in most cases it was after 2 Nivo-DHAP cycles. For various reasons, auto-HSCT was performed only in 23 out of 36 patients. The median follow-up of patients after auto-HSCT was 24 months.&#x0D; Results. After completing the pre-transplantation stage of the program to the full extent, which included Nivo, Nivo, and 4 Nivo-DHAP cycles, 36 patients showed a 100 % overall objective response. Complete response was achieved in 27 (75 %) patients, and partial response was reported in 9 (25 %) patients. The signs of hematological toxicity grade 3/4 were manifested in 26 % of patients. In the total cohort of 36 patients with (n = 23) and without (n = 13) auto-HSCT, progression-free survival (PFS) was 81 % with the follow-up of 12 months, 78 % with the follow-up of 24 months, and 74 % with the follow-up of 36 months. Overall survival (OS) in the total cohort with the same follow-up end-points was 95 %. A comparative assessment revealed that PFS was 87 % in the cohort with auto-HSCT with the follow-up of 12, 24, and 36 months and 70 %, 64 %, and 48 % in the cohort without auto-HSCT with the same follow-up end-points, respectively (p = 0.056).&#x0D; Conclusion. A combination of PD-1 inhibitors with chemotherapy as a stage prior to HDCT followed by auto-HSCT is a promising strategy resulting in high PFS and OS rates. Preliminary data on using PD-1 inhibitors combined with chemotherapy cannot yet provide substantial basis for disregarding HDCT with subsequent auto-HSCT which is considered to be the optimal method for remission consolidation.

Clinical benefit analysis of PD-1 inhibitors in patients with advanced, recurrent or metastatic cervical cancer: a meta-analysis and systematic review.

This study aims to comprehensively evaluate the efficacy and safety of programmed cell death protein-1 (PD-1) in patients with advanced, recurrent, or metastatic cervical cancer (ARMCC) and identify the population that may benefit the most. We conducted a search of PubMed, EMBASE, and the Cochrane Collaboration Library from their inception to September 2023. We extracted and analyzed the results related to the efficacy and safety of PD-1 in patients with ARMCC. The primary endpoints included the overall objective response rate (ORR) and adverse events (AEs), while the secondary endpoints encompassed the 1-year overall survival (OS) rate, 1-year progression-free survival (PFS) rate, as well as OS and PFS. We used a random effects model to conduct a meta-analysis on single-group rates, and the Mantel-Haenszel method was utilized to compare the ORR and the incidence of AEs. Our study included a total of 21 trials involving 2,097 patients. The ORR of the combination of PD-1 inhibitors with chemotherapy was 56.36%, the combination of PD-1 inhibitors with anti-angiogenic agents was 38.72%, the combination of PD-1 inhibitors with Cytotoxic T-lymphocyte antigen 4 inhibitors was 25.60%, and PD-1 inhibitor monotherapy was 15.99%. The subgroup analysis showed that the group of patients with squamous cell carcinoma (SCC) exhibited a significantly higher ORR compared to the non-SCC group in patients who received PD-1 inhibitors combined with other anti-tumor drugs (Odds Ratio =2.43, P=0.002). Additionally, the group of patients with a programmed death-ligand 1 combined positive score (PD-L1 CPS) ≥1 exhibited a significantly higher ORR compared to the PD-L1 CPS <1 group in patients who received PD-1 inhibitor monotherapy (OR=4.14, P=0.02). PD-1 inhibitor monotherapy or PD-1 inhibitors combined with chemotherapy did not significantly increase the incidence of all grades of adverse events (Relative Risk=0.99, p=0.788) or the incidence of serious adverse events (RR=0.99, p=0.788) compared to chemotherapy alone. PD-1 inhibitors demonstrate outstanding efficacy in the treatment of patients with ARMCC. Patients with SCC may benefit more from treatments including PD-1 inhibitors in combination with other anti-tumor drugs, and PD-L1 CPS ≥1 can be considered a favorable indicator of immune therapy response. Importantly, the use of PD-1 inhibitor monotherapy or PD-1 inhibitors in combination with chemotherapy did not lead to an increased incidence of AEs compared with chemotherapy alone, indicting safety during treatment. PROSPERO (CRD42023457945).

PD-1 Inhibitors combined with paclitaxel (Albumin-bound) and cisplatin for larynx preservation in locally advanced laryngeal and hypopharyngeal squamous cell carcinoma: a retrospective study.

laryngeal and hypopharyngeal squamous cell carcinoma (SCC) is a common head and neck cancer with significant impact on quality of life due to its crucial roles in vocalization, airway protection, and swallowing. This retrospective study aims to evaluate the efficacy and larynx organ preservation of neoadjuvant treatment with PD-1 inhibitors in combination with paclitaxel (Albumin-bound) and cisplatin for locally advanced laryngeal and hypopharyngeal SCC. Medical records of consecutive patients diagnosed with histologically or cytologically confirmed locally advanced SCC of the larynx and hypopharynx, who received PD-1 inhibitor therapy at a single tertiary care center, were reviewed from January 1, 2019, to December 15, 2022. The patients were treated with a combination of PD-1 inhibitors, paclitaxel (Albumin-bound) 260mg/m2, and cisplatin 60mg/m2 (TP) as their first-line therapy. Survival outcomes, laryngectomy-free survival (LFS) rates and response rates were assessed. The study cohort comprised 156 patients, predominantly male, with a median age of 60.4 years. The estimated one-year overall survival (OS) rate was 94.1%, two-year OS rate was 82.5%, one-year progression-free survival (PFS) rate was 80.4%, and two-year PFS rate was 66.3%. The one-year LFS was 86.4%, and the two-year LFS rate was 73.0%. The overall response rate after TP + PD-1 inhibitors therapy was 88.5%. Common treatment-associated adverse events included rash, thyroid function abnormalities, myelosuppression, and colitis. Neoadjuvant therapy with PD-1 inhibitors in combination with paclitaxel (Albumin-bound) and cisplatin showed promising efficacy and tolerability for larynx preservation in locally advanced laryngeal and hypopharyngeal SCC. The high response rates and favorable survival outcomes suggest this approach as a potential treatment option. Prospective randomized controlled trials are needed to further validate these findings and establish the role of immunotherapy in larynx preservation.

Meta-analysis of studies on the effectiveness of adding anti-PD1 antibodies to the first-line chemotherapy in advanced esophageal cancer

Introduction: The results of six randomized control trials have been published by 2022, which evaluated the efficacy of adding PD-1 inhibitors to the first-line chemotherapy in patients with metastatic esophageal cancer. However, it still remains unclear which patients derive the most clinical benefit from combined therapy. Therefore, it is necessary to evaluate the efficacy of the combination of anti-PD1 treatment with chemotherapy in different patient subgroups.Materials and methods: We conducted a meta-analysis of randomized controlled trials in patients with stage IV esophageal cancer who received anti-PD1 drugs with different chemotherapeutic regimens in the first-line setting to select patients who benefit the most from the combined therapy.Results: Six randomized trials were included in the analysis for a total of 3,813 patients. Patients who received combination therapy had significantly longer OS (HR = 0.69, 95% CI: 0.63-0.75; p &lt; 0.001), PFS (HR = 0.62, 95% CI: 0.56-0.69; p &lt; 0.001), and better ORR (OR = 2.12, 95% CI: 1.85-2.42; p &lt; 0.001) than those who received chemotherapy alone. Subgroup analyses showed no benefit of adding PD1-inhibitors to chemotherapy in patients with PD-L1 CPS &lt;1 in terms of OS (HR = 0.58, 95 % CI: 0.31-1.1; p = 0.1) as well as in never-smokers (HR = 0.9, 95% CI: 0.67-1.23; p = 0.52).Conclusions: The addition of PD-1 inhibitors to the first-line chemotherapy in patients with metastatic esophageal cancer significantly improves treatment outcomes. Our results could not strongly suggest the selected patients' cohort which would benefit the most from the combination of PD-1 inhibitors and chemotherapy use.

The success of anti-PD-1 with chemotherapy for esophageal squamous cell carcinoma

In the ASTRUM-007 randomized double-blind phase III study, Song etal.1 showed that the combination of PD-1 inhibitors with first-line fluoropyrimidine and platinum-based chemotherapy improves outcomes in PD-L1-overexpressing esophageal squamous cell carcinomas.

PD-1 blockade enhances cytokine-induced killer cell-mediated cytotoxicity in B-cell non-Hodgkin lymphoma cell lines.

The clinical utility of immune checkpoint inhibitors, such as programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors used alone or in combination with other therapies, is currently gaining attention. In this particular scenario, the inclusion of cytokine-induced killer (CIK) cells has proven to be a novel therapeutic approach. CIK cells have shown anticancer activity in various hematopoietic malignancies, but their defined cytotoxicity in B-cell non-Hodgkin lymphoma (B-NHL) remains to be fully elucidated. The present study investigated the role of PD-1/PD-L1 blockades on the cytotoxic efficacy of CIK cells primarily in B-NHL cell lines. The current analysis revealed that CIK cells prompted cytotoxicity against B-NHL cell lines (DAUDI and SU-DHL-4), and a significant increase in PD-L1 expression was observed when CIK cells were co-cultured with B-NHL cells. Additionally, a combination of PD-1 and PD-L1 antibodies with CIK cells significantly decreased cell viability only in DAUDI cells. Furthermore, IFN-γ elevation was observed in both cell lines treated with CIK alone or with PD-1 antibody, but this tendency was not observed for PD-L1. Since PD-1 can suppress immune inactivation, whereas CD40L can promote it, the effects of CD40L blockade were also examined; however, no significant changes in cell viability were observed. Overall, the present in vitro data suggested that CIK cells exerted a cytotoxic function in B-NHL cells, and a combination of PD-1 inhibitors with CIK cells may provide a potential therapeutic option for this type of lymphoma. Nevertheless, in vivo experiments are warranted to undermine the extent to which PD-1 inhibitors may be used to enhance the antitumor activity of CIK cells in B-NHL.

Efficacy and safety of PD-1 inhibitors as first- and second- line treatments for advanced gastroesophageal cancers: A network meta-analysis of phase III clinical trials.

e16032 Background: Advanced gastroesophageal tumors are among the most prevalent and burdensome cancers worldwide. They have a poor prognosis and limited treatment options. Recent studies show that PD-1/PD-L1 inhibitors can improve outcomes, but the results are inconsistent across trials. Herein, we compare the effectiveness and safety of PD-1/PD-L1 inhibitors with chemotherapy in patients with ERBB2 negative advanced/metastatic gastric and esophageal cancers. Methods: We searched bibliographic databases (PubMed, Embase, Cochrane Central, Web of Science, Medline, Scopus) and ClinicalTrials.gov from January 1, 2010, to November 23, 2020. We included phase III randomized clinical trials comparing anti-PD-1/PD-L1 single-agent or in combination with chemotherapy (chemoimmunotherapy) for advanced gastric or esophageal cancers in the first- or second-line settings. We performed a network meta-analysis with a frequentist approach and a random-effects model using the package ‘netmeta’ for R statistical software. A prospective protocol was uploaded to PROSPERO (CRD42020221822). Results: The final analysis included a total of 8 trials that compared different anti-PD-1 agents; none of them involved anti-PD-L1 agents. The four first-line studies involved 3817 patients. Chemoimmunotherapy improved OS and PFS with no significant safety difference: Nivolumab + chemotherapy, OS (HR, 0.83; 95% CI, 0.75-0.92), PFS (HR, 0.68; 95% CI, 0.57-0.81), SAE (OR 0.54; 0;95% CI, 0.1-2.92); Pembrolizumab + chemotherapy: OS (HR, 0.77; 95% CI, 0.67-0.88), PFS (HR, 0.72; 95% CI, 0.60-0.85), SAE (OR, 1.31; 0;95% CI, 0.23-7.35). Pembrolizumab monotherapy was the safest first-line treatment, SAE (OR, 0.02; 95% CI, 0.00-0.2), but did not improve survival, OS (HR, 0.91; 95% CI, 0.71-1.16), PFS (HR, 1.62; 95% CI, 1.23-2.14). The four second-line studies totalized 2087 individuals. Anti-PD-1 drugs were significantly safer but did not significantly improve survival: camrelizumab, OS (HR 0.71; 95% CI, 0.54-0.93), PFS (HR 0.69; 95% CI, 0.45-1.06), SAE (OR, 0.37; 95% CI, 0.24-0.56); nivolumab, OS (HR 0.77; 95% CI, 0.58-1.02), PFS (HR 1.08; 95% CI, 0.77-1.66), SAE (OR, 0.13; 95% CI, 0.08-0.2) pembrolizumab, OS (HR 0.86; 95% CI, 0.72-1.04), PFS (HR 1.28; 95% CI, 0.96-1.71), SAE (OR, 0.4; 95% CI, 0.30-0.53). Conclusions: the combination of PD-1 inhibitors with chemotherapy improves OS and PFS in previously untreated gastroesophageal cancers. Single-agent anti-PD-1 drugs improve safety in refractory disease, with no significant change in OS and PFS.

Addition of chemotherapy to nivolumab after PD-1 inhibitor failure as bridge to allogeneic stem cell transplantation in classical Hodgkin's lymphoma: report on three cases and literature review.

The poor prognosis of refractory or relapsed (R/R) classical Hodgkin’s lymphoma (cHL) after autologous stem cell transplantation has improved greatly due to the introduction of brentuximab vedotin and PD-1 inhibitors. However, the duration of response achieved with these novel agents is too short. The information about the management of patients after anti-PD-1 therapy failure is very limited in cHL, although chemotherapy alone or combined with PD-1 inhibitors has shown encouraging results. We report three cases of heavily pretreated cHL, refractory to nivolumab monotherapy, successfully rescued with the addition of chemotherapy to nivolumab, as a bridge to allogeneic stem cell transplantation (allo-SCT). All three patients presented poor clinical features such as three to four previous lines including brentuximab vedotin and autologous stem cell transplantation, refractoriness to the last line of therapy previous to nivolumab, and rapid disease progression. Notwithstanding these characteristics and nivolumab failure, they achieved a complete response after the addition of chemotherapy, were consolidated with allo-SCT, and still remain in complete response. There are few studies concerning the combination of PD-1 inhibitors and chemotherapy after nivolumab failure, including one retrospective study and one phase II trial with nivolumab plus bendamustine. Therefore, only few patients are consolidated with allo-SCT. However, there are several ongoing trials investigating new combinations of chemotherapy and PD-1 inhibitors in R/R cHL, as well as in first line. All these data suggest that anti-PD-1 therapy may reprogram the immune system, activating and inhibiting effector and immunosuppressive cells, respectively, leading to overtake of chemorefractoriness. Allo-SCT can increase the immune-related events of patients treated with anti-PD-1 previously, consistent on acute graft-versus-host disease, sinusoidal obstruction syndrome, and noninfectious febrile syndrome. In conclusion, the combination of PD-1 inhibitor and chemotherapy may be a feasible therapy after anti-PD-1 treatment failure as a bridge to allo-SCT.

Immunotherapy In Advanced Lung Cancer

Historically, platinum-based chemotherapy was the standard of care for metastatic lung cancer. However, since the success of immune checkpoint inhibitors (ICIs) in melanoma, PD-1/PD-L1 and CTLA-4 immune checkpoint pathways have been established as effective therapies to manage advanced non-small cell lung cancer (NSCLC) and extensive-stage (ES) small cell lung cancer (SCLC). Multiple large-scale randomized clinical trials have analyzed the effects of ICIs in NSCLC, and results of these trials have since translated to the approval of single-agent PD-1/PD-L1 inhibitors, and the combination of PD-1 inhibitors with platinum-based chemotherapy has become the new standard of care for patients with advanced NSCLC. Furthermore, in ES SCLC, in which chemotherapy or chemoradiation has been the standard of care for decades, 2 anti-PD-1/PD-L1 agents have been approved for use in the frontline setting for ES SCLC, in combination with chemotherapy. Despite progressive integration of immunotherapy into treatment regimens, there remains a need for reliable biomarkers to precisely determine therapy candidates.

Abstract A184: T-cell rejuvenation is associated with vorinostat-induced immune response in combination with immune checkpoint blockade

Abstract Background: Immune checkpoint inhibitors targeting the PD-1/PD-L1 axis have shown clinical benefit in solid tumor patients, including renal cell carcinoma (RCC). However, the rate of clinical response remains modest. Growing evidence suggests that epigenetic modifying agents may have an immunomodulatory role. Our group has previously demonstrated that the selective class I histone deacetylase (HDAC) inhibitor entinostat decreases the function of regulatory T-cells (Treg) and myeloid-derived suppressor cells (MDSC), and synergizes with PD-1 blockade. In this study, we assessed the immunomodulatory activity and efficacy of combining PD-1 blockade with the pan-HDAC inhibitor vorinostat in a RCC model. Methods: To test the efficacy of a combination therapy with a PD-1 inhibitor, mDX-400 (10 and 20 mg/kg I.P) (Merck &amp; Co., Inc.) and a pan-HDAC inhibitor, vorinostat (100 and 150 mg/kg I.P) (Merck &amp; Co., Inc.), we utilized a syngeneic mouse model of metastatic RCC following orthotopic implantation of luciferase expressing RENCA cells in immunocompetent BALB/c mice. Antitumor activity was assessed by bioluminescence technique as well as end point measurements of tumor weights. Immune landscape profiling of tumor infiltrating lymphocytes (TILs) was performed by flow cytometry, immunohistochemistry, and immunofluorescence. Survival analysis was performed by Kaplan–Meier estimates and log-rank statistic. Differences in chromatin accessibility in peripheral blood mononuclear cells (PBMC) were assessed by Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq). Results: Statistically significant reductions in end point tumor weights, as well as lung metastases nodules, were observed in mice treated with the combination of vorinostat (100 mg/kg P=0.0391; 150 mg/kg P=0.0165) and mDX-400 (20 mg/kg) compared to vehicle, while no statistical significant reduction was observed in those treated with single-agent mDX-400. Combination therapy also significantly lengthened the survival of the mice (median survival = 60 days; P=0.009) compared to treatment with the single agent mDX-400 (median survival=42 days). Immune landscape profiling did not demonstrate a significant increase in CD8+ tumor infiltration (P=0.479), but a statistically significant increase in natural killer cell infiltration (P=0.048) was observed. Though the CD8+ tumor infiltration was unchanged, a significant reduction (P=0.049) of exhausted CD8+ T-cells (CD8+PD1+) was observed in the combination treatment compared to mDX400 alone. Furthermore, a decrease was observed in the immunosuppressive Tregs (CD4+FOXP4+) and MDSC (CD11b+Gr1+) in the combination group compared to mDX400 alone. Bioinformatic analyses of ATAC-seq data from the PBMC cells of mice in the combination treatment and mDX400 alone showed increased chromatin accessibility between the two conditions. Pathway analysis of genes associated with more accessible chromatin in the combination treatment than mDX400 treatment identified enrichment of cell cycle control and immune cell activation pathways. Conclusions: Our results demonstrate that the pan-HDAC inhibitor vorinostat augments the antitumor effect of immune checkpoint inhibitor mDX-400 and prolongs survival in the RENCA model. This combination advantage was achieved by changing the immune landscape in TILs, especially by decreasing the exhausted subset of T-cells. The combination of these drugs is associated with higher chromatin accessibility near genes involved in cell cycle progression and immune cell activation. Taken together, our results support the clinical testing of pan-HDAC inhibitors in combination of PD-1 inhibitors and provide a novel potential immunomodulatory effect of epigenetic drugs. Citation Format: Nur P. Damayanti, Justin A. Budka, Josue D. Ordaz, Ashley Orillion, Khunsha Ahmed, Xioana Chu, Yue Wang, Yunlong Liu, Roberto Pili. T-cell rejuvenation is associated with vorinostat-induced immune response in combination with immune checkpoint blockade [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A184.

OS09.5 Synergistic effect of reirradiation and PD-1 inhibitors in recurrent high-grade gliomas

Abstract Background: To date, studies of single agent PD-1 or PDL-1 inhibitors in recurrent high-grade gliomas (HGG) have shown infrequent responses (< 10%) and limited efficacy. Reirradiation is considered one of the standard salvage regimens for selected patients with recurrent gliomas but tumor responses are also infrequent (< 5%). Radiotherapy counteracts the immunosuppressive tumor microenvironment by increasing MHC class I expression and enhancing tumor neoantigen presentation and has a significant synergistic effect with PD-1 inhibition in preclinical models of glioma. Methods: From December 2014 to June 2016, 20 patients (14 men, 6 women) with recurrent HGG were treated with the combination of reirradiation and PD-1 inhibitors. 18 patients had a glioblastoma, 1 anaplastic astrocytoma and 1 anaplastic oligodendroglioma. The median KPS at the start of this regimen was 70 (50 to 80). The median number of prior treatments for recurrent tumor was 2 (1–4), 100% had prior radaition, 95% prior temozolomide and 55% prior bevacizumab. 8 patients received pembrolizumab (2 mg/Kg every 3 weeks) and 12 patients received nivolumab (3 mg/Kg or 240 mg flat dose every 2 weeks). Median reirradiation dose was 35 Gy (12 Gy to 35 Gy). Results: There were 7 confirmed partial responses (35% objective response rate, ORR), 5 stable disease and 8 progressive disease. The median duration of response was 5 months (2.2 to 10+ months). Median PFS was 4 months and median OS was 10 months. Most common side effects were increased ALT (3 patients) and fatigue (2 patients). There was no obvious case of cerebral edema related to treatment. 5 patients required a mild increase of dexamethasone (2–4 mg) and all other 15 patients had decreased or stable dexamethasone dosage after the reirradiation. Conclusions: PD-1 inhibitors in combination with re-irradiation can be administered safely to patients with recurrent HGG. The ORR of 35% is an early signal of the potential synergist effect of the combination of PD-1 inhibitors with re-irradiation in HGG. This retrospective analysis of a heavily pre-treated population of recurrent HGG showed significantly higher ORR than either PD-1 inhibitors or re-irradiation alone. A clinical trial under development to test this hypothesis.