Anti-programmed Death Research Articles

Insulin-like growth factor 2 drives fibroblast-mediated tumor immunoevasion and confers resistance to immunotherapy.

T cell exclusion is crucial in enabling tumor immune evasion and immunotherapy resistance. However, the key genes driving this process remain unclear. We uncovered a notable increase of insulin-like growth factor 2 (IGF2) in immune-excluded tumors, predominantly secreted by cancer-associated fibroblasts (CAFs). Using mice with systemic or fibroblast-specific deletion of IGF2, we demonstrated that IGF2 deficiency enhanced the infiltration and cytotoxic activity of CD8+ T cells, leading to a reduction in tumor burden. Integration of spatial and single-cell transcriptomics revealed that IGF2 promoted interaction between CAFs and T cells via CXCL12 and programmed death ligand 1 (PD-L1). Mechanistically, autocrine IGF2 activated PI3K/AKT signaling by binding to the IGF1 receptor (IGF1R) on CAFs, which was required for the immunosuppressive functions of CAFs. Furthermore, genetic ablation of IGF2 or targeted inhibition of the IGF2/IGF1R axis with the inhibitor linsitinib markedly boosted the response to immune checkpoint blockade. Clinically, elevated levels of IGF2 in tumors or plasma correlated with an adverse prognosis and reduced efficacy of anti-programmed death 1 treatment. Together, these results highlight the pivotal role of IGF2 in promoting CAF-mediated immunoevasion, indicating its potential as a biomarker and therapeutic target in immunotherapy.

Machine Learning-enhanced Signature of Metastasis-related T Cell Marker Genes for Predicting Overall Survival in Malignant Melanoma.

In this study, we aimed to investigate disparities in the tumor immune microenvironment (TME) between primary and metastatic malignant melanoma (MM) using single-cell RNA sequencing (scRNA-seq) and to identify metastasis-related T cell marker genes (MRTMGs) for predicting patient survival using machine learning techniques. We identified 6 distinct T cell clusters in 10×scRNA-seq data utilizing the Uniform Manifold Approximation and Projection (UMAP) algorithm. Four machine learning algorithms highlighted SRGN, PMEL, GPR143, EIF4A2, and DSP as pivotal MRTMGs, forming the foundation of the MRTMGs signature. A high MRTMGs signature was found to be correlated with poorer overall survival (OS) and suppression of antitumor immunity in MM patients. We developed a nomogram that combines the MRTMGs signature with the T stage and N stage, which accurately predicts 1-year, 3-year, and 5-year OS probabilities. Furthermore, in an immunotherapy cohort, a high MRTMG signature was associated with an unfavorable response to anti-programmed death 1 (PD-1) therapy. In conclusion, primary and metastatic MM display distinct TME landscapes with different T cell subsets playing crucial roles in metastasis. The MRTMGs signature, established through machine learning, holds potential as a valuable biomarker for predicting the survival of MM patients and their response to anti-PD-1 therapy.

Novel immunotherapeutic approaches in lung cancer: driving beyond programmed death-1/programmed death ligand-1 and cytotoxic T-lymphocyte-associated Protein-4.

In this review, our aim is to highlight the latest novel immunotherapeutic approaches for advanced nonsmall cell lung cancer (NSCLC) beyond anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) and anti- cytotoxic T-lymphocyte-associated Protein-4 (CTLA4). Immune checkpoint inhibitors (ICIs) revolutionized the treatment of advanced NSCLC. Despite that, patients develop primary or acquired resistance to ICIs. The discovery of novel approaches represents both an unmet need and an opportunity to improve outcomes in these patients. We summarized the most relevant novel immune checkpoints, many of them in their early phase of testing, to provide a comprehensive overview of the state of the art of immunotherapy in NSCLC beyond PD-1/PD-L1 and CTL-4 inhibitors.

Anlotinib plus TQB2450, a PD-L1 Antibody, in Patients with Advanced Alveolar Soft Part Sarcoma: a single-arm, phase 2 trial.

Alveolar soft part sarcoma (ASPS) is an ultra-rare soft-tissue sarcoma with a high rate of metastasis and no established treatment. This study aimed to explore the efficacy and safety of anlotinib (a tyrosine-kinase inhibitor) and TQB2450 (a PD-L1 inhibitor) in ASPS patients. This single-arm, phase 2 study evaluated the efficacy of TQB2450, an anti-programmed death ligand 1 (PD-L1) agent, combined with anlotinib, a TKI, in adults with advanced ASPS. TQB2450 was given intravenously (1,200 mg) on day 1, and anlotinib (12 mg/day) was taken orally from day 1 to day 14 every 3 weeks. The primary endpoint was overall response rate, with secondary endpoints including duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Lymphocyte infiltration and tertiary lymphoid structure (TLS) were also analyzed as potential prognostic biomarkers. The study enrolled 29 patients, with 28 evaluable (one withdrew due to acute pancreatitis). An objective response was achieved in 82.1% of patients, including 4 complete and 19 partial responses. The median time to response was 2.8 months, and the DOR was not reached, with an estimated median PFS of 35.2 months. Grade 3-4 treatment-related adverse events occurred in 44.8% of patients, with no study-related deaths. Responders had a higher proportion of TLS area, density, and CD20-positive immune cells. The combination of anlotinib and TQB2450 is effective and tolerable in ASPS patients. TLS may serve as a prognostic biomarker, meriting further investigation.

Phase I/II study of BMS-986156 with ipilimumab or nivolumab with or without stereotactic ablative radiotherapy in patients with advanced solid malignancies

BackgroundBMS-986156 is an agonist of the glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein (GITR) and promotes increased effector T-cell activation. Combined anti-GITR, anti-programmed death-1, anti-cytotoxic T-lymphocyte-associated protein 4 antibodies and...

Complete Response to Locoregional Therapy Plus Immunotherapy for Hepatocellular Carcinoma

Previous studies showed that 42% to 50% of patients with locally advanced hepatocellular carcinoma (HCC) achieved complete remission (CR) after combined locoregional therapy (LRT) plus immunotherapy (IO). However, data on predictors of CR and long-term clinical outcomes without surgery and after discontinuation of IO are lacking. To assess the long-term clinical outcomes among patients with unresectable HCC who achieved CR after LRT-IO and were placed on a watch-and-wait protocol. This cohort study included patients with unresectable HCC who achieved CR after LRT-IO in 2 prospective studies between January 2018 and December 2022. The time of data cutoff was June 2023. Radiologic CR was defined per modified Response Evaluation Criteria in Solid Tumors. All patients underwent close surveillance after CR without surgical interventions, and IO was discontinued. All patients had received stereotactic body radiotherapy followed by anti-programmed cell death protein 1 or anti-programmed death ligand 1 therapy. Forty-nine patients had received a dose of transarterial chemoembolization before stereotactic body radiotherapy. The primary outcome was the 3-year overall survival (OS) rate. Secondary outcomes included the 3-year time-to-progression rate, 3-year local control rate, and relapse pattern. Factors associated with CR were analyzed using multivariate analyses. A total of 63 patients were enrolled (58 male [92.1%]; median age, 69 years [range, 18-90 years]); 38 patients (60.3%) had macrovascular invasion, and the median tumor diameter was 10 cm (range, 3.8-31.1 cm). The median follow-up time was 34.7 months (95% CI, 6.5-64.6 months). Twenty-nine patients (46.0%) achieved CR. The patients achieving CR had a significantly better 3-year OS rate than patients not achieving CR (75.5% [95% CI, 58.2%-98.3%] vs 28.1% [95% CI, 7.4%-29.4%]; P < .001). Among the 29 patients with CR, the 3-year time-to-progression rate was 58.7% (95% CI, 38.7%-79.1%) and the 3-year local control rate was 90.5% (95% CI, 78.2%-100%). Ten patients (34.5%) developed recurrence; among them, 6 (60.0%) with solitary intrahepatic disease relapse underwent curative surgical treatment. The absence of tumor vascular invasion (odds ratio, 0.30; 95% CI, 0.10-0.89) and the sum of the largest lesion diameters of 8 cm or less (odds ratio, 0.26; 95% CI, 0.07-0.98) were associated with CR. This cohort study of LRT-IO with long-term follow-up data found a durable response in patients with locally advanced unresectable HCC. Long-term survival was attainable in patients with radiologic CR. Further randomized clinical trials are warranted.

Neoadjuvant Immunotherapy Alone for Patients With Locally Advanced and Resectable Metastatic Colorectal Cancer of dMMR/MSI-H Status.

The use of programmed death-1 blockade has a significant therapeutic effect in patients with mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. However, data on preoperative single-agent programmed death-1 blockade are rare. This study aims to evaluate the effectiveness and safety of preoperative programmed death-1 blockade as a conversion strategy in patients with locally advanced and resectable metastatic mismatch repair-deficient/microsatellite instability-high colorectal cancer. This is a retrospective observational study. This study was conducted at a high-volume tertiary referral cancer center in China. Twenty-four patients of consecutive cases since 2020 to 2022 with mismatch repair-deficient/microsatellite instability-high colorectal cancer who received preoperative single-agent programmed death-1 blockade were retrospectively reviewed. These patients had either bulking tumors scheduled for multivisceral resection, a strong desire for organ preservation, or potentially resectable metastatic lesions. Pathological complete response, clinical complete response, toxicity, R0 resection rate, and complications were evaluated. Patients tolerated preoperative immunotherapy well. The R0 resection rate was 95.2%, and the pathological complete response rate was 47.6%. Three patients (12.5%) were evaluated as having a clinical complete response and then underwent "watch and wait." One-half of the patients with cT4b were spared multivisceral resection, whereas 60% (3/5) achieved pathological complete response. All 3 patients with liver metastases obtained complete response of all liver lesions after programmed death-1 blockade treatment. Grade III postoperative complications occurred in 2 patients. The limitations of this study are as follows: retrospective study, small sample size, and short follow-up. Preoperative anti-programmed death-1 therapy alone as a conversion strategy in initially resected difficult mismatch repair-deficient/microsatellite instability-high colorectal cancer can achieve a high tumor complete response. The use of immunopreoperative therapy in patients with T4b colon cancer or low rectal cancer can reduce multivisceral resection and achieve high organ function preservation. See the Video Abstract . ANTECEDENTES:El uso del bloqueo de muerte programada-1 tiene un efecto terapéutico significativo en pacientes con cáncer colorrectal metastásico deficiente en reparación de desajustes/inestabilidad de microsatélites-alta (dMMR/MSI-H). Sin embargo, los datos sobre el bloqueo preoperatorio de muerte programada-1 con un solo agente son escasos.OBJETIVO:Este estudio tiene como objetivo evaluar la eficacia y seguridad del bloqueo preoperatorio de muerte programada-1 como estrategia de conversión en pacientes con cáncer colorrectal localmente avanzado y metastásico resecable con dMMR/MSI-H.DISEÑO:Este es un estudio observacional retrospectivo.ESCENARIO:Este estudio se realizó en un centro oncológico terciario de referencia de gran volumen en China.PACIENTES:Se revisaron retrospectivamente veinticuatro pacientes de casos consecutivos desde 2020-2022 con cáncer colorrectal y dMMR/MSI-H que recibieron bloqueo preoperatorio de muerte programada-1 con un solo agente. Estos pacientes tenían un tumor voluminoso programado para resección multivisceral, un fuerte deseo de preservación del órgano o lesiones metastásicas potencialmente resecables.PRINCIPALES MEDIDAS DE RESULTADO:Se evaluaron la respuesta patológica completa, la respuesta clínica completa, la toxicidad, la tasa de resección R0 y las complicaciones.RESULTADOS:Los pacientes toleraron bien la inmunoterapia preoperatoria. La tasa de resección R0 fue del 95,2% y la tasa de respuesta patológica completa fue del 47,6%. Tres pacientes (12,5%) fueron evaluados como respuesta clínica completa y luego sometidos a "observar y esperar". La mitad de los pacientes cT4b se salvaron de la resección multivisceral, mientras que el 60% (3/5) lograron una respuesta patológica completa. Los tres pacientes con metástasis hepáticas obtuvieron respuesta completa de todas las lesiones hepáticas después del tratamiento de bloqueo de muerte programada-1. En dos pacientes se produjeron complicaciones postoperatorias de grado III.LIMITACIONES:Las limitaciones de este estudio son las siguientes: estudio retrospectivo, tamaño de muestra pequeño y seguimiento corto.CONCLUSIONES:La terapia preoperatoria anti muerte programada-1 sola como estrategia de conversión en el cáncer colorrectal inicialmente difícil de resecar con dMMR/MSI-H puede lograr una alta respuesta completa tumoral. El uso de terapia inmunopreoperatoria en pacientes con cáncer de colon T4b o cáncer de recto bajo puede reducir la resección multivisceral y lograr una alta preservación de la función del órgano. (Traducción-Dr. Felipe Bellolio ).

Phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: the desmoid tumors

BackgroundDual inhibition using anti-programmed death-1 (PD-1) and anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) checkpoint inhibitors has proven effective in many cancers. However, its efficacy in rare solid cancers remains unclear. Desmoid tumors...

Long-term survival and post-hoc analysis of toripalimab plus definitive chemoradiotherapy for oesophageal squamous cell carcinoma: insights from the EC-CRT-001 phase II trial

In the EC-CRT-001 phase II study, the combination of toripalimab (an anti-programmed death-1 antibody) and definitive chemoradiotherapy (CRT) has shown promising efficacy in patients with locally advanced oesophageal squamous cell carcinoma (ESCC). Here, we reported the long-term outcomes and post-hoc exploratory analyses. This single-arm, phase II trial enrolled 42 patients diagnosed with unresectable stage I-IVA ESCC was conducted at Sun Yat-sen University Cancer Center between November 2019 and January 2021. Treatment consisted of chemotherapy (weekly 50mg/m2 of paclitaxel and 25mg/m2 of cisplatin for five cycles), concurrent radiotherapy (50.4Gy in 28 fractions), and toripalimab (240mg every 3 weeks for up to 1 year). The primary endpoint was clinical complete response (CR) rate at 3 months after CRT completion. The 3-year overall survival (OS) and progression-free survival (PFS) rates were evaluated. Additionally, the exploratory objectives included analysing recurrence patterns, assessing the associations between immune-related adverse events (irAEs) and efficacy, and identifying potential predictors for irAEs. The trial was registered with ClinicalTrials.gov (NCT04005170). With a median follow-up of 44.3 months (IQR 40.8-46.1), the 3-year OS and PFS rates were 44.8% (95% CI 31.9-62.8) and 35.7% (95% CI 23.8-53.6), respectively. Patients who failed to achieve a clinical complete response (CR) demonstrated significantly worse OS (hazard ratio [HR]=13.73, 95% CI 4.43-42.54, P<0.0001) and PFS (HR=32.08, 95% CI 8.57-120.10, P<0.0001). Disease recurrence occurred in 23 of 42 patients (55%), with recurrences being earlier and more frequent in the non-CR group compared to the CR group. Patients experiencing irAEs showed a significantly higher CR rate (72% vs. 39%, P=0.082) and better PFS (HR=0.43, 95% CI 0.19-0.93, P=0.027) than those without irAEs. GON4L mutation was associated with a lower incidence of irAEs (P=0.036). The updated survival outcomes confirmed the efficacy of toripalimab plus definitive CRT in locally advanced ESCC. Moreover, the development of irAEs may predict a more favourable prognosis. National Natural Science Foundation of China, Beijing Xisike Clinical Oncology Research Foundation, and Sci-Tech Project Foundation of Guangzhou.

Sabatolimab in combination with spartalizumab in patients with non-small cell lung cancer or melanoma who received prior treatment with anti-PD-1/PD-L1 therapy: a phase 2 multicentre study

ObjectiveThis study evaluates the safety/efficacy of sabatolimab plus spartalizumab in patients with melanoma or non-small cell lung cancer (NSCLC).Design, setting and participantsThis is a phase 1–1b/2, open-label, multinational, multicentre study...

Camrelizumab plus apatinib in patients with advanced or recurrent endometrial cancer after failure of at least one prior systemic therapy (CAP 04): a single-arm phase II trial

BackgroundThe combination of anti-programmed death 1 (PD-1) inhibitors and tyrosine kinase inhibitors is an effective treatment strategy in endometrial cancer. We aimed to explore the efficacy and safety of camrelizumab plus apatinib as an alternative therapeutic option in patients with previously treated endometrial cancer.MethodsThis single-arm Simon’s two-stage phase II trial was conducted at the Fudan University Shanghai Cancer Center. Patients with advanced or recurrent endometrial cancer who had failed at least one prior systemic therapy were screened for potential participation. Eligible patients were treated with intravenous camrelizumab (200 mg d1 q2w) and oral apatinib (250 mg qd) every 4 weeks. The primary end point was the objective response rate (ORR) per RECIST v1.1 in the intention-to-treat principle.ResultsBetween January 20, 2020, and October 14, 2022, 36 patients (29 with microsatellite stability/mismatch repair proficient [MSS/pMMR] tumors; two with microsatellite instability-high/mismatch repair deficient [MSI-H/dMMR] tumors) were enrolled and treated. The confirmed ORR was 44.4% (95% CI: 27.9, 61.9) and the disease control rate was 91.7% (95% CI: 77.5, 98.2). The median duration of response was 9.3 (95% CI: 4.3, not reached) months, the median progression-free survival was 6.2 (95% CI: 5.3, 11.1) months, and the median overall survival was 21.0 (95% CI: 13.4, not reached) months during a median follow-up of 14.2 (interquartile range: 10.3, 27.6) months. Treatment-related adverse events of grade 3 or 4 occurred in 20 (55.6%) patients, with the most common being increased γ-glutamyl transferase (27.8%), alanine aminotransferase (16.7%) and aspartate aminotransferase (13.9%), and hypertension (11.1%). No treatment-related death occurred.ConclusionsCamrelizumab plus apatinib showed promising antitumor activity with manageable toxicity in patients with advanced or recurrent endometrial cancer who had failed at least one prior systemic therapy. The findings of this study support further investigation of camrelizumab plus apatinib as an alternative therapeutic option, especially for patients with MSS/pMMR tumors.Trial registrationThis trial was retrospectively registered with ChiCTR.org.cn, number ChiCTR2000031932.

In vivo fluorescence flow cytometry reveals that the nanoparticle tumor vaccine OVA@HA-PEI effectively clears circulating tumor cells

Tumor vaccine therapy offers significant advantages over conventional treatments, including reduced toxic side effects. However, it currently functions primarily as an adjuvant treatment modality in clinical oncology due to limitations in tumor antigen selection and delivery methods. Tumor vaccines often fail to elicit a sufficiently robust immune response against progressive tumors, thereby limiting their clinical efficacy. In this study, we developed a nanoparticle-based tumor vaccine, OVA@HA-PEI, utilizing ovalbumin (OVA) as the presenting antigen and hyaluronic acid (HA) and polyethyleneimine (PEI) as adjuvants and carriers. This formulation significantly enhanced the proliferation of immune cells and cytokines, such as CD3, CD8, interferon-[Formula: see text], and tumor necrosis factor-[Formula: see text], in vivo, effectively activating an immune response against B16–F10 tumors. In vivo fluorescence flow cytometry (IVFC) has already become an effective method for monitoring circulating tumor cells (CTCs) due to its direct, noninvasive, and long-term detection capabilities. Our study utilized a laboratory-constructed IVFC system to monitor the immune processes induced by the OVA@HA-PEI tumor vaccine and an anti-programmed death-1 (PD-1) antibody. The results demonstrated that the combined treatment of OVA@HA-PEI and anti-PD-1 antibody significantly improved the survival time of mice compared to anti-PD-1 antibody treatment alone. Additionally, this combination therapy substantially reduced the number of CTCs in vivo, increased the clearance rate of CTCs by the immune system, and slowed tumor progression. These findings greatly enhance the clinical application prospects of IVFC and tumor vaccines.

Surufatinib plus toripalimab in advanced soft tissue sarcoma (STS): Results from a multicenter, single-arm, basket study.

42 Background: Soft tissue sarcomas (STS) are highly malignant despite their low incidence and prone to recurrence, with limited therapeutic options after failure of first-line treatment. Several antiangiogenic monotherapies have shown some efficacy but limited benefit. The open-label, multi-cohort, single-arm, basket study was performed to evaluate the efficacy and safety of the combination of surufatinib (a small-molecule inhibitor of VEGFR 1-3, FGFR1 and CSF-1R) with toripalimab (an anti-programmed death 1 [PD-1] antibody) for Chinese patients (pts) with advanced solid tumors. Here, we reported the results from the STS cohort. Methods: Pts with STS who had progressed on ≤ 2 lines of systemic chemotherapy, or were intolerant to standard treatment, or for whom there was currently no effective therapy were eligible. They received 21-day cycles of surufatinib 250 mg orally, once daily, plus toripalimab 240 mg intravenously, once every 3 weeks, until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Results: As of data cutoff (Feb 28, 2023), a total of 20 pts (incl. 4 treatment-naïve pts) were enrolled and received the combination treatment (mean duration: 5.81 months [m]). Median (range) age was 50 (23-74) years, 10 pts were male, 17 pts were TNM stage IV. The pathological types include leiomyosarcoma (n=4, incl. 1 naïve patient), synovial sarcoma (n=4), alveolar soft part sarcoma (n=3, incl. 2 naïve pts), undifferentiated pleomorphic sarcoma (n=3), liposarcoma (n=2, incl. 1 naïve patient) and fibrosarcoma (n=1), malignant fibrous histiocytoma (n=1) and others (n=2). Seven (35%) pts had PD-L1 combined positive score of ≥1. The median follow-up duration was 27.14 m. Confirmed ORR and disease control rate (DCR) for 19 efficacy-evaluable pts was 10.5% and 68.4%, respectively; median duration of response was 7.05m. The median progression-free survival (mPFS) and median overall survival (mOS) was 2.69 m and 16.23 m for all dosed pts. For 16 previously treated pts, ORR and DCR was 6.3% and 62.5% respectively; median duration of response (DoR) was 7.13 m; mPFS was 2.65 m; mOS was 14.32 m. 18 (90%) pts experienced at least one treatment-related adverse event (TRAE), and 7 (35%) of them reported grade ≥3 TRAEs. The incidence of immune-related adverse events (irAEs) was 70%, only 2 pts had grade ≥3 irAEs, which were immune-related pancreatitis and immune-related diabetes. 2 pts were permanently discontinued due to TRAEs, which were grade 2 renal impairment and grade 3 hyperglycemia. No new safety signals were observed. Conclusions: Surufatinib plus toripalimab had a promising antitumor activity and a manageable safety profile in pts with advanced STS. Clinical trial information: NCT04169672 .

The development of anti-PD-1 antibody-induced spinal cord injury in bone marrow transplant C57BL/6 Rag1-/- mouse model.

Aims: This paper was to scrutinize the toxicity mechanism of anti-programmed death 1 (anti-PD-1) therapy-caused spinal cord injury (SCI).Methods: Bone marrow transplant Rag1-/- mice were used to establish SCI model.Results: Anti-PD-1 results in SCI via CD8+ T-cells activation, while excessive activation of CD8+ T-cells further aggravated SCI. Both anti-PD-1 and the activation of CD8+ T-cells induced the expression of apoptosis-related perforin, GrB and FasL, but suppressed PI-9 level. The opposite results were observed in the effects of neuroserpin on these factors. CD8+ T-cells activation induced neurotoxicity via upregulation perforin, GrB and FasL and inhibiting PI-9. Additionally, neuroserpin suppressed CD8+ T-cells activation via perforin/GrB/PI-9/FasL pathways.Conclusion: These results may provide theoretical foundation for the clinical treatment of SCI caused by anti-PD-1.

The Development of Persistent Gastrointestinal Symptoms in Patients With Melanoma Who Have Had an Immune Checkpoint Inhibitor-Related Gastrointestinal Toxicity.

Immune-related adverse events (irAE) secondary to immune checkpoint inhibitors (ICI) have gastrointestinal (GI) manifestations, including gastritis, enteritis, and/or colitis. The long-term sequelae of ICI-associated GI toxicities (GI-irAE), particularly the development of disorders of gut-brain interaction, are not well known. We characterized the incidence of persistent GI symptoms after GI-irAE. This is a retrospective study of adults with melanoma treated with ICI and diagnosed with GI-irAE at our institution from 2013 to 2021. All patients had endoscopic and histologic evidence of GI-irAE. The primary outcome was incidence of persistent GI symptoms (diarrhea, abdominal pain, bloating, constipation, fecal incontinence, nausea, vomiting) after resolution of GI-irAE. Hazard ratios evaluated the association between parameters and time to persistent GI symptoms. One hundred four patients with melanoma (90% stage IV disease) and GI-irAE met inclusion criteria. Thirty-four percent received anti-cytotoxic T lymphocyte-associated protein-4 therapy, 33% anti-programmed death-1, and 34% dual therapy. Patients were treated for GI-irAE for an average of 9 ± 6 weeks. Twenty-eight (27%) patients developed persistent GI symptoms 1.6 ± 0.8 years after GI-irAE. The most common symptom was constipation (17%), followed by bloating (8%) and diarrhea (5%). Over 453 person-years, the incident rate was 6.2% per 100 person-years. Use of cytotoxic T lymphocyte-associated protein-4 single or dual therapy was associated with a 3.51× risk of persistent GI symptoms (95% confidence interval 1.20-10.23). In this cohort of melanoma patients who experienced GI-irAE, 26% developed persistent GI symptoms, most frequently constipation. Future studies should characterize the GI sequelae after GI-irAE, which may shed light on disorders of gut-brain interaction pathogenesis and improve the lives of cancer survivors.

Concerning Safety and Efficacy of Concurrent and Consolidative Durvalumab With Thoracic Radiation Therapy in PDL1-Unselected Stage III Non-Small Cell Lung Cancer: Brief Report

IntroductionConsolidative durvalumab, an anti-programmed death ligand 1 (PDL1) immune checkpoint inhibitor, administered after concurrent chemoradiation improves outcomes of patients with locally advanced non-small cell lung cancer (NSCLC) without substantially increasing toxicities. We studied a chemotherapy-free regimen of thoracic radiotherapy (RT) with concurrent and consolidative durvalumab. MethodsThis single-arm phase II trial enrolled patients with stage III NSCLC (regardless of tumor PDL1 expression), performance status ECOG 0-1, adequate pulmonary function, and RT fields meeting standard organ constraints. Participants received two cycles of durvalumab (1500 mg every 4 weeks) concurrently with thoracic RT (60 Gy in 30 fractions), followed by up to 13 cycles of consolidative durvalumab. ResultsAfter 10 patients were enrolled, the trial was closed due to poor clinical outcomes. With a median follow-up of 12 months, five patients had disease progression and eight patients died. Six patients experienced 15 treatment-related, grade ≥3 events, including one grade 4 acute kidney injury during consolidation and two fatal pulmonary events. One fatal pulmonary event occurred during the concurrent phase in an active smoker; the other occurred after the first cycle of consolidative durvalumab. The primary endpoint of progression-free survival (PFS) at 12 months was 20% (50% for PDL1≥1% versus 0% for PDL1 unavailable or <1%). Median overall survival (OS) was not reached, 10.5 months, and 7 months, for PDL1 ≥1%, <1%, and unavailable, respectively. ConclusionsIn PDL1 unselected stage III NSCLC, thoracic RT plus concurrent and consolidative durvalumab is associated with high-grade toxicity and early disease progression.

Fecal microbiota transplantation improves anti-PD-1 inhibitor efficacy in unresectable or metastatic solid cancers refractory to anti-PD-1 inhibitor

The gut microbiome significantly influences immune responses and the efficacy of immune checkpoint inhibitors. We conducted a clinical trial (NCT04264975) combining an anti-programmed death-1 (PD-1) inhibitor with fecal microbiota transplantation (FMT) from anti-PD-1 responder in 13 patients with anti-PD-1-refractory advanced solid cancers. FMT induced sustained microbiota changes and clinical benefits in 6 of 13 patients, with 1 partial response and 5 stable diseases, achieving an objective response rate of 7.7% and a disease control rate of 46.2%. The clinical response correlates with increased cytotoxic Tcells and immune cytokines in blood and tumors. We isolated Prevotella merdae Immunoactis from a responder to FMT, which stimulates Tcell activity and suppresses tumor growth in mice by enhancing cytotoxic Tcell infiltration. Additionally, we found Lactobacillus salivarius and Bacteroides plebeius may inhibit anti-tumor immunity. Our findings suggest that FMT with beneficial microbiota can overcome resistance to anti-PD-1 inhibitors in advanced solid cancers, especially gastrointestinal cancers.

Determinants of resistance and response to melanoma therapy.

Metastatic melanoma is among the most enigmatic advanced cancers to clinically manage despite immense progress in the way of available therapeutic options and historic decreases in the melanoma mortality rate. Most patients with metastatic melanoma treated with modern targeted therapies (for example, BRAFV600E/K inhibitors) and/or immune checkpoint blockade (for example, anti-programmed death 1 therapy) will progress, owing to profound tumor cell plasticity fueled by genetic and nongenetic mechanisms and dichotomous host microenvironmental influences. Here we discuss the determinants of tumor heterogeneity, mechanisms of therapy resistance and effective therapy regimens that hold curative promise.

Synergistic action of gemcitabine and celecoxib in promoting the antitumor efficacy of anti-programmed death-1 monoclonal antibody by triggering immunogenic cell death.

Emerging evidence suggests that immunogenic chemotherapy not only kills tumor cells but also improves the immune-suppressive tumor microenvironment by inducing immunogenic cell death (ICD), leading to sustained anti-tumor effects. The lack of ICD inducers explored in lung cancer necessitates investigation into new inducers for this context, therefore, this study aims to explore whether the gemcitabine (GEM) and celecoxib can activate the immunogenic chemotherapy progress in lung cancer tissue. We assessed five chemotherapeutic agents for their ability to trigger ICD using ex vivo and in vivo experiments, including western blotting (WB), flow cytometry, and tumor preventive vaccine assays. Additionally, we evaluated the synergistic effects of GEM, celecoxib, and anti-programmed death 1 monoclonal antibody (aPD-1) in tumor-bearing mice to understand how GEM activates antitumor immunity and enhances immunochemotherapy. GEM was identified as an effective ICD inducer, showing high expression of calreticulin (CRT) and heat shock protein 90 (HSP90). Co-culture with GEM-treated cells [Lewis lung carcinoma (LLC) and CMT-64] enhanced dendritic cell (DC) activity, evidenced by maturation markers and increased phagocytic capacity. Moreover, celecoxib was found to enhance ICD by reducing indoleamine 2,3-dioxygenase 1 (IDO1) expression and increasing reactive oxygen species (ROS)-based endoplasmic reticulum (ER) stress. The combination therapy [GEM, celecoxib, and aPD-1 (GCP)] exhibited potent and sustained antitumor activity in immunocompetent mice, with enhanced recruitment of tumor-infiltrating lymphocytes. These findings support the potential use of GCP therapy as a treatment option for lung cancer patients.

Immunomodulatory effects of antiangiogenic tyrosine kinase inhibitors in renal cell carcinoma models: Impact on following anti-PD-1 treatments

The approval of immune checkpoint inhibitors (ICIs) has revolutionized the management of metastatic renal cell carcinoma (RCC), introducing several ICI-based combinations as the new standard of care for affected patients. Nonetheless, monotherapy with antiangiogenic tyrosine kinase inhibitors (TKIs), such as pazopanib or sunitinib, still represents a first-line treatment option for selected patients belonging to the favorable risk group according to the International mRCC Database Consortium (IMDC) model. After TKI monotherapy, the main second-line option is represented by ICI monotherapy with the anti-Programmed Death Receptor 1(PD-1) nivolumab.To date, the expected clinical outcomes are similar with pazopanib or sunitinib and there is no clear indication for selecting one TKI over the other. Moreover, their impact on subsequent ICI treatment outcomes is not well defined, yet.Based on these premises, we investigated the immunomodulatory activity of these drugs in vitro and in vivo.Both TKIs induced Programmed Cell Death Ligand-1 (PD-L1) expression and soluble PD-L1 release in RCC cells, and hampered T cell activation, reducing cytokine production and the proportion of activated T cells. Nevertheless, in a syngeneic co-culture system with peripheral blood mononuclear cells (PBMCs) and tumor cells, incubation with anti-PD-1 antibody following TKIs treatment significantly restored T cell function, potentiating the cytotoxic effects against tumor cells. Pazopanib and sunitinib followed by anti-PD-1 antibody produced a comparable inhibition of tumor growth in a RCC syngeneic mouse model. Our findings suggest that pazopanib and sunitinib, showing similar immunomodulatory effects, may have a comparable impact on the subsequent effectiveness of PD-1/PD-L1 blockade.