PD-1 Immune Checkpoint Inhibitor Research Articles

Lactylated Apolipoprotein C-II Induces Immunotherapy Resistance by Promoting Extracellular Lipolysis.

Mortality rates due to lung cancer are high worldwide. Although PD-1 and PD-L1 immune checkpoint inhibitors boost the survival of patients with non-small-cell lung cancer (NSCLC), resistance often arises. The Warburg Effect, which causes lactate build-up and potential lysine-lactylation (Kla), links immune dysfunction to tumor metabolism. The role of non-histone Kla in tumor immune microenvironment and immunotherapy remains to be clarified. Here, global lactylome profiling and metabolomic analyses of samples from patients with NSCLC is conducted. By combining multi-omics analysis with in vitro and in vivo validation, that intracellular lactate promotes extracellular lipolysis through lactyl-APOC2 is revealed. Mechanistically, lactate enhances APOC2 lactylation at K70, stabilizing it and resulting in FFA release, regulatory T cell accumulation, immunotherapy resistance, and metastasis. Moreover, the anti-APOC2K70-lac antibody that sensitized anti-PD-1 therapy in vivo is developed. This findings highlight the potential of anti lactyl-APOC2-K70 approach as a new combination therapy for sensitizing immunotherapeutic responses.

Efficacy and Safety of Re-Challenging PD-1 Inhibitors in Second-Line Treatment in Metastatic Nasopharyngeal Carcinoma Previously Treated with Chemotherapy and PD-1 Inhibitors.

We aim to evaluate the efficacy and safety of anti-PD1 rechallenge in combination with chemotherapy in patients with metastatic nasopharyngeal carcinoma (mNPC) who have progressed on prior anti-PD1 therapy. We enrolled patients with mNPC who received chemotherapy combined with PD-1 immune-checkpoint inhibitors (ICIs) or chemotherapy alone after prior progression of anti-PD1 therapy. The primary endpoint was progress-free survival (PFS), and the secondary endpoints included overall survival (OS), disease control rate (DCR) and objective response rate (ORR). A total of 96 patients were eligible between January 2015 and December 2020. Thirty-seven (38.5%) were in the PD-1 ICIs re-challenge group, while the remaining 59 patients (61.5%) were in the chemotherapy group. The ORR and DCR of PD-1 ICIs group and chemotherapy group were 37.8% vs 23.7% and 86.5% vs.74.5%, respectively. After a median follow-up period of 21.1 months (IQR 16.1-28.7), the log-rank analysis demonstrated a significantly improved PFS in the PD-1 ICIs re-challenge group compared to the chemotherapy group (8.4 months [95% CI 4.3-14.0] vs 5.0 months [95% CI 2.8-7.2], P = 0.03). However, no significant difference in OS was observed between the two groups (28.3 vs 24.1 months, P = 0.09). The two groups had similar adverse reactions, but the incidence of grade 3 or 4 thrombocytopenia was significantly higher in the PD-1 ICIs re-challenge group (18.9% vs 3.4%, P = 0.025). mNPC patients who progressed from prior anti-PD1 therapy could benefit from the anti-PD1 rechallenge in combination with chemotherapy. However, further validation is needed.

Phase 2 study of livmoniplimab in combination with budigalimab in patients with hepatocellular carcinoma.

TPS4189 Background: Patients (pts) with hepatocellular carcinoma (HCC) often present with unresectable advanced/metastatic disease and have a poor prognosis. Gene expression profiles of HCC tumors suggest transforming growth factor (TGF)-β signaling as a possible mechanism of immune escape. First-in-class monoclonal antibody (mAb) livmoniplimab (livmo; ABBV-151) targets the GARP–TGF-β1 complex and prevents release of active TGF-β1. Budigalimab (budi) is an anti–PD-1 immune checkpoint inhibitor (ICI) mAb. Promising clinical activity was seen with livmo + budi in a phase 1 study (NCT03821935); overall response rate=42% (5/12; n=4 per RECIST v1.1, n=5 per iRECIST) in pts with advanced HCC that progressed on/after a first-line (1L) systemic therapy not including a PD-1/PD-L1 inhibitor. Approved ICI combinations have low response rates of ~20–30% in pts with 1L HCC; most will eventually experience relapse and require additional treatment options. This phase 2 trial will investigate dosing, safety, and efficacy of livmo + budi in pts with locally advanced/metastatic HCC that progressed after a 1L ICI-containing regimen. Methods: This open-label, randomized study (EU CT: 2022-502948-13-00) will enroll pts ≥18 years with locally advanced/metastatic HCC, evaluable or measurable disease per RECIST v1.1, Child-Pugh A, ECOG PS ≤1, who experienced failure of an ICI-containing regimen in 1L HCC and completed a ≥28-day washout period for prior systemic treatment. Pts with active/untreated central nervous system metastases will be excluded. Primary objectives include identifying the optimal livmo dose in combination with budi and determining the recommended phase 3 dose (RP3D), and evaluating efficacy (best overall response rate) of livmo + budi. Secondary and exploratory objectives are to evaluate efficacy (duration of response, progression-free survival, overall survival), safety, tolerability, immunogenicity, pharmacokinetics/pharmacodynamics (PK/PD), predictive biomarkers, and pt-reported symptoms and tolerability. Pts (n=120) will be randomized 1:1:1 to receive 400mg sorafenib BID/8-12mg lenvatinib QD orally (control; investigator choice), low- or high-dose IV livmo (selected based on mode of action, clinical efficacy and safety, and clinical PK/PD modeling) + IV budi Q3W in 21-day cycles. Pts will be treated until confirmed disease progression, other discontinuation criteria are met, or for 2 years (whichever comes first). A nonbinding futility interim analysis will be conducted after 60 pts (20 per cohort) are enrolled and had ≥2 tumor assessments, a primary analysis at ≥4 months after first dosing of the last enrolled pt, and the final analysis at completion of a 90-day safety follow-up after ≤2 years of study treatment. The RP3D for livmo will be selected based on all available preclinical and clinical data. Enrollment began in July 2023 and up to 60 sites in ~7 countries will be included. Clinical trial information: 2022-502948-13-00.

Randomized phase II trial of pembrolizumab/lenvatinib (P+L) +/- responder fecal microbiota transplant (R-FMT) in PD-1 relapsed/refractory (R/R) cutaneous melanoma (MEL).

TPS9607 Background: A significant portion of patients (pts) with advanced MEL develop resistance to immune checkpoint inhibitors (ICI). The gut microbiome is a major tumor-extrinsic regulator of ICI response. In mice, gut microbiota modulate therapeutic activity of ICI, and administration of certain gut commensals or responder-derived fecal microbiota transplantation (R-FMT) promotes anti-PD-1 efficacy in melanoma-bearing mice. In the LEAP-004 trial, P+L produced 21% ORR in PD-1 R/R MEL with Gr3+ TRAE 45.6%. Longitudinal analyses of gut microbiome samples from ICI-treated cancer pts suggests key species including Actinobacteria and Firmicutes are associated with favorable response. We and others have previously demonstrated that microbiome modulation using R-FMT reversed PD-1 non-response in PD-1 R/R MEL. In PD-1 naïve MEL, healthy donor FMT (hdFMT) augments benefit of PD-1 monotherapy. We hypothesized that intestinal dysbiosis mediates PD-1 resistance in PD-1 R/R MEL, microbiome modulation may reverse TKI toxicity, and that R-FMT may resensitize MEL to PD-1 blockade. Methods: This is an investigator-initiated, randomized, phase II trial of P+L vs. P+L+R-FMT in PD-1 R/R MEL. Pts must have measurable disease per RECIST v1.1, no active CNS metastases (or if present, previously treated and stable on repeat imaging), and no contraindications to FMT administration. R-FMT is derived from non-obese, advanced MEL with durable response (mPFS ≥24 months) following prior PD-1 ICI, with no recent (≤1 month) antibiotic exposure. Donors are screened broadly for infectious agents including SARS-CoV-2 using bookend screening. R-FMT is processed to make fecal infusates and orally bioavailable capsules. Eligible pts are randomized 1:1 to either P+L [P 200mg every 3 weeks (Q3W) along with L 20mg orally once daily] or P+L+R-FMT. R-FMT is administered endoscopically on D1, and D42, and thereafter via capsules until progression or unacceptable toxicity. Response is assessed at D73, and thereafter Q12W. Pts undergo biopsies at baseline and W8, with optional biopsy at progression. Primary endpoint: ORR assessed using RECIST v1.1 by Blinded Independent Central Review (BICR). Secondary endpoints include: safety, progression-free survival (PFS), overall survival (OS), and landmark PFS/OS. Key translational endpoints include immune activation (tumor tissue, blood), metagenomic engraftment, and transcriptomic analyses of intestinal luminal myeloid cells and exfoliome. The null hypothesis that the true ORR is 20% will be tested versus a one-sided alternative hypothesis of ≥50%. This design has a type I error rate 0.10 and power 0.8 when the true response rate is 0.25. Enrollment has commenced. Clinical trial information: NCT06030037 .

Clinical Outcomes and Molecular Predictors of Pembrolizumab (Keytruda) as a PD-1 Immune Checkpoint Inhibitor in Advanced and Metastatic Cervical Cancer: A Systematic Review and Meta-Analysis

This systematic review evaluates the clinical outcomes and molecular predictors of response to pembrolizumab in patients with advanced and metastatic cervical cancer. We adhered to the PRISMA guidelines for systematic reviews, conducting a database search in PubMed, Scopus, and Embase. The eligibility criteria centered on clinical outcomes, including the overall survival (OS), progression-free survival (PFS), and immune-related biomarkers post-pembrolizumab therapy. We included both prospective and retrospective studies that detailed clinical outcomes and molecular characteristics predictive of therapeutic response. Our search yielded six studies involving 846 patients treated with pembrolizumab from 2017 to 2022. The meta-analysis of these studies showed that pembrolizumab, used as monotherapy or in combination with chemotherapy, extended the OS by a weighted median of 10.35 months and the PFS by 8.50 months. The treatment demonstrated a pooled objective response rate (ORR) of 22.39%, although the I2 test result of 67.49% showed a high heterogeneity among the studies. Notably, patients with high PD-L1 expression (CPS ≥ 10) experienced improved outcomes in terms of the PFS and OS. The most common complications were fatigue, diarrhea, and immune-related adverse events. Pembrolizumab significantly enhances clinical outcomes in metastatic cervical cancer, particularly among patients with high PD-L1 expression. The drug maintains a good safety profile, reinforcing its treatment potential for patients with advanced and metastatic cervical cancer. Future studies should explore long-term effects and strategies to integrate pembrolizumab optimally into current treatment regimens, aiming to maximize patient benefits and effectively manage side effects.

Immunotherapy in Non-Small Cell Lung Cancer (NSCLC): Chance and Challenge

Non-small cell lung cancer (NSCLC) is the major type of lung cancer, accounting for 85%. The common options for treatment include surgery, radiotherapy, chemotherapy, immunotherapy, and molecularly targeted therapy depending on the stage, histology, genetic changes, and health condition of patients. Sadly, just 15% of individuals with stage III NSCLC are still alive after five years, which indicates a bad outlook. Because of the use of PD-1 and CTLA-4 immune checkpoint inhibitors (ICIs), immunotherapy has unquestionably made the most progress in the field of NSCLC. This article offers a comprehensive exploration of NSCLC, encompassing its epidemiological characteristics, pathological processes of different classification, and the diverse treatment modalities available. It emphasizes the pivotal role of immunotherapy, particularly immune checkpoint inhibitors (ICIs) for treatment some classification of patients. The article discusses challenges and prospects, such as identifying patient populations that benefit most from immunotherapy and addressing issues like immune-related adverse events (irAEs) and immune resistance. Through this analysis, the article underscores the significant strides made in NSCLC treatment and the ongoing efforts to improve patient outcomes.

Abstract 4512: Discovery of highly potent, selective, and orally bioavailable IKZF2 degrader and its anti-tumor activity in syngeneic mouse models

Abstract Molecular glue degraders (MGDs) are emerging as innovative therapeutic modalities, owing to their efficacy in targeting previously undruggable targets. MGDs induce close proximity between the target protein and E3 ligase, resulting in the degradation of the target protein. In the wake of the remarkable success of PD-1/PD-L1 inhibitors, various approaches to modulate the activity of regulatory T cells (Tregs) activity have been explored. Tregs represent the primary immune suppressor and significantly impede antitumor immune responses. IKZF2, a marker of stable suppressive Treg, is essential for maintaining the stable Treg cell phenotype. Depletion of IKZF2 can induce a transition from Treg to effector T cell (Teff) phenotypes, thereby enhancing anti-tumor responses. Leveraging an Immunomodulatory drug (IMiD), Novartis has developed the IKZF2 degrader DKY709, which is currently undergoing Phase I clinical trials, both as a monotherapy and in combination with a PD-1 immune checkpoint inhibitor. In this presentation, we present the preclinical results of the best-in-class IKZF2 degrader, PRT-101. PRT-101 elicits rapid and robust degradation of IKZF2, demonstrating subnanomolar DC50 and achieving 100% Dmax in a proteasome- and CRBN-dependent manner. However, PRT-101 does not induce the degradation of well-known neosubstrates, including IKZF1, IKZF3, SALL4, and CK1a. Global proteomic analysis reveals that PRT-101 exclusively facilitates IKZF2 degradation. The degradation of IKZF2 by PRT-101results in an increase in IL-2 secretion, a marker of T effector function. Furthermore, oral administration of PRT-101 exhibits excellent pharmacokinetics, concurrent with IKZF2 degradation, yielding superior anti-tumor effects compared to DKY709 in the MC38 mouse syngeneic model. In conclusion, our findings underscore the potential of the novel IKZF2 degrader as a promising immuno-oncology target for the treatment of solid tumors. Citation Format: Seulki Park, Jeong Hee Moon, Gaseul Lee, Hyun Jin Kim, Jeong-Hoon Kim, Jong Yeon Hwang. Discovery of highly potent, selective, and orally bioavailable IKZF2 degrader and its anti-tumor activity in syngeneic mouse 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 4512.

A Comparison of Spatial and Phenotypic Immune Profiles of Pancreatic Ductal Adenocarcinoma and Its Precursor Lesions.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a 5-year survival rate of 12.5%. PDAC predominantly arises from non-cystic pancreatic intraepithelial neoplasia (PanIN) and cystic intraductal papillary mucinous neoplasm (IPMN). We used multiplex immunofluorescence and computational imaging technology to characterize, map, and compare the immune microenvironments (IMEs) of PDAC and its precursor lesions. We demonstrate that the IME of IPMN was abundantly infiltrated with CD8+ T cells and PD-L1-positive antigen-presenting cells (APCs), whereas the IME of PanIN contained fewer CD8+ T cells and fewer PD-L1-positive APCs but elevated numbers of immunosuppressive regulatory T cells (Tregs). Thus, immunosuppression in IPMN and PanIN seems to be mediated by different mechanisms. While immunosuppression in IPMN is facilitated by PD-L1 expression on APCs, Tregs seem to play a key role in PanIN. Our findings suggest potential immunotherapeutic interventions for high-risk precursor lesions, namely, targeting PD-1/PD-L1 in IPMN and CTLA-4-positive Tregs in PanIN to restore immunosurveillance and prevent progression to cancer. Tregs accumulate with malignant transformation, as observed in PDAC, and to a lesser extent in IPMN-associated PDAC (IAPA). High numbers of Tregs in the microenvironment of PDAC went along with a markedly decreased interaction between CD8+ T cells and cancerous epithelial cells (ECs), highlighting the importance of Tregs as key players in immunosuppression in PDAC. We found evidence that a defect in antigen presentation, further aggravated by PD-L1 expression on APC, may contribute to immunosuppression in IAPA, suggesting a role for PD-L1/PD-1 immune checkpoint inhibitors in the treatment of IAPA.

A murine model to evaluate immunotherapy effectiveness for human Fanconi anemia-mutated acute myeloid leukemia.

Fanconi anemia (FA)-mutated acute myeloid leukemia (AML) is a secondary AML with very poor prognosis and limited therapeutic options due to increased sensitivity to DNA-damaging agents. PD-1 immune checkpoint inhibitors upregulate T-cell killing of cancer cells and is a class of promising treatment for FA-AML. Here, we developed a novel FA-AML murine model that allows the study of human AML with a humanized immune system in order to investigate immunotherapeutic treatments in vivo. FA-AML1 cells and non-FA-mutated Kasumi-1 cells were injected into 8-10 week old NSG mice. Once leukemic engraftment was confirmed by HLA-DR expression in the peripheral blood, human peripheral blood mononuclear cells (hPBMCs) were injected into the mice. One week post-hPBMCs injection, Nivolumab (PD-1 inhibitor) or PBS vehicle control was administered to the mice bi-weekly. In our Nivolumab treated mice, FA-AML1, but not Kasumi-1-engrafted mice, had significantly prolonged overall survival. Both FA-AML1 and Kasumi-1 engrafted mice had decreased spleen weights. Higher leukemic infiltration into vital organs was observed in FA-AML1 engrafted mice compared to Kasumi-1 engrafted mice. In conclusion, our novel humanized murine model of FA-mutated AML is an attractive tool for supporting further studies and clinical trials using PD-1 inhibitors to treat FA-mutated AML.

Zanzalintinib (XL092) plus atezolizumab versus regorafenib in previously treated MSS/MSI-low metastatic colorectal cancer (mCRC): The randomized phase 3 STELLAR-303 study.

TPS229 Background: Patients with microsatellite stable/microsatellite instability-low (MSS/MSI-low) mCRC account for ~95% of mCRC cases, and there is a significant unmet need in patients with treatment-refractory MSS/MSI-low mCRC. Although immune checkpoint inhibitors (ICIs) have shown limited activity in this patient population, the addition of tyrosine kinase inhibitors (TKIs) may increase sensitivity to ICIs by promoting an immune-permissive tumor microenvironment. Furthermore, TKI-ICI combinations have demonstrated encouraging clinical activity in patients with mCRC, particularly in subgroups of patients without liver metastases (LM). Most recently, in the phase 3 LEAP-017 study of patients with non–MSI-high/mismatch repair deficient (dMMR) mCRC, although pembrolizumab + lenvatinib did not improve overall survival (OS) vs standard of care, subgroup analysis suggested the potential for clinical benefit in patients without LM (Kawazoe et al, ESMO-WCGI 2023). Zanzalintinib is a novel multi-kinase inhibitor targeting VEGFR, MET, and the TAM kinases (TYRO3, AXL, MER). In a phase 1 study, zanzalintinib alone and in combination with atezolizumab (an anti–PD-L1 ICI) showed preliminary anti-tumor activity and a manageable safety profile across multiple tumor types (Sharma et al, ESMO 2022). Methods: STELLAR-303 (NCT05425940) is a global, randomized, open-label phase 3 study to assess the efficacy and safety of zanzalintinib + atezolizumab versus regorafenib in adult patients with MSS/MSI-low mCRC. Patients must have documented MSI/MMR status (non–MSI-high/dMMR) and RAS status by tissue-based analysis, measurable disease per RECIST v1.1, ECOG PS 0 or 1, and radiographic progression during/after or intolerance to standard of care treatments for mCRC. Prior regorafenib, trifluridine/tipiracil, or PD-L1/PD-1 ICIs are not allowed. Patients with or without active LM at baseline are eligible; those with definitively treated LM (includes surgical resection, microwave/radiofrequency ablation, or stereotactic body radiation therapy, but not yttrium-90 or chemoembolization alone) are considered to have non-active LM if treated ≥6 months before enrollment with no evidence of radiologic progression on subsequent imaging. Patients are randomized 1:1 to receive zanzalintinib + atezolizumab or regorafenib. Planned enrollment is 874 patients; number of patients with LM will be capped to ensure results of the study are relevant to the real-world mCRC population. Primary endpoint is OS in patients without LM. The key secondary efficacy endpoint is OS in all randomized patients. A hierarchical testing strategy will be employed for primary and key secondary endpoints. Safety will also be assessed. Enrollment is ongoing in the US, Europe, and Asia-Pacific region. Clinical trial information: NCT05425940 .

Combination of radiotherapy and immunotherapy for drug-resistant TNBC

Triple-negative breast cancer (TNBC) is a specific subtype, the most lethal and with the worst prognosis, and is prone to develop drug resistance during advanced chemotherapy. The combined application of radiotherapy and immunotherapy has gradually entered the public eye. The PD-L1 / PD-1 immune checkpoint inhibitors can enhance the local effect of radiotherapy and relieve the immunosuppressive effect in tumor patients, and the up-regulation of PD-L1 expression caused by radiotherapy also helps the checkpoint inhibitors to play a stronger effect. More patients with TNBC can gain a higher benefit from this.

PARP14 inhibition restores PD-1 immune checkpoint inhibitor response following IFNγ-driven acquired resistance in preclinical cancer models

Resistance mechanisms to immune checkpoint blockade therapy (ICBT) limit its response duration and magnitude. Paradoxically, Interferon γ (IFNγ), a key cytokine for cellular immunity, can promote ICBT resistance. Using syngeneic mouse tumour models, we confirm that chronic IFNγ exposure confers resistance to immunotherapy targeting PD-1 (α-PD-1) in immunocompetent female mice. We observe upregulation of poly-ADP ribosyl polymerase 14 (PARP14) in chronic IFNγ-treated cancer cell models, in patient melanoma with elevated IFNG expression, and in melanoma cell cultures from ICBT-progressing lesions characterised by elevated IFNγ signalling. Effector T cell infiltration is enhanced in tumours derived from cells pre-treated with IFNγ in immunocompetent female mice when PARP14 is pharmacologically inhibited or knocked down, while the presence of regulatory T cells is decreased, leading to restoration of α-PD-1 sensitivity. Finally, we determine that tumours which spontaneously relapse in immunocompetent female mice following α-PD-1 therapy upregulate IFNγ signalling and can also be re-sensitised upon receiving PARP14 inhibitor treatment, establishing PARP14 as an actionable target to reverse IFNγ-driven ICBT resistance.

Pegylated Liposomal Alendronate Biodistribution, Immune Modulation, and Tumor Growth Inhibition in a Murine Melanoma Model.

While tumor-associated macrophages (TAM) have pro-tumoral activity, the ablation of macrophages in cancer may be undesirable since they also have anti-tumoral functions, including T cell priming and activation against tumor antigens. Alendronate is a potent amino-bisphosphonate that modulates the function of macrophages in vitro, with potential as an immunotherapy if its low systemic bioavailability can be addressed. We repurposed alendronate in a non-leaky and long-circulating liposomal carrier similar to that of the clinically approved pegylated liposomal doxorubicin to facilitate rapid clinical translation. Here, we tested liposomal alendronate (PLA) as an immunotherapeutic agent for cancer in comparison with a standard of care immunotherapy, a PD-1 immune checkpoint inhibitor. We showed that the PLA induced bone marrow-derived murine non-activated macrophages and M2-macrophages to polarize towards an M1-functionality, as evidenced by gene expression, cytokine secretion, and lipidomic profiles. Free alendronate had negligible effects, indicating that liposome encapsulation is necessary for the modulation of macrophage activity. In vivo, the PLA showed significant accumulation in tumor and tumor-draining lymph nodes, sites of tumor immunosuppression that are targets of immunotherapy. The PLA remodeled the tumor microenvironment towards a less immunosuppressive milieu, as indicated by a decrease in TAM and helper T cells, and inhibited the growth of established tumors in the B16-OVA melanoma model. The improved bioavailability and the beneficial effects of PLA on macrophages suggest its potential application as immunotherapy that could synergize with T-cell-targeted therapies and chemotherapies to induce immunogenic cell death. PLA warrants further clinical development, and these clinical trials should incorporate tumor and blood biomarkers or immunophenotyping studies to verify the anti-immunosuppressive effect of PLA in humans.

Effect of X-ray irradiation combined with PD-1 inhibitor treatment on lung tissue injury in mice

PurposeTo determine the effect of X-ray irradiation combined with PD-1 immune checkpoint inhibitor administration on lung tissue injury in a mouse model and its potential mechanism. MethodsIn all, 20 C57BL/6J mice were randomly divided into four groups with five mice in each group: control group, PD-1 inhibitor group, irradiation group, and irradiation combined with PD-1 inhibitor group. Hematoxylin-eosin staining of the lung tissue was performed 30 days after the end of irradiation to evaluate the morphological and pathological changes in the tissue. Masson staining and analysis of hydroxyproline were used to evaluate the degree of pulmonary fibrosis. The levels of transforming growth factor-β1 (TGF-β1) and tumor necrosis factor α(TNF-α) were evaluated by Enzyme-Linked immunosorbent assay (ELISA). CD3+, CD4+, and CD8+ T lymphocytes in the lung tissue were detected by immunohistochemistry. The expression levels of TGF-β1, Smad3, cGAS, and STING in the lung tissue were evaluated by Western blotting. ResultsThe lung injury scores and pulmonary fibrosis indices in the irradiation group were higher than those in the control group. Meanwhile, lung pneumonia score, pulmonary fibrosis index, percentage of CD4 cells and expression of TGF-β1, p-Smad3, and STING in the lung tissue of mice in irradiation combined with PD-1 inhibitor group were higher than those in the other three groups. ConclusionLung injury and pulmonary fibrosis were induced by whole chest X-ray irradiation in mice, and PD-1 inhibitor could aggravate lung injury and pulmonary fibrosis in mice. Thus, radiotherapy combined with PD-1 inhibitors may affect the immune inflammatory microenvironment in the lung tissues of mice by activating TGF-β1/Samd3 and cGAS/STING signaling pathways, thus aggravating lung tissue damage induced by radiation.

An overview of current advances of PD-L1 targeting immuno-imaging in cancers.

The programmed death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) pathway plays a significant role in immune evasion. PD-1 or PD-L1 immune checkpoint inhibitors (ICIs) have become a standard treatment for multiple types of cancer. To date, PD-L1 has served as a biomarker for predicting the efficacy of ICIs in several cancers. The need to establish an effective detection method that could visualize PD-L1 expression and predict the efficacy of PD-1/PD-L1 ICIs has promoted a search for new imaging strategies. PD-L1-targeting immuno-imaging could provide a noninvasive, real-time, repeatable, dynamic, and quantitative assessment of the characteristics of all tumor lesions in individual patients. This study analyzed the existing evidence in the literature on PD-L1-based immuno-imaging (2015-2022). Original English-language articles were searched using PubMed and Google Scholar. Keywords, such as "PD-L1," "PET," "SPECT," "PET/CT," and "SPECT/CT," were used in various combinations. A total of nearly 50 preclinical and clinical studies of PD-L1-targeting immuno-imaging were selected, reviewed, and included in this study. Therefore, in this review, we conducted a study of the advances in PD-L1-targeting immuno-imaging for detecting the expression of PD-L1 and the efficacy of ICIs. We focused on the different types of PD-L1-targeting agents, including antibodies and small PD-L1-binding agents, and illustrated the strength and weakness of these probes. Furthermore, we summarized the trends in the development of PD-L1-targeting immuno-imaging, as well as the current challenges and future directions for clinical workflow.

The role of immune checkpoint inhibitors (ICI) as adjuvant treatment in renal cell carcinoma (RCC): A systematic review and meta-analysis.

Pembrolizumab, a PD-1 ICI is approved for the adjuvant treatment of postnephrectomy patients with clear cell RCC in some countries worldwide. However, recent negative data from randomized clinical trials (RCT) with another ICIs makes the benefit of this treatment uncertain. A systematic review and study-level meta-analysis was performed to evaluate the benefit of disease-free survival (DFS) with adjuvant ICI treatment for patients with localized and/or metastatic resected RCC. Using the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement, a systematic search was performed in PUBMED/MEDLINE, Scopus and EMBASE up to September 15, 2022. The statistical analysis was performed by ProMeta 3 software in intention-to-treat (ITT) population and in predetermined subgroups. Four RCT totalizing 3407 patients were included in this analysis. Systemic immunotherapy was pembrolizumab, atezolizumab, nivolumab, and ipilimumab plus nivolumab in 496, 390, 404, and 405 patients, respectively. In the ITT population there was a nonstatistically significant DFS benefit with adjuvant ICI (HR: 0.85, 95% CI: 0.69-1.04). Regarding the subgroups, there was a DFS benefit for PD-L1 positive (HR: 0.72; 95% CI: 0.55-0.94), intermediate-high risk patients (HR: 0.77; 95% CI: 0.63-0.94), and patients with sarcomatoid component (HR: 0.66; 95% CI: 0.43-0.99). This meta-analysis did not demonstrate a statistically significant DFS benefit in overall population, however considering the heterogeneity between the RCTs the use of adjuvant ICI should be individualized.

STELLAR-303: A phase 3 study of XL092 in combination with atezolizumab versus regorafenib in patients with previously treated metastatic colorectal cancer.

TPS3630 Background: Metastatic colorectal cancer (mCRC) is associated with poor prognosis and limited treatment options for patients who have progressed on first- and second-line chemotherapy. Regorafenib and trifluridine-tipiracil are approved in third- or later-line setting, but survival benefit is limited. Immune checkpoint inhibitor (ICI) therapy with nivolumab ± ipilimumab or single-agent pembrolizumab is approved in microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) mCRC; however, MSI-H mCRC is present in only ~5% patients. Phase 1/2 studies have evaluated the tyrosine kinase inhibitor (TKI) cabozantinib in combination with the ICIs atezolizumab and durvalumab and have demonstrated encouraging clinical activity, with data suggesting greater benefit in RAS wild-type (wt) versus RAS mutant (mut) mCRC (Abrams TA, et al. ASCO GI 2022:Abs 121; Saeed A, et al. ASCO GI 2022:Abs 135). XL092 is a TKI that targets MET, VEGFR2, and the TAM kinases AXL and MER, which are implicated in tumor growth, metastasis, angiogenesis, and immunosuppression of the tumor microenvironment. XL092 displays immunomodulatory properties that may promote an immunopermissive tumor microenvironment and its half-life of 16–22 hours is supportive of once daily (QD) dosing. The phase 3 STELLAR-303 study (NCT05425940) is evaluating the efficacy and safety of XL092 in combination with atezolizumab versus regorafenib in patients with microsatellite stable or microsatellite instability-low mCRC who have progressed after or are intolerant to standard of care (SOC) therapy. Methods: STELLAR-303 is a global, randomized, open-label, phase 3 study. Eligible patients are aged ≥18 years with non-MSI-H/dMMR mCRC (determined by tissue-based analysis) that is measurable per RECIST v1.1 and have an ECOG performance status of 0–1 and adequate organ function. Patients must have progressed during/after or be intolerant to SOC therapies for mCRC; prior regorafenib, trifluridine-tipiracil, or anti–PD-L1/PD-1 ICIs are not allowed. Patients are randomized 1:1 to XL092 100 mg PO QD + atezolizumab 1200 mg IV Q3W or to regorafenib 160 mg PO QD (21 days/28-day cycle); randomization is stratified by geographic region (Asia, other), RAS status (wt, mut), and liver metastases (yes, no). Enrollment of 600 patients is planned (400 RASwt, 200 RASmut). The primary endpoint is duration of overall survival (OS) in the RASwt population, with other efficacy endpoints (progression-free survival, objective response rate, and duration of response per RECIST v1.1 by investigator and change in tumor markers) assessed in the RASwt population and, with OS, in the RASmut populations and in all randomized patients. Additional endpoints will assess safety, quality of life, changes in biomarkers, pharmacokinetics, immunogenicity, and healthcare utilization. Enrollment is ongoing. Clinical trial information: NCT05425940 .

Antitumor Effects of a Distinct Sonodynamic Nanosystem through Enhanced Induction of Immunogenic Cell Death and Ferroptosis with Modulation of Tumor Microenvironment.

Sonodynamic therapy (SDT) holds great promise to be applied for cancer therapy in clinical settings. However, its poor therapeutic efficacy has limited its applications owing to the apoptosis-resistant mechanism of cancer cells. Moreover, the hypoxic and immunosuppressive tumor microenvironment (TME) also weakens the efficacy of immunotherapy in solid tumors. Therefore, reversing TME remains a formidable challenge. To circumvent these critical issues, we developed an ultrasound-augmented strategy to regulate the TME by utilizing an HMME-based liposomal nanosystem (HB liposomes), which can synergistically promote the induction of ferroptosis/apoptosis/immunogenic cell death (ICD) and initiate the reprograming of TME. The RNA sequencing analysis demonstrated that apoptosis, hypoxia factors, and redox-related pathways were modulated during the treatment with HB liposomes under ultrasound irradiation. The in vivo photoacoustic imaging experiment showed that HB liposomes enhanced oxygen production in the TME, alleviated TME hypoxia, and helped to overcome the hypoxia of the solid tumors, consequently improving the SDT efficiency. More importantly, HB liposomes extensively induced ICD, resulting in enhanced T-cell recruitment and infiltration, which normalizes the immunosuppressive TME and facilitates antitumor immune responses. Meanwhile, the HB liposomal SDT system combined with PD1 immune checkpoint inhibitor achieves superior synergistic cancer inhibition. Both in vitro and in vivo results indicate that the HB liposomes act as a sonodynamic immune adjuvant that is able to induce ferroptosis/apoptosis/ICD via generated lipid-reactive oxide species during the SDT and reprogram TME due to ICD induction. This sonodynamic nanosystem integrating oxygen supply, reactive oxygen species generation, and induction of ferroptosis/apoptosis/ICD is an excellent strategy for effective TME modulation and efficient tumor therapy.

A study of using epigenetic modulators to enhance response to pembrolizumab (MK-3475) in microsatellite stable advanced colorectal cancer

BackgroundApproximately 95% of advanced colorectal cancer patients (CRC) have mismatch repair MMR-proficient (MMRp) tumors, which do not respond to PD1 blockade alone. Preclinical studies have shown that combined histone deacetylases (HDAC) and/or DNA methyltransferases (DNMT) inhibition can induce susceptibility to immune checkpoint therapy and inhibit tumor growth. We conducted a pilot trial evaluating PD-1 immune checkpoint inhibitor therapy in combination with DNMT and HDAC inhibitors in MMRp CRC. The study was designed with a biological endpoint of change in immune cell infiltration, to determine the optimal epigenetic combination that optimizes the tumor microenvironment. This trial was designed to test that hypothesis.ResultsFrom January 2016 to November 2018, 27 patients were enrolled with median age of 57 (range 40–69) years. Median progression-free survival and overall survival were 2.79 months and 9.17, respectively. One patient in Arm C achieved a durable partial response by RECIST criteria, lasting for approximately 19 months. The most common treatment-related hematological adverse events in all arms were anemia (62%), lymphopenia (54%) and thrombocytopenia (35%), and non-hematological AEs were anorexia (65%), nausea (77%), and vomiting (73%).ConclusionsThe combination of 5-azacitidine and romidepsin with pembrolizumab was safe and tolerable in patients with advanced MMRp CRC, but with a minimal activity. Further mechanistic investigations are needed to understand epigenetic-induced immunologic shift and to expand the potential applicability of checkpoint inhibitors in this setting.

The abscopal effect: inducing immunogenicity in the treatment of brain metastases secondary to lung cancer and melanoma.

The phenomenon of radiation therapy (RT) causing regression of targeted lesions as well as lesions outside of the radiation field is known as the abscopal effect and is thought to be mediated by immunologic causes. This phenomena has been described following whole brain radiation (WBRT) and stereotactic radiosurgery (SRS) of brain metastasis (BM) in advanced melanoma and non-small-cell lung cancer (NSCLC). We systematically reviewed the available literature to identify which radiation modality and immunotherapy (IT) combination may elicit the abscopal effect, the optimal timing of RT and IT, and potential adverse effects inherent to the combination of RT and IT. Using PRISMA guidelines, a search of PubMed, Medline, and Web of Science was conducted to identify studies demonstrating the abscopal effect during treatment of NSCLC or melanoma with BM. 598 cases of irradiated BM of melanoma or NSCLC in 18 studies met inclusion criteria. The most commonly administered ITsincluded PD-1 or CTLA-4 immune checkpoint inhibitors (ICI), with RT most commonly administered within 3 months of ICI. Synergy between ICI and RT was described in 16 studies including evidence of higher tumor response within and outside of the irradiated field. In the 12 papers (n = 232 patients) that reported objective response rate (ORR) in patients with BM treated with RT and concurrent systemic IT, the non-weighted mean ORR was 49.4%; in the 5 papers (n = 110 patients) that reported ORR for treatment with RT or IT alone, the non-weighted mean ORR was 27.8%. No studies found evidence ofsignificantly increased toxicity in patients receiving RT and ICI. The combination of RT and ICIs may enhance ICI efficacy and induce more durable responses via the abscopal effect in patients with brain metastases of melanoma or NSCLC.