Combination Of Immune Checkpoint Blockade Research Articles

Safety and tolerability of radiotherapy in combination with systemic targeted therapies for treatment of hepatocellular carcinoma: a narrative review.

Palliative radiotherapy (RT) and systemic immuno- or targeted therapy both play significant roles in the treatment of advanced hepatocellular carcinoma (HCC). Concurrent application of these therapies is increasing, however, no guidelines exist regarding the combination of systemic therapy with RT. This narrative review summarises the existing literature reporting toxicity observed after concurrent treatment with RT and immuno- or targeted therapeutic agents commonly used in HCC. The PubMed database was searched for studies published between 2011 and 2023 reporting toxicity data on patients treated concurrently with RT and targeted agents used in HCC. Due to the paucity of relevant literature in HCC, the inclusion criteria were expanded to include non-HCC cohorts treated with targeted therapies commonly used in advanced HCC. Sixty-seven articles were included in this review. Twenty-two articles reported combined RT with sorafenib, one with regorafenib, 22 with bevacizumab, three with lenvatinib and 19 with immune checkpoint inhibitors. Significant findings include a high rate severe hepatotoxicity with combination RT and sorafenib, ranging from 0-19% with liver stereotactic body radiotherapy (SBRT) and 3-18% with conventionally fractionated liver RT. Severe gastrointestinal (GI) toxicities including perforation and ulceration were seen with combination bevacizumab and RT, ranging from 0-27% in the acute setting and 0-23% in the late setting. The safety profile of combination immune checkpoint blockade agents and RT was similar to that seen in monotherapy. Existing data suggests that combination RT and targeted therapy given the risk of severe adverse events including hepatotoxicity and GI toxicity. There is an urgent need for future studies specifically examining the impact of combination therapy in HCC patients to guide clinical decision-making in the evolving landscape of immune- and targeted therapies.

Photoactivated Formation of an Extravascular Dynamic Hydrogel as an Intelligent Blood Flow Regulator to Reprogram the Immunogenic Landscape.

Long-term tumor starvation may be a potential strategy to elevate the antitumor immune response by depriving nutrients. However, combining long-term starvation therapy with immunotherapy often yields limited efficacy due to the blockage of immune cell migration pathways. Herein, an intelligent blood flow regulator (BFR) is first established through photoactivated in situ formation of the extravascular dynamic hydrogel to compress blood vessels, which can induce long-term tumor starvation to elicit metabolic stress in tumor cells without affecting immune cell migration pathways. By leveraging methacrylate-modified nanophotosensitizers (HMMAN) and biodegradable gelatin methacrylate (GelMA), the developed extravascular hydrogel dynamically regulates blood flow via enzymatic degradation. Additionally, aPD-L1 loaded into HMMAN continuously blocks immune checkpoints. Systematic in vivo experiments demonstrate that the combination of immune checkpoint blockade (ICB) and BFR-induced metabolic stress (BIMS) significantly delays the progression of Lewis lung and breast cancers by reshaping the tumor immunogenic landscape and enhancing antitumor immune responses.

Efficacy and safety of bispecific antibodies vs. immune checkpoint blockade combination therapy in cancer: a real-world comparison.

Emerging tumor immunotherapy methods encompass bispecific antibodies (BSABs), immune checkpoint inhibitors (ICIs), and adoptive cell immunotherapy. BSABs belong to the antibody family that can specifically recognize two different antigens or epitopes on the same antigen. These antibodies demonstrate superior clinical efficacy than monoclonal antibodies, indicating their role as a promising tumor immunotherapy option. Immune checkpoints are also important in tumor immunotherapy. Programmed cell death protein-1 (PD-1) is a widely acknowledged immune checkpoint target with effective anti-tumor activity. PD-1 inhibitors have demonstrated notable therapeutic efficacy in treating hematological and solid tumors; however, more than 50% of patients undergoing this treatment exhibit a poor response. However, ICI-based combination therapies (ICI combination therapies) have been demonstrated to synergistically increase anti-tumor effects and immune response rates. In this review, we compare the clinical efficacy and side effects of BSABs and ICI combination therapies in real-world tumor immunotherapy, aiming to provide evidence-based approaches for clinical research and personalized tumor diagnosis and treatment.

Combinatorial Checkpoint Blockade and Laser Interstitial Thermal Therapy: A Single Center Study

INTRODUCTION: Immune checkpoint blockade (ICB) has gained acceptance as a life-extending therapy in a variety of solid tumor types. For patients with brain metastases, combination stereotactic radiosurgery (SRS) and ICB remains an area of clinical equipoise. Similarly, for recurrent or difficult-to-access intracranial lesions, safety and synergy of laser interstitial thermal therapy (LITT) and ICB has yet to be explored. METHODS: In accordance with an IRB-approved protocol, all patients undergoing LITT at a tertiary center from 2015-2022 were retrospectively reviewed. Patients who received ICB within 6 weeks of LITT were included in the LITT + ICB cohort. Demographic, clinical, and survival data were collected. RESULTS: Combination LITT and ICB occurred in 25 patients with clinically recurrent tumors. The median cohort age was 62 (40-78) and 12 (48%) were female. The median KPS was 80 (50-100). The most common primary pathology was non-small cell lung cancer (NSCLC) in 15 patients (60%), followed by melanoma in 3 (12%); two high-grade gliomas were additionally treated. The majority of the cohort (24 patients, 96%) recieved single agent ICB in combination with LITT, with pembrolizumab (12, 48%) and nivolumab (6, 24%) most common. Median duration between ICB dosing and LITT was 2.85 (0.85-5.84) weeks. Ten patients (40%) had evidence of immune-related adverse events attributable to ICB, with only 1 event > grade 3 according to Common Terminology Criteria; 17 (68%) had a pre-LITT steroid requirement. Intracranial adverse events related to LITT were rare, with median overall survival for the cohort of 8.6 months (1.4-26.4 months). CONCLUSIONS: Combination LITT and ICB appears safe and feasible. No prospective studies have compared cytoreduction with LITT to LITT + ICB; construction of a matched NSCLC cohort is ongoing. Exploration of the immune consequences of LITT + ICB is needed.

Peripheral blood biomarkers associated with combination of immune checkpoint blockade plus chemotherapy in NSCLC.

Biomarkers predicting clinical outcomes of treating non-small cell lung cancer (NSCLC) with combination of immune checkpoint inhibitors (ICIs) and chemotherapy would be valuable. This study aims to seek predictors of combination of ICI/chemotherapy response in NSCLC patients using peripheral blood samples. Patients diagnosed with advanced NSCLC between July 2019 and May 2021 receiving combination of ICI/chemotherapy were included and assessed for partial responses (PR), stable disease (SD) or progressive disease (PD). We measured circulating immune cells, plasma cytokines and chemokines. Nineteen patients were enrolled. The proportions of circulating natural killer (NK) cells within CD45 + cells, programmed death 1 (PD-1) + Tim-3 + T cells within CD4 + cells, and the amount of chemokine C-X-C ligand (CXCL10) in the plasma were significantly elevated in PR relative to SD/PD patients (median 8.1%-vs-2.1%, P= 0.0032; median 1.2%-vs-0.3%, P= 0.0050; and median 122.6pg/ml-vs-76.0pg/ml, P= 0.0125, respectively). Patients with 2 or 3 elevated factors had longer progression-free survival than patients with 0 or only one (not reached-vs-5.6months, P= 0.0002). We conclude that NK cells, CD4 + PD-1 + Tim-3 + T cells, and CXCL10 levels in pre-treatment peripheral blood may predict the efficacy of combination of ICI/chemotherapy in NSCLC.

Inhibitory receptors of plasmacytoid dendritic cells as possible targets for checkpoint blockade in cancer.

Plasmacytoid dendritic cells (pDCs) are the major producers of type I interferons (IFNs), which are essential to mount antiviral and antitumoral immune responses. To avoid exaggerated levels of type I IFNs, which pave the way to immune dysregulation and autoimmunity, pDC activation is strictly regulated by a variety of inhibitory receptors (IRs). In tumors, pDCs display an exhausted phenotype and correlate with an unfavorable prognosis, which largely depends on the accumulation of immunosuppressive cytokines and oncometabolites. This review explores the hypothesis that tumor microenvironment may reduce the release of type I IFNs also by a more pDC-specific mechanism, namely the engagement of IRs. Literature shows that many cancer types express de novo, or overexpress, IR ligands (such as BST2, PCNA, CAECAM-1 and modified surface carbohydrates) which often represent a strong predictor of poor outcome and metastasis. In line with this, tumor cells expressing ligands engaging IRs such as BDCA-2, ILT7, TIM3 and CD44 block pDC activation, while this blocking is prevented when IR engagement or signaling is inhibited. Based on this evidence, we propose that the regulation of IFN secretion by IRs may be regarded as an "innate checkpoint", reminiscent of the function of "classical" adaptive immune checkpoints, like PD1 expressed in CD8+ T cells, which restrain autoimmunity and immunopathology but favor chronic infections and tumors. However, we also point out that further work is needed to fully unravel the biology of tumor-associated pDCs, the neat contribution of pDC exhaustion in tumor growth following the engagement of IRs, especially those expressed also by other leukocytes, and their therapeutic potential as targets of combined immune checkpoint blockade in cancer immunotherapy.

Abstract A083: Personalized targeted circulating tumor DNA (ctDNA) and T-cell responses after combined neoantigen vaccine and immune checkpoint blockade in ovarian cancer

Abstract A083: Personalized targeted circulating tumor DNA (ctDNA) and T-cell responses after combined neoantigen vaccine and immune checkpoint blockade in ovarian cancer

A gut microbial signature for combination immune checkpoint blockade across cancer types

Immune checkpoint blockade (ICB) targeting programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte protein 4 (CTLA-4) can induce remarkable, yet unpredictable, responses across a variety of cancers. Studies suggest that there is a relationship between a cancer patient’s gut microbiota composition and clinical response to ICB; however, defining microbiome-based biomarkers that generalize across cohorts has been challenging. This may relate to previous efforts quantifying microbiota to species (or higher taxonomic rank) abundances, whereas microbial functions are often strain specific. Here, we performed deep shotgun metagenomic sequencing of baseline fecal samples from a unique, richly annotated phase 2 trial cohort of patients with diverse rare cancers treated with combination ICB (n = 106 discovery cohort). We demonstrate that strain-resolved microbial abundances improve machine learning predictions of ICB response and 12-month progression-free survival relative to models built using species-rank quantifications or comprehensive pretreatment clinical factors. Through a meta-analysis of gut metagenomes from a further six comparable studies (n = 364 validation cohort), we found cross-cancer (and cross-country) validity of strain–response signatures, but only when the training and test cohorts used concordant ICB regimens (anti-PD-1 monotherapy or combination anti-PD-1 plus anti-CTLA-4). This suggests that future development of gut microbiome diagnostics or therapeutics should be tailored according to ICB treatment regimen rather than according to cancer type.

Integration of CD4+ T cells and molecular subtype predicts benefit from PD-L1 blockade in muscle-invasive bladder cancer.

Muscle-invasive bladder cancer (MIBC) is a disease characterized by molecular and clinical heterogeneity, posing challenges in selecting the most appropriate treatment in clinical settings. Considering the significant role of CD4+ T cells, there is an emerging need to integrate CD4+ T cells with molecular subtypes to refine classification. We conducted a comprehensive study involving 895 MIBC patients from four independent cohorts. The Zhongshan Hospital (ZSHS) and The Cancer Genome Atlas (TCGA) cohorts were included to investigate chemotherapeutic response. The IMvigor210 cohort was included to assess the immunotherapeutic response. NCT03179943 was used to evaluate the clinical response to a combination of immune checkpoint blockade (ICB) and chemotherapy. Additionally, we evaluated genomic characteristics and the immune microenvironment to gain deeper insights into the distinctive features of each subtype. We unveiled four immune-molecular subtypes, each exhibiting distinct clinical outcomes and molecular characteristics. These subtypes include luminal CD4+ Thigh, which demonstrated benefits from both immunotherapy and chemotherapy; luminal CD4+ Tlow, characterized by the highest level of fibroblast growth factor receptor 3 (FGFR3) mutation, thus indicating potential responsiveness to FGFR inhibitors; basal CD4+ Thigh, which could benefit from a combination of ICB and chemotherapy; and basal CD4+ Tlow, characterized by an immune suppression microenvironment and likely to benefit from transforming growth factor-β (TGF-β) inhibition. This immune-molecular classification offers new possibilities for optimizing therapeutic interventions in MIBC.

Abstract PR03: CSF-1R antibody targeting therapy with combined metronomic chemotherapy and immune checkpoint blockade enhance a B and T cell response to attenuate metastatic triple negative breast cancer

Abstract Background: Increased macrophage infiltration and elevated levels of Epithelial to Mesenchymal Transition (EMT) gene signatures are associated with a poor outcome following neo-adjuvant chemotherapy in patients with triple negative breast cancer (TNBC). Further, metastatic disease with overall the poorest survival rates has a cold tumor immune microenvironment (TIME), especially in lung and liver metastases. Interestingly, an abundance of macrophages are observed at these metastatic sites. We have extensively characterized multiple preclinical syngeneic Trp53-/- tumor models that have extensive Tumor Associated Macrophage (TAM) infiltration. These tumor models transcriptionally resemble “claudin-low”, “basal-like” and “luminal-like” breast cancers. From these models the “claudin-low” closely phenocopy the high EMT/TAM subtype observed in patients. Objective: Accordingly, we asked if SNDX-ms6352 a novel specific, high affinity monoclonal antibody targeting CSF-1R in combination with Chemotherapy (CTX) and immune checkpoint blockade might provide an alternative approach for treating established lung and liver metastases. Methods: Single cells from primary T12 mammary tumors were introduced either via tail vein injection to obtain lung metastases or portal vein (PV) injection for liver metastases. Mice were injected with BrdU and multiple lung and liver tissues are harvested randomly to identify established metastases. The mice were randomized into treatment groups and administered four weekly treatments of IgG, CTX, SNDX-ms6352, CTX+SNDX-ms6352 or CTX+SNDX-ms6352+aPD1. Tissues were harvested and fixed overnight in 4% PFA then placed in 70% EtOH for paraffin embedding and stained for H&E, Immunohistochemistry (IHC), Immunofluorescence (IF) and Imaging Mass Cytometry (IMC). Results: Following four weekly treatments of IgG, SNDX-ms6352 and CTX+/-SNDX-ms6352 we observed a decrease in lung metastatic burden and an increase in overall survival as compared to IgG, CTX and SNDX-ms6352 alone. Interestingly we also observed increased CD8 T-cell infiltration, but only in the combination treated mice 28 and 56 days post treatment. However, lung metastases recurred in all of the mice several weeks later. Data from IMC showed intra-tumoral heterogeneity with increased PD-L1 and Ki67. Short term treated lung and liver metastases with the addition of aPD1 demonstrated increased CD20+ B and CD8+ T cell expansion and cleared most of the lung and liver metastatic burden. These results suggest that targeting macrophages enhances the immunostimulatory effect of metronomic CTX with immune checkpoint blockade in treating not only primary tumors, but also established lung and liver metastases via the activation of the tumor immune microenvironment. Supported by R01CA148761-12 and American Cancer Society – AutoZone Breast Cancer Postdoctoral Fellowship, PF-22-163-01-MM grants. Citation Format: Diego A Pedroza, Qian Zhu, Weigou Wu, Paul Porter, Xiang H-F Zhang, Jeffrey M Rosen. CSF-1R antibody targeting therapy with combined metronomic chemotherapy and immune checkpoint blockade enhance a B and T cell response to attenuate metastatic triple negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr PR03.

A phase 1b/2 trial of pepinemab and avelumab as second line therapy for patients with metastatic pancreatic adenocarcinoma.

TPS712 Background: Pancreatic adenocarcinoma (PDAC) is a leading cause of cancer-related mortality with poor prognosis despite maximal therapy and is unresponsive to immune checkpoint blockade (ICB). This failure of response is hypothesized to be driven in part by the characteristic immunosuppressive tumor microenvironment. In PDAC, Semaphorin 4D (SEMA4D) expression is prognostic in patients who have undergone surgical resection and correlates with tumor infiltration of activated CD8+ T-cells. Additionally, preclinical models suggest that antibody-mediated SEMA4D blockade promotes tumoral infiltration and activation of CD8+ T-cells and sensitizes PDAC to ICB, with improved overall survival with standard of care chemotherapy and ICB in combination with pepinemab (humanized anti-SEMA4D). Thus, we hypothesized that pepinemab may improve clinical outcomes in PDAC by sensitizing tumors to ICB. Methods: We designed a phase Ib/II single-arm clinical trial to evaluate the safety, tolerability, and efficacy of humanized anti-SEMA4D (pepinemab) with anti-PD-L1 (avelumab) in patients with chemotherapy-refractory PDAC. Patients must have failed first-line 5-fluorouracil or gemcitabine-based combination chemotherapy. The study follows a dose de-escalation schema starting at a dose combination of 20mg/kg pepinemab and 800mg avelumab every two weeks. Patient accrual for phase 1b utilizes the Bayesian Optimal Interval Design (BOIN) targeting a dose-limiting toxicity rate of 30% or less. After 16 subjects receive a given combination dose, a Simon’s two stage assessment of futility will be undertaken with expansion to phase 2 if 2 or more subjects demonstrate response. The trial is designed to evaluate a total cohort of 40 subjects and powered to detect a response rate of 23% or greater, with alpha set at 0.1% and 80% power. Treatment response is assessed via RECIST 1.1 criteria with surveillance CT prior to enrollment and after completion of two cycles (8 weeks). Baseline and on-treatment tumor biopsies (after completion of one cycle, 4 weeks) are performed to analyze changes in immune, stromal, and genomic profiles to elucidate mechanisms of treatment response and failure. Patient reported outcomes are incorporated (FACT-Hep and FAACT subdomains) to assess disease-specific symptoms. To date, 7 patients have been enrolled (Clinical Trial NCT05102721). Clinical trial information: NCT05102721 .

Immune checkpoint blockade combined with targeted therapies to provide disease control in mismatch repair-proficient colorectal cancer with peritoneal metastases.

133 Background: Metastatic colorectal adenocarcinoma (mCRC) with proficient mismatch repair (pMMR) is associated with poor response to cytotoxic chemotherapy in the refractory setting, with a median overall survival (OS) of 10.8 months. Recent immunotherapy (IO) regimens utilizing a combination of immune checkpoint blockade (ICB) and tyrosine kinase inhibitors (TKIs) that suppress tumor-associated macrophages (TAMs) have shown promise for extra-hepatic, but not hepatic metastases. However, few studies include patients with peritoneal metastases (PMs) and the response rate of PMs to these therapies is unknown. We sought to examine the disease control rates (DCR) and OS of patients treated with PM who were treated with ICB regimens. Methods: Patients with pMMR tumors treated with ICB and TKI after progression on 1st and 2nd-line therapy from 2015 to 2022 were identified. Date of start of therapy, end of therapy, last follow up and vital status were determined from the medical record. Radiographic disease response within each metastasis site at 6 months and at last follow-up on therapy was determined for each patient. Overall survival was estimated using the Kaplan-Meier method. Results: A total of 93 patients treated with an ICB and TKI after at least two lines of cytotoxic systemic therapy were identified. Five were excluded due to dMMR/MSI-H status and eight due to lack of follow-up. A total of 33 patients with PM, with or without other metastases, had a median follow-up on therapy of 6.1 months and median follow-up until death or censoring of 9.8 months. Median OS was 15.1 (9.7-29.5) months, and 18-month survival was 43% (95%CI: 24-62%). OS was not associated with either BRAF (HR 0.98, 0.38-2.6, p=0.98) or RAS (HR 1.50, 0.62- 3.63, p=0.37) mutation status. Partial response of PM was noted in 5 patients (15%), stable disease in 14 (42%) and progressive disease in 14 (42%), resulting in DCR of 57%. Disease control for all metastatic sites was noted in 9 (27%) of patients, and median OS was not reached at 2 years. Median OS for patients without peritoneal progression was 22.0 months [12.3-NR], and PM progression was associated with worse OS (HR 0.66, p=0.024). A total of 32 patients with any metastatic site were treated for at least 6 months. Median follow-up was 16.1 months for this cohort. DCR at 6 months for CRLM was 23% (3/13), PM was 58% (14/24, p=0.08 vs CRLM) and for LM was 62% (8/13, p=0.11 vs CRLM). Conclusions: Response to ICB and targeted therapy combinations can vary widely by metastatic site, with liver trending towards less response than peritoneum or lung. Disease control in the peritoneum can be achieved in the majority of patients, and median OS compares favorably to standard-of-care therapy in the refractory setting. Patients with peritoneal disease should be included in future trials of ICBs as treatment options are otherwise limited.

Natural history and patterns of progression for dMMR/MSI-H colorectal cancer treated with immune checkpoint blockade: A single center retrospective analysis.

145 Background: Deficiency in mismatch repair or high microsatellite instability (dMMR/MSI-H), occurring in approximately 20% of all colorectal cancer (CRC) cases and approximately 4% of metastatic CRC (mCRC), predicts clinical benefit of immune checkpoint blockade (ICB). With response rates of about 50% in mCRC and higher in localized cases, ICB is providing durable benefit and even cure in a meaningful portion of cases. However, further understanding of those patients who progress and treatment options following progression are needed. Methods: A single institution retrospective review was performed on 151 dMMR/MSI-H CRC patients receiving ICB at MD Anderson Cancer Center from 2014 to 2023. Data was collected including patient demographics, tumor and mutational data, ICB treatment data, progression patterns, and treatment following progression. Progression patterns were classified as intrinsic (progression at initial restaging with pseudoprogression excluded) or adaptive progression and oligometastatic (3 or less sites of metastatic disease regardless of organs involved) or systemic progression. Results: The median time to progression (TTP) of all patients treated with ICB was 88 months (m). Median follow up was 40 m. Of the 151 patients, 59 (39%) progressed on ICB. The majority of these were treated with monotherapy anti-PD1 (49, 83%) while only 10 (17%) were treated with combination ICB. Of those that progressed, 29 (49%) were considered intrinsic while 30 (51%) were considered adaptive. In the adaptive group, average TTP was 21 m. The majority progressed at a metastatic site (51, 86%) and at a prior site of disease (47, 80%). Progression was oligometastatic in 30 (51%) patients and systemic in 29 (49%) patients. The median TTP for oligometastatic progression was 9 m while median TTP for systemic progression was 4 m (p=0.005). The median OS for those with systemic progression was 17 m while the median OS for oligometastatic progression was not reached (p=0.027). Of those with progression, 12 (20%) had non-surgical local therapy to progressing sites, 6 (10%) underwent surgery to progressing sites, and 31 (52%) received alternative systemic therapy (chemotherapy or ICB). Of the 16 patients who received local therapy (non-surgical, surgical, or both), 7 (44%) remain with no evidence of disease. Conclusions: This is one of the largest reviews of dMMR/MSI-H CRC progressors on ICB. Adaptive progression represented approximately one half of all progression events and local-modality therapy was utilized in 27% of patients. Long-term disease control was seen in oligometastatic adaptive progressors who received local modality therapy.

Correlation between tumor size change and outcome in a rare cancer immunotherapy basket trial.

RECIST criteria for progressive disease, partial response, and complete response, reflecting +20%, -30%, and -100% tumor size changes, respectively, are critical outcome variables in oncology clinical trials. Herein, we evaluated post-immunotherapy tumor size change correlation with outcomes. We used a unique clinical trial data resource, a multicenter basket trial in patients with rare solid tumors treated with nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) between 2017 and 2023 (National Cancer Institute/Southwest Oncology Group-sponsored DART trial [NCT02834013]) (open at 1083 sites at its peak). Outcome associations were evaluated by survival analysis techniques including Martingale residuals. In 638 evaluable patients, we found strong linear relationships between percent change in tumor measurement up to a 40%-50% increase and progression-free (PFS) and overall survival (OS) (both Cox regression P < .001; landmark analyses based on day 65). Pearson R correlation between survival estimates and tumor change category were -0.94, -0.89, and -0.89 (PFS) and -0.84, -0.90, and -0.90 (OS) for median, 6-month (PFS), and 1-year (OS) and for 1-year (PFS) and 2-year (OS) estimates. Percent change in tumor measurement per RECISTv1.1 (the sum of longest dimensions of target lesions) has a linear association with PFS and OS up to a 40% to 50% increase in tumor measurement in this cohort of patients with rare cancers who received combination immune checkpoint blockade. Quantitative first scan tumor measurement changes include important information to evaluate the potential efficacy of a therapy beyond the proportion of patients who achieve an objective response.

Designing Peptide-Based Nanoinhibitors of Programmed Cell Death Ligand 1 (PD-L1) for Enhanced Chemo-immunotherapy.

The combination of immune checkpoint blockade (ICB) and chemotherapy has shown significant potential in the clinical treatment of various cancers. However, circulating regeneration of PD-L1 within tumor cells greatly limits the efficiency of chemo-immunotherapy and consequent patient response rates. Herein, we report the synthesis of a nanoparticle-based PD-L1 inhibitor (FRS) with a rational design for effective endogenous PD-L1 suppression. The nanoinhibitor is achieved through self-assembly of fluoroalkylated competitive peptides that target PD-L1 palmitoylation. The FRS nanoparticles provide efficient protection and delivery of functional peptides to the cytoplasm of tumors, showing greater inhibition of PD-L1 than nonfluorinated peptidic inhibitors. Moreover, we demonstrate that FRS synergizes with chemotherapeutic doxorubicin (DOX) to boost the antitumor activities via simultaneous reduction of PD-L1 abundance and induction of immunogenic cell death in murine colon tumor models. The nano strategy of PD-L1 regulation present in this study is expected to advance the development of ICB inhibitors and overcome the limitations of conventional ICB-assisted chemo-immunotherapy.

Radiotherapy-Triggered In Situ Tumor Vaccination Boosts Checkpoint Blockaded Immune Response via Antigen-Capturing Nanoadjuvants.

In situ vaccination (ISV) formed with the aid of intratumorally injected adjuvants has shed bright light on enhancing the abscopal therapeutic effects of radiotherapy. However, the limited availability of antigens resulting from the radiotherapy-induced immunogenic cell death largely hampers the clinical outcome of ISV. To maximally utilize the radiotherapy-induced antigen, we herein developed a strategy by capturing the radiotherapy-induced antigen in situ with a nanoadjuvant comprised of CpG-loaded Fe3O4 nanoparticles. The highly efficient click reaction between the maleimide residue on the nanoadjuvant and sulfhydryl group on the antigen maximized the bioavailability of autoantigens and CpG adjuvant in vivo. Importantly, combined immune checkpoint blockade can reverse T cell exhaustion after treatment with radiotherapy-induced ISV, thereby largely suppressing the treated and distant tumor. Mechanistically, metabolomics reveals the intratumorally injected nanoadjuvants disrupt redox homeostasis in the tumor microenvironment, further inducing tumor ferroptosis after radiotherapy. Overall, the current study highlights the immense potential of the innovative antigen-capturing nanoadjuvants for synergistically enhancing the antitumor effect.

Harnessing p53 to Improve Immunotherapy for Lung Cancer Treatment.

Immunotherapy, especially immune checkpoint blockade (ICB), has become a critical therapy for lung cancer treatment in recent years. Tumor mutational burden (TMB) is one of the decisive biomarkers for predicting ICB effect. Writing in Cancer Cell, Zhu and colleagues use autochthonous and syngeneic mouse models to show that p53 mutation and tumor heterogeneity may be responsible for resistance in patients with lung cancer. Pole-induced high TMB shows enhanced immunogenicity in KrasG12D mice, however, loss of p53 in KrasG12D PoleP286/+ mice can lead to an immune suppressive profile of lung tumors, which diminishes immune response to ICB. Moreover, high TMB causes high shared mutations, which helps promote immune protection and immune memory. Heterogeneity can drive immune escape to tumor cells causing resistance to ICB. Decreased cGAS/STING signaling may explain possible resistance to ICB. On the basis of the new model found by Zhu and colleagues for lung cancer, combined ICB with STING agonists or p53 inducers may be new therapeutic options to improve the efficacy of ICB for patients with lung cancer with high TMB.

Immunotherapy combination approaches: mechanisms, biomarkers and clinical observations.

The approval of the first immune checkpoint inhibitors provided a paradigm shift for the treatment of malignancies across a broad range of indications. Whereas initially, single-agent immune checkpoint inhibition was used, increasing numbers of patients are now treated with combination immune checkpoint blockade, where non-redundant mechanisms of action of the individual agents generally lead to higher response rates. Furthermore, immune checkpoint therapy has been combined with various other therapeutic modalities, including chemotherapy, radiotherapy and other immunotherapeutics such as vaccines, adoptive cellular therapies, cytokines and others, in an effort to maximize clinical efficacy. Currently, a large number of clinical trials test combination therapies with an immune checkpoint inhibitor as a backbone. However, proceeding without inclusion of broad, if initially exploratory, biomarker investigations may ultimately slow progress, as so far, few combinations have yielded clinical successes based on clinical data alone. Here, we present the rationale for combination therapies and discuss clinical data from clinical trials across the immuno-oncology spectrum. Moreover, we discuss the evolution of biomarker approaches and highlight the potential new directions that comprehensive biomarker studies can yield.

Treatment-related adverse events, including fatal toxicities, in patients with solid tumours receiving neoadjuvant and adjuvant immune checkpoint blockade: a systematic review and meta-analysis of randomised controlled trials

Incorporating immune checkpoint blockade into perioperative cancer therapy has improved clinical outcomes. However, the safety of immune checkpoint blockade needs better evaluation, given the chances of more prolonged disease-free survival. We aimed to assess how adding immune checkpoint blockade to perioperative therapy affects treatment-related adverse events. For this systematic review and meta-analysis, we searched PubMed/MEDLINE, Embase, Web of Science, and the Cochrane Library from database inception until Aug 8, 2023, for randomised controlled trials that assessed the addition of immune checkpoint blockade to neoadjuvant or adjuvant therapy for cancer, reported treatment-related deaths, and had a design in which the experimental group assessed immune checkpoint blockade in combination with the therapy used in the control group. Meta-analysis was done to pool odds ratios (ORs) of treatment-related deaths, any grade and grade 3-4 treatment-related adverse events, serious adverse events, and adverse events leading to treatment discontinuation. The protocol is registered with PROSPERO, CRD42022343741. 28 randomised controlled trials with 16 976 patients were included. The addition of immune checkpoint blockade was not significantly associated with increased treatment-related deaths (OR 1·76, 95% CI 0·95-3·25; p=0·073), consistent across immune checkpoint blockade subtype (I2=0%). 40 fatal toxicities were identified across 9864 patients treated with immune checkpoint blockade, with pneumonitis being the most common (six [15·0%]); 13 fatal toxicities occurred among 7112 patients who were not treated with immune checkpoint blockade. The addition of immune checkpoint blockade increased the incidence of grade 3-4 treatment-related adverse events (OR 2·73, 95% CI 1·98-3·76; p<0·0001), adverse events leading to treatment discontinuation (3·67, 2·45-5·51; p<0·0001), and treatment-related adverse events of any grade (2·60 [1·88-3·61], p<0·0001). The immune checkpoint blockade versus placebo design primarily used as adjuvant therapy was associated with increased incidence of treatment-related deaths (4·02, 1·04-15·63; p=0·044) and grade 3-4 adverse events (5·31, 3·08-9·15; p<0·0001), whereas the addition of immune checkpoint blockade in the neoadjuvant setting was not associated with increased incidence of treatment-related death (1·11, 95% CI 0·38-3·29; p=0·84) or grade 3-4 adverse events (1·17, 0·90-1·51; p=0·23). The addition of immune checkpoint blockade to perioperative therapy was associated with an increase in grade 3-4 treatment-related adverse events and adverse events leading to treatment discontinuation. These findings provide safety insights for further clinical trials assessing neoadjuvant or adjuvant immune checkpoint blockade therapy. Clinicians should closely monitor patients for treatment-related adverse events to prevent treatment discontinuations and morbidity from these therapies in earlier-stage settings. None.

ICBcomb: a comprehensive expression database for immune checkpoint blockade combination therapy.

The success of immune checkpoint blockade (ICB) promotes the immunotherapy to be a new pillar in cancer treatment. However, the low response rate of the ICB therapy limits its application. To increase the response rate and enhance efficacy, the ICB combination therapy has emerged and its clinical trials are increasing. Nevertheless, the gene expression profile and its pattern of ICB combination were not comprehensively studied, which limits the understanding of the ICB combination therapy and the identification of new drugs. Here, we constructed ICBcomb (http://bioinfo.life.hust.edu.cn/ICBcomb/), a comprehensive database, by analyzing the human and mouse expression data of the ICB combination therapy and comparing them between groups treated with ICB, other drugs or their combinations. ICBcomb contains 1399 samples across 29 cancer types involving 52 drugs. It provides a user-friendly web interface for demonstrating the results of the available comparisons in the ICB combination therapy datasets with five functional modules: [1, 2] the 'Dataset/Disease' modules for browsing the expression, enrichment and comparison results in each dataset or disease; [3] the 'Gene' module for inputting a gene symbol and displaying its expression and comparison results across datasets/diseases; [4] the 'Gene Set' module for GSVA/GSEA enrichment analysis on the built-in gene sets and the user-input gene sets in different comparisons; [5] the 'Immune Cell' module for immune cell infiltration comparison between different groups by immune cell abundance analysis. The ICBcomb database provides the first resource for gene expression profile and comparison in ICB combination therapy, which may provide clues for discovering the mechanism of effective combination strategies and new combinatory drugs.