Immune Checkpoint Blockers Research Articles

GD2 is a Crucial Ganglioside in the Signal Modulation and Application as a Target of Cancer Therapeutics.

While various glycosphingolipids were identified as cancer-associated carbohydrate antigens to be used as tumor markers, disialylated gangliosides such as GD3 and GD2 have particularly attracted attention from many researchers as promising cancer-associated antigens. Simultaneously, their functions in cancer and normal tissues have also been reported. Although GD3 is expressed at the early neural developmental stage and in various cancers, it is also found in the activated status of some normal cells such as astrocytes and lymphocytes. On the other hand, GD2 is expressed in more restricted cells than GD3, enabling anti-GD2 immune therapy to be more applicable for immunotherapy. Recently, the expression of GD2 has been reported in various epithelial cancers and neuroectoderm-derived tumors. The involvement of GD2 in cancer stem cell propertiesand the roles of GD2 in the signal modulation to bring about cancer stemness are now some of the most fascinating research topics. Cancer immunotherapy targeting GD2 by anti-GD2 antibody or anti-GD2 CAR-T is now widely being challenged with various modifications such as combination with cytokines, chemotherapy, or immune checkpoint blocking.

Cancer Stem Cells and the Renin–Angiotensin System in the Tumor Microenvironment of Melanoma: Implications on Current Therapies

Multiple signaling pathways are dysregulated in melanoma, notably the Ras/RAF/MAPK/ERK and PI3K/AKT/mTOR pathways, which can be targeted therapeutically. The high immunogenicity of melanoma has been exploited using checkpoint inhibitors. Whilst targeted therapies and immune checkpoint inhibitors have improved the survival of patients with advanced melanoma, treatment resistance, their side effect profiles, and the prohibitive cost remain a challenge, and the survival outcomes remain suboptimal. Treatment resistance has been attributed to the presence of cancer stem cells (CSCs), a small subpopulation of pluripotent, highly tumorigenic cells proposed to drive cancer progression, recurrence, metastasis, and treatment resistance. CSCs reside within the tumor microenvironment (TME) regulated by the immune system, and the paracrine renin–angiotensin system, which is expressed in many cancer types, including melanoma. This narrative review discusses the role of CSCs and the paracrine renin–angiotensin system in the melanoma TME, and its implications on the current treatment of advanced melanoma with targeted therapy and immune checkpoint blockers. It also highlights the regulation of the Ras/RAF/MAPK/ERK and PI3K/AKT/mTOR pathways by the renin–angiotensin system via pro-renin receptors, and how this may relate to CSCs and treatment resistance, underscoring the potential for improving the efficacy of targeted therapy and immunotherapy by concurrently modulating the renin–angiotensin system.

Construction and characterization of a novel secreted MsC-CAR-T cell in solid tumors

The CD47-SIRPα signaling has been acknowledged as a significant immune checkpoint and CD47 blocking has been proved as a potential therapeutic strategy for the treatment of solid tumor. However, the potential application of CAR-T cells secreted antibody fragment simultaneously in solid tumor is rarely explored. In this study, we searched bioinformatic databases and investigated the characteristics of CD47 in solid tumors. Then we consulted bioinformatic databases to design, optimize and construct a novel MsC-CAR which could target MAGE-A1 and self-secrete CD47-scFv. The engineering T cells containing MsC-CAR were transfected, verified and characterized. The tumor-inhibitory role of MsC-CART cells was further determined in vitro and in vivo. The results showed that MsC-CARs were successfully constructed and MsC1-CARs demonstrated the preferable features of recognizing MAGE-A1 and secreting CD47-scFv. Engineering T cells transfecting with MsC1-CAR (MsC1-CART cells) exerted the prominent tumor-inhibitory effectiveness, both in different cancer cell lines and LUAD xenograft tumors. The present data highlighted that MsC1-CART cells elaborately combined the adoptive cellular immunotherapy and immune checkpoint inhibitor therapy, may represent a new direction for the treatment of MAGE-A1 positive solid tumors.

Oligometastatic NSCLC: Current Perspectives and Future Challenges

Oligometastatic non-small cell lung cancer (NSCLC) represents a separate entity with a different biology and prognosis compared to stage IV NSCLC. Challenges range from the very definition of oligometastatic disease to the timing and techniques of local treatments, and their benefit in prolonging patient survival. Most of the international consensus and guidelines agree on the need for shared criteria, such as appropriate stadiation and even tissue biopsy if needed, in order to select patients that could really benefit from personalised strategies. Multidisciplinary evaluation is crucial in order to define if every lesion is amenable to radical local treatment, which appears to be the most important criterion across different guidelines. A distinction must be made depending on the time of oligo-disease detection, separating de novo oligometastatic disease from oligorecurrence, oligoprogression and oligoresidual disease. These separate entities imply a different biology and prognosis, and treatment strategies consequently must be tailored. Locoregional approaches are therefore often contemplated in order to ensure the best outcome for the patient. In non-oncogene-addicted disease, the advent of immune checkpoint blockers (ICBs) allows physicians to take into consideration consolidative treatments, but timing, technique and subsequent systemic treatment remain open issues. In oncogene-addicted NSCLC, local treatments are nowadays preferably reserved to cases of oligoprogression, but the advent of new, more potent drugs might challenge that. In this review, we summarised the current knowledge, consensuses and data from retrospective and prospective trials, with the aim of shedding some light on the topic and emphasising the unmet clinical need.

De-Escalation Strategies With Immune Checkpoint Blockers in Non-Small Cell Lung Cancer: Do We Already Have Enough Evidence?

Immune checkpoint blockers (ICBs) have revolutionized the treatment of non-small cell lung cancer (NSCLC). Currently, one-dose-fits-all maximalist regimens have been considered the standard of care, with ICBs administered at flat doses regardless of patients' weight. Treatment duration with ICBs is often arbitrary across stages, ranging from a fixed time point to until disease progression or unacceptable toxicity. However, the pharmacokinetic and pharmacodynamic properties of ICBs differ significantly from those of traditional cytotoxic drugs and the approved and selected doses on the basis of the maximum tolerated dose are often overestimated as there is limited evidence supporting a direct relationship between therapeutic intensity and outcomes. This can lead to overtreatment of patients, resulting in an increased risk of toxicity without enhanced efficacy. In addition, the use of these drugs is associated with significant costs that burden the global health care system and exacerbate disparities in access to care. De-escalating treatment by reducing the dose, duration, and frequency of administration of ICBs could optimize treatment efficacy, reduce toxicities, improve patients' quality of life, and even decrease costs. Ultimately, de-escalation strategies may help to reduce treatment inequalities and to improve drug access worldwide. The aim of this review is to summarize and discuss the main issues and challenges regarding the de-escalation of ICBs in patients with NSCLC, focusing on dose-intensity reduction and treatment duration selection. Moreover, we assess the economic impact of implementing de-escalation approaches.

Training the synergy between Bacillus Calmette-Guérin and immune checkpoint-blocking antibodies in bladder cancer.

Training the synergy between Bacillus Calmette-Guérin and immune checkpoint-blocking antibodies in bladder cancer.

Nanostructured lipid carriers based mRNA vaccine leads to a Tcell-inflamed tumour microenvironment favourable for improving PD-1/PD-L1 blocking therapy and long-term immunity in a cold tumour model.

mRNA-based cancer vaccines show promise in triggering antitumour immune responses. To combine them with existing immunotherapies, the intratumoral immune microenvironment needs to be deeply characterised. Here, we test nanostructured lipid carriers (NLCs), the so-called Lipidots®, for delivering unmodified mRNA encoding Ovalbumin (OVA) antigen to elicit specific antitumour responses. We evaluated whether NLC OVA mRNA complexes activate dendritic cells (DCs) invitro and identified the involved signalling pathways using specific inhibitors. We tested the anti-tumoral impact of Ova mRNA vaccine in B16-OVA and E.G7-OVA cold tumour-bearing C57Bl6 female mice as well as its synergy effect with an anti-PD-1 therapy by following the tumour growth and performing immunophenotyping of innate and adaptive immune cells. The intratumoral vaccine-related gene signature was assessed by RNA-sequencing. The immune memory response was assessed by re-challenging surviving treated mice with tumour cells. Our vaccine activates DCs invitro through the TLR4/8 and ROS signalling pathways and induces specific Tcell activation while exhibits significant preventive and therapeutic antitumour efficacy invivo. A profound intratumoral remodelling of the innate and adaptive immunity in association with an increase in the gene expression of chemokines (Cxcl10, Cxcl11, Cxcl9) involved in CD8+ T cell attraction were observed in immunised mice. The combination of vaccine and anti-PD-1 therapy improves the rates of complete responses and memory immune responses compared to monotherapies. Lipidots® are effective platform for the development of vaccines against cancer based on mRNA delivery. Their combination with immune checkpoint blockers could counter tumour resistance and promote long-term antitumour immunity. This work was supported by Inserm Transfert, la Région Auvergne Rhône Alpes, FINOVI, and the French Ministry of Higher Education, research and innovation (LipiVAC, COROL project, funding reference N° 2102992411).

Facile integration of a binary nano-prodrug with αPD-L1 as a translatable technology for potent immunotherapy of TNBC.

Immune checkpoint blockers (ICBs)-based immunotherapy is a favorable approach for efficient triple-negative breast cancer (TNBC) treatment. However, the therapeutic efficacy of ICBs is greatly compromised by immunosuppressive tumor microenvironments (TMEs) and low expression levels of programmed cell death ligand-1 (PD-L1). Herein, we constructed an amphiphilic prodrug by linking a hydrophobic STING agonist, MSA-2 and a hydrophilic chemotherapeutic drug, gemcitabine (GEM) via an ester bond, which can self-assemble into GEM-MSA-2 (G-M) nanoparticles (NPs) with a tumor growth inhibition (TGI) value of 87.1% in a murine 4T1 transplantation tumor model. Notably, the immunogenic cell death (ICD)-triggering effect of GEM together with the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway activation properties of MSA-2 enables efficient infiltration of non-exhausting T cells and repolarization of macrophages from M2 to M1 types in the tumor microenvironment for transforming a cold tumor to a hot one. Most importantly, G-M NPs treatment increases the PD-L1 expression levels, thus providing a unique opportunity for further integration with anti-PD-L1 monoclonal antibody (αPD-L1) for eliciting stronger immunity that ultimately leads to a TGI value of 98.0% in the primary tumor and significantly protects against distal and disseminated tumor rechallenge. Overall, this study presents a minimalist nano-prodrug combined with αPD-L1 as a simple yet robust translatable nanotechnology for potent chemo-immunotherapy of TNBC. STATEMENT OF SIGNIFICANCE: Enhancing the therapeutic efficacy of αPD-L1 for tumor immunotherapy via a translatable technology remains a challenge. We report herein facile integration of a binary nano-prodrug with αPD-L1 for potent immunotherapy of TNBC. An amphiphilic prodrug is constructed by linking a hydrophobic STING agonist, MSA-2 and a hydrophilic chemotherapeutic drug, gemcitabine (GEM) via an ester bond. The resulting self-assembled GEM-MSA-2 (G-M) nanoparticles (NPs) show a tumor growth inhibition (TGI) value of 87.1% in a murine 4T1 transplantation tumor model. Besides the induced immunogenic cell death (ICD) and activated cGAS-STING pathway, G-M NPs increase the PD-L1 expression levels, providing a unique opportunity for further integration with αPD-L1 to elicit stronger immunity that ultimately leads to a TGI value of 98.0% in the primary tumor and significantly protects against distal and disseminated tumor rechallenge.

Metabolic Tumor Volume Assessed by 18F FDG-PET CT Scan as a Predictive Biomarker for Immune Checkpoint Blockers in Advanced NSCLC and Its Biological Correlates.

This study aimed to explore metabolic tumor volume (MTV) as assessed by 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG-PET/CT) and understand its biological meaning in patients with non-small cell lung cancer (NSCLC) exposed to immune checkpoint blockers (ICB). In this study, patients with advanced NSCLC and a positive PET scan within 42 days of first-line treatment were enrolled in 11 institutions across four countries. Total MTV (tMTV) was analyzed, with a 42% maximum standardized uptake value threshold. Survival was analyzed according to high tMTV (≥median). Plasma proteomic profile, whole exome, transcriptome, and other analyses were performed on monocentric cohorts to explore its biological correlates. Of the 518 patients included, 167 received ICBs, 257 had chemotherapy plus ICBs, and 94 had chemotherapy. Median tMTV was 99 cm3. Median overall survival (OS) for patients with high tMTV treated with ICBs was 11.4 vs. 29.6 months (P < 0.0012) for those with low tMTV. In patients who received chemotherapy-ICB, tMTV did not correlate with OS (P = 0.099). In patients with programmed death-ligand 1 (PD-L1) ≥1% and high tMTV, chemotherapy-ICB combination was associated with longer OS compared with ICBs alone (20 vs. 11.4 months; P = 0.026), while no survival differences were observed in the low tMTV group. High tMTV correlated (and its detrimental effect seems to be driven) with a specific proteomic profile and increase in genomic instability. Our analysis indicates high tMTV is linked to an increase in systemic inflammation, specific cytokines production, and chromosomal instability. tMTV may serve as one of the biomarkers to select the best upfront strategy in patients with PD-L1-positive advanced NSCLC.

Caryophylli Cortex Suppress PD-L1 Expression in Cancer Cells and Potentiates Anti-Tumor Immunity in a Humanized PD-1/PD-L1 Knock-In MC-38 Colon Cancer Mouse Model.

Immune checkpoints are essential for regulating excessive autoimmune responses and maintaining immune homeostasis. However, in the tumor microenvironment, these checkpoints can lead to cytotoxic T cell exhaustion, allowing cancer cells to evade immune surveillance and promote tumor progression. The expression of programmed death-ligand 1 (PD-L1) in cancer cells is associated with poor prognoses, reduced survival rates, and lower responses to therapies. Consequently, downregulating PD-L1 expression has become a key strategy in developing immune checkpoint inhibitors (ICIs). Caryophylli cortex (CC), derived from the bark of the clove tree Syzygium aromaticum, possesses antioxidant and cytotoxic properties against cancer cells, yet its potential as an ICI remains unclear. In this study, we aimed to investigate whether CC extract modulates PD-L1 expression in cancer cells and activates T cell immunity through a co-culture system of cancer cells and T cells, as well as in hPD-L1/MC-38 tumor-bearing animal models. Our findings indicate that CC extract significantly downregulated both constitutive and inducible PD-L1 expression at non-toxic concentrations for cancer cells while simultaneously enhancing cancer cell mortality and T cell activity in the co-culture system. Furthermore, the administration of CC extract to hPD-L1/MC-38 tumor-bearing mice resulted in a greater than 70% reduction in tumor growth and increased infiltration of CD8+ T cells within the tumor microenvironment. Principal component analysis identified bergenin, chlorogenic acid, and ellagic acid as active ICIs. These findings suggest that CC extract exerts a potent antitumor effect as an immune checkpoint blocker by inhibiting PD-L1 expression in cancer cells and disrupting the PD-1/PD-L1 interaction.

Genetically Engineered T Cells and Recombinant Antibodies to Target Intracellular Neoantigens: Current Status and Future Directions

Recombinant antibodies and, more recently, T cell receptor (TCR)-engineered T cell therapies represent two immunological strategies that have come to the forefront of clinical interest for targeting intracellular neoantigens in benign and malignant diseases. T cell-based therapies targeting neoantigens use T cells expressing a recombinant complete TCR (TCR-T cell), a chimeric antigen receptor (CAR) with the variable domains of a neoepitope-reactive TCR as a binding domain (TCR-CAR-T cell) or a TCR-like antibody as a binding domain (TCR-like CAR-T cell). Furthermore, the synthetic T cell receptor and antigen receptor (STAR) and heterodimeric TCR-like CAR (T-CAR) are designed as a double-chain TCRαβ-based receptor with variable regions of immunoglobulin heavy and light chains (VH and VL) fused to TCR-Cα and TCR-Cβ, respectively, resulting in TCR signaling. In contrast to the use of recombinant T cells, anti-neopeptide MHC (pMHC) antibodies and intrabodies neutralizing intracellular neoantigens can be more easily applied to cancer patients. However, different limitations should be considered, such as the loss of neoantigens, the modification of antigen peptide presentation, tumor heterogenicity, and the immunosuppressive activity of the tumor environment. The simultaneous application of immune checkpoint blocking antibodies and of CRISPR/Cas9-based genome editing tools to engineer different recombinant T cells with enhanced therapeutic functions could make T cell therapies more efficient and could pave the way for its routine clinical application.

Preclinical Evaluation and Pilot Clinical Study of CD137 PET Radiotracer for Noninvasive Monitoring Early Responses of Immunotherapy.

Given the variability in the effectiveness of immune checkpoint blocking therapy among patients and tumor types, development of noninvasive methods for longitudinal assessment of immune cell function and early tumor response is crucial for precision immunotherapy. CD137 (4-1BB), a marker of activated T cells, plays a significant role in immunotherapy. However, its potential as an imaging biomarker for activated T cells in the tumor microenvironment has not been explored. This study introduces a bicyclic peptide-based probe that targets CD137 for noninvasive PET imaging of tumor-infiltrating activated T cells. Methods: A bicyclic peptide-based probe, [18F]AlF-NOTA-BCP137, was first designed and synthesized for quantitative and longitudinal whole-body visualization of CD137 dynamics. Initially, [18F]AlF-NOTA-BCP137 was assessed in mouse models with varying CD137 expression levels. Next, [18F]AlF-NOTA-BCP137 was used for longitudinal monitoring of systemic CD137 changes in a humanized tumor-bearing mouse model. Lastly, the probe was further evaluated in a small group of patients with hepatocellular carcinoma undergoing immunotherapy or combination immunotherapy. Results: [18F]AlF-NOTA-BCP137 PET accurately characterized CD137 expression in homologous transplanted mouse models and tumor patients. The findings from animal studies indicated that uptake of [18F]AlF-NOTA-BCP137 was predictive of the early therapeutic response to combination immunotherapies and was positively associated with the increased survival rates of mice with tumors. A preliminary clinical study involving small patient cohorts demonstrated that [18F]AlF-NOTA-BCP137 imaging effectively predicted early patient responses to immunotherapeutic interventions. Conclusion: [18F]AlF-NOTA-BCP137 PET imaging of CD137 is a promising and reliable method for evaluating the efficacy of multiple combination immunotherapies and merits further validation in larger-scale clinical trials. This approach has the potential for early noninvasive visualization of individual patient responses in combination cancer immunotherapy and will aid in tailoring personalized strategies for patients.

Circulating immune landscape in melanoma patients undergoing anti-PD1 therapy reveals key immune features according to clinical response to treatment.

Immune checkpoint blockers (ICB) bring unprecedented clinical success, yet many patients endure immune mediated adverse effects and/or fail to respond. Predictive signatures of response to ICB and mechanisms of clinical efficacy or failure remain understudied. DC subsets, in network with conventional αβ T (Tconv), NK, γδ T and iNKT cells, harbor pivotal roles in tumor control, yet their involvement in response to ICB remained underexplored. We performed an extensive longitudinal monitoring of circulating immune cells from melanoma patients treated with first-line anti-PD1, before (T0) and during treatment. We assessed the phenotypic and functional features of DC and effector cells' subsets by multi-parametric flow cytometry and ProcartaPlex® dosages. We revealed differences according to response to treatment and modulations of patterns during treatment, highlighting a strong link between the immune landscape and the outcome of anti-PD1 therapy. Responders exhibited higher frequencies of circulating cDC1s, CD8+ T cells, and γδ2+ T cells in central memory (CM) stage. Notably, we observed a distinct remodeling of ICP expression profile, activation status and natural cytotoxicity receptor patterns of immune subsets during treatment. Anti-PD1 modulated DCs' functionality and triggered deep changes in the functional orientation of Tconv and γδT cells. Overall, our work provides new insights into the immunological landscape sustaining favorable clinical responses or resistance to first-line anti-PD1 therapy in melanoma patients. Such exploration participates in uncovering the mechanism of action of anti-PD1, discovering innovative predictive signatures of response, and paves the way to design pertinent combination strategies to improve patient clinical benefits in the future.

High-resolution crystal structure of PD-1 in complex with retifanlimab, the FDA-approved immune checkpoint blocking antibody for treating Merkel cell carcinoma

Retifanlimab is a humanized monoclonal antibody that specifically targets programmed cell death protein 1 (PD-1), an essential immune checkpoint that modulates T-cell immune responses. Several anti-PD-1 antibodies have been market-approved, marking a significant advancement in the treatment of diverse tumor types by restoring the T-cell immune response. Recently, the US FDA approved retifanlimab for treating metastatic or recurrent locally advanced Merkel cell carcinoma. We present the crystal structure of PD-1 in complex with the retifanlimab Fab at a resolution of 1.54 Å to elucidate the structural basis for the mechanism of action of this antibody. This work clarifies the detailed interactions and conformational alterations that occur upon antibody binding. The epitope of retifanlimab partially overlaps with the ligand binding site, and its binding induced unique conformations of the flexible loops within PD-1, including BC, C'D, and FG loops, thereby optimizing interactions with the antibody. A thorough analysis of its interaction with PD-1 and other FDA-approved anti-PD-1 antibodies may provide valuable insights into the rational design of enhanced therapies to regulate immune responses in cancer treatment.

Breakthrough in RAS targeting with pan-RAS(ON) inhibitors RMC-7977 and RMC-6236

The multi-selective tri-complex RAS(ON) inhibitors RMC-7977 and RMC-6236 signal new avenues for RAS targeting. This systematic review aims to comprehensively present the available preclinical and early clinical data on these agents. We screened Medline, Scopus, the ESMO and ASCO conference sites and ClinicalTrials.gov for related studies and found four published preclinical studies and one clinical trial. In these reports, RMC-7977 and RMC-6236 effectively drove tumor suppression, especially in non-small cell lung cancer and pancreatic ductal adenocarcinoma, and minimal effects in healthy tissue were observed. MYC amplification was reported to be a main contributor to the development of resistance. Six trials are currently ongoing, including one randomized trial, and promising results are expected from combination with other agents, such as immune-checkpoint blockers.

Harnessing Cross-strand π-π Interlocking for Synergistic Enhancement of Immune Checkpoint Blocking and Ferroptosis.

The dynamic nature of noncovalent bonds in peptide self-assembly allows for selective accommodation of guest molecules. However, it remains unclear how to harness coassembly to reinforce the host peptides and simultaneously improve the application defects of guest molecules. This study aims to achieve supramolecular synergy between the host and guest, further expanding the functional space of the hybrid nanostructures. Herein, we utilized the aromatic regions present in β-sheet peptides to accommodate aromatic molecules, forming long-range nanotubes (NQ40@AIF) through a unique 'cross-strand π-π interlocking'. This strategy not only stabilizes the coassembly effectively but also synergizes the biological functions of the host and guest molecules. Moreover, due to the chemical diversity of the coassembled NQ40@AIF, it exhibits advantages in tumor combination therapy, achieving effective synergy between ferroptosis and immune checkpoint blocking. This work provides a minimalistic strategy for constructing peptide nanostructures with complex functionalities.

Natural killer cells and engagers: Powerful weapons against cancer.

Natural killer (NK) cells are innate immune effectors whose functions rely on receptors binding cytokines, recognizing self-molecules, or detecting danger signals expressed by virus-infected or tumor cells. The potent cytotoxic potential makes NK cells promising candidates for cancer immunotherapy. To enhance their activity strategies include cytokine administration, blocking of immune checkpoints, and designing of antibody-based NK cell engagers (NKCEs). NKCEs represent a cutting-edge approach to cancer therapy: they strengthen the NK-to-target cell interactions and optimize tumor killing, possibly overcoming the immunosuppressive tumor microenvironment. NK cells belong to the innate lymphoid cells (ILCs) and are categorized into different subsets also including cells with a memory-like phenotype: this complexity needs to be explored in the context of cancer immunotherapy, particularly when designing NKCEs. Two strategies to enhance NK cell activity in cancer patients can be adopted: activating patients' own NK cells versus the adoptive transfer of exvivo activated NK cells. Furthermore, the capability of NKCEs to activate γδ T cells could have a significant synergistic effect in immunotherapy.

Fc Effector Function of Immune Checkpoint Blocking Antibodies in Oncology.

Antagonistic monoclonal antibodies (mAbs) targeting inhibitory immune checkpoints have revolutionized the field of oncology. CTLA-4, PD-1, and LAG3 are three co-inhibitory receptors, which can be expressed by subsets of T cells and which play a role in the regulation of adaptive immune responses. Blocking these immune checkpoints receptors (or their ligands) with antagonistic antibodies can lead to tumor regressions and lasting remissions in some patients with cancer. Two anti-CTLA4, six anti-PD1, three anti-PD-L1, and one anti-LAG3 antibodies are currently approved by the FDA and EMA. Their mechanism of action, safety, and efficacy are linked to their affinity with Fc gamma receptors (FcγR) (so called "effector functions"). The anti-CTLA-4 antibodies ipilimumab (IgG1) and tremilimumab (IgG2a), and the anti-PD-L1 avelumab (IgG1) have isotypes with high affinity for activating FcγR and thereby can induce ADCC/ADCP. The effector function is required for the invivo efficacy of anti-CTLA4 antibodies. For anti-PD(L)1 antibodies, where a pure antagonistic function ("checkpoint blockade") is sufficient, some mAbs are IgG1 but have been mutated in their Fc sequence (e.g., durvalumab and atezolizumab) or are IgG4 (e.g., nivolumab and pembrolizumab) to have low affinity for FcγR. Here, we review the impact of FcγR effector function on immune checkpoint blockers safety and efficacy in oncology.

Development of an Educational Website for Patients With Cancer and Preexisting Autoimmune Diseases Considering Immune Checkpoint Blockers: Usability and Acceptability Study.

Patients with cancer and an underlying autoimmune disease who are considering immune checkpoint blockers (ICBs) need to know about the benefits and risks of severe immune-related adverse events and flares of the autoimmune condition. This study aims to develop and alpha test an educational website for patients with cancer. Learning topics, images, and website architecture (including flow and requirements) were developed and iteratively reviewed by members of a community scientist program, a patient advisory group, and content experts. Alpha testing was performed, measuring the site's usability using the Suitability Assessment of Materials and its acceptability using the Ottawa Acceptability Measure. The website included a home page; general information about ICBs; comprehensive modules on the benefits and risks of ICBs for patients with cancer and preexisting autoimmune diseases; general wellness information; and features such as a quiz, additional resources, and a glossary. For the alpha testing, 9 users assessed the newly developed website. Patient reviewers (n=5) had rheumatoid arthritis, Crohn disease, Sjogren syndrome, or vasculitis. Health care provider reviewers (n=4) were medical oncologists or rheumatologists. The median Suitability Assessment of Materials rating was 75 (IQR 70-79; range 0-100) for patients versus 66 (IQR 57-72; range 0-100) for providers (scores ≥70 indicate no substantial changes needed). Recommendations for improvement, mostly involving navigation and accessibility, were addressed. All participants expressed that the website was acceptable and balanced in terms of discussion of benefits and harms. Because half (2/4, 50%) of the providers suggested we increase the amount of information, we extended the content on the impact of having an autoimmune disease when considering ICB treatment, the probability of flares, and the management of flares in this context. The feedback led to minor revisions to enhance readability, navigation, and accessibility, ensuring the website's suitability as a decision-making aid. The newly developed website could become a supporting tool to facilitate patient-physician discussion regarding ICBs.

Photothermal Fe3O4 nanoparticles induced immunogenic ferroptosis for synergistic colorectal cancer therapy

Photothermal therapy (PTT) is a promising non-invasive treatment that has shown great potential in eliminating tumors. It not only induces apoptosis of cancer cells but also triggers immunogenic cell death (ICD) which could activate the immune system against cancer. However, the immunosuppressive tumor microenvironment (TIME) poses a challenge to triggering strong immune responses with a single treatment, thus limiting the therapeutic effect of cancer immunotherapy. In this study, dual-targeted nano delivery system (GOx@FeNPs) combined with αPD-L1 immune checkpoint blocker could inhibit colorectal cancer (CRC) progression by mediating PTT, ferroptosis and anti-tumor immune response. Briefly, specific tumor delivery was achieved by the cyclic arginine glycyl aspartate (cRGD) peptide and anisamide (AA) in GOx@FeNPs which not only had a good photothermal effect to realize PTT and induce ICD, but also could deplete glutathione (GSH) and catalyze the production of reactive oxygen species (ROS) from endogenous H2O2. All these accelerated the Fenton reaction and augmented the process of PTT-induced ICD. Thus, a large amount of tumor specific antigen was released to stimulate the maturation of dendritic cells (DCs) in lymph nodes and enhance the infiltration of CD8+ T cells in tumor. At the same time, the combination with αPD-L1 has favorable synergistic effectiveness against CRC with tumor inhibition rate over 90%. Furthermore, GOx@FeNPs had good magnetic resonance imaging (MRI) capability under T2-weighting owing to the presence of Fe3+, which is favorable for integrated diagnosis and treatment systems of CRC. By constructing a dual-targeted GOx@FeNPs nanoplatform, PTT synergistically combined with ferroptosis was realized to improve the immunotherapeutic effect, providing a new approach for CRC immunotherapy.