Systemic Immunotherapy Research Articles

OP-10 Gut microbiota dysbiosis as a driver of inflammation in Ocular Mucous Membrane Pemphigoid.

Gut microbiome profiles between OcMMP patients (n=49) and healthy controls (n=40) were compared by extracting DNA from faecal samples and amplified for the V4 region of the 16S rRNA gene followed by Illumina Miseq platform sequencing. Sequencing reads were processed using the bioinformatics pipeline available in the mothur v.1.44.1 software. Using multivariable model and adjustment for participant factors, OcMMP cohort was found to be associated with lower number of operational taxonomic units (OTUs) and Shannon Diversity Index when compared to healthy controls. OcMMP OTUs were found to be significantly correlated with both the bulbar conjunctival inflammation score (p=0.03) and the current use of systemic immunotherapy (p=0.02). Linear discriminant analysis effect size scores found Streptococcus and Lachnoclostridium enriched in OcMMP. By contrast, healthy controls were enriched with Oxalobacter, Clostridia uncultured genus-level group (UCG) 014, Christensenellaceae R-7 group and butyrate-producing bacteria such as Ruminococcus, Lachnospiraceae, Coprococcus, Roseburia, Oscillospiraceae UCG 003, 005, NK4A214 group (Log10 LDA score <2, FDR-adjusted p<0.05). In conclusion, OcMMP patients have gut dysbiosis that correlated with bulbar conjunctival inflammation and the use of systemic immunotherapies. This provides a framework for future longitudinal deep phenotyping studies on the role of the gut microbiome in the pathogenesis of OcMMP. Low L, Suleiman K, Shamdas M, Bassilious K, Poonit N, Rossiter AE, Acharjee A, Loman N, Murray PI, Wallace GR, Rauz S. Gut dysbiosis in ocular mucous membrane pemphigoid. Front. Cell. Infect. Microbiol. 2022;12:780354. https://doi.org/10.3389/fcimb.2022.780354.

Alliance A082002 -a randomized phase II/III trial of modern immunotherapy-based systemic therapy with or without SBRT for PD-L1-negative, advanced non-small cell lung cancer

IntroductionTreatment of advanced stage non-small cell lung cancer (NSCLC) has changed dramatically due to immunotherapy. However, patients without Programmed Death-Ligand 1 (PD-L1) protein expression often benefit less from immunotherapy. This trial is designed to test if stereotactic body radiation therapy (SBRT) to a single tumor site can significantly enhance the outcome of patients with advanced stage PD-L1(-) NSCLC when added to systemic therapy including immunotherapy. Materials and MethodsAlliance A082002 is based on subgroup analysis from the randomized phase II PEMBRO-RT trial., PEMBRO-RT compared pembrolizumab alone or with SBRT and revealed improved progression-free and overall survival (PFS and OS, respectively) in PD-L1(-) patients when adding SBRT (8 Gy x 3 fractions). In A082002, patients without PD-L1 expression will be randomized to SBRT (8 Gy x3) plus systemic therapy vs. systemic therapy alone. The primary endpoint of the phase II portion of the trial is PFS and will require 100 patients. The primary endpoint of the phase III portion of the trial is OS and will require an additional 284 patients. This trial will clarify whether adding SBRT to systemic therapy can improve PFS and OS in a larger multi-institutional cohort. Several systemic treatment options are allowed including either immunotherapy alone or chemo-immunotherapy. ConclusionsThis phase II/III Alliance trial A082002 will test whether the addition of SBRT to a single tumor site will enhance the anti-tumor activity of systemic immunotherapy or chemo-immunotherapy in patients with stage IV PD-L1(-) NSCLC. It is now open in the National Clinical Trials Network (NCTN).

Effectiveness of Immune Checkpoint Inhibition vs Chemotherapy in Combination With Radiation Therapy Among Patients With Non–Small Cell Lung Cancer and Brain Metastasis Undergoing Neurosurgical Resection

Patients with brain metastases from non-small cell lung cancer (NSCLC) have regularly been excluded from prospective clinical trials that include therapy with immune checkpoint inhibitors (ICIs). Clinical data demonstrating benefit with ICIs, specifically following neurosurgical brain metastasis resection, are scarce. To evaluate and compare the association of radiation therapy with ICIs vs classic therapy involving radiation therapy and chemotherapy regarding overall survival in a cohort of patients who underwent NSCLC brain metastasis resection. This single-center 1:1 propensity-matched comparative effectiveness study at the largest neurosurgical clinic in Germany included individuals who had undergone craniotomy with brain metastasis resection from January 2010 to December 2021 with histologically confirmed NSCLC. Of 1690 patients with lung cancer and brain metastasis, 480 were included in the study. Key exclusion criteria were small-cell lung cancer, lack of tumor cells by means of histopathological analysis on brain metastasis resection, and patients who underwent biopsy without tumor resection. The association of overall survival with treatment with radiation therapy and chemotherapy vs radiation therapy and ICI was evaluated. Radiation therapy and chemotherapy vs radiation therapy and ICI following craniotomy and microsurgical brain metastasis resection. Median overall survival. From the whole cohort of patients with NSCLC (N = 384), 215 (56%) were male and 169 (44%) were female. The median (IQR) age was 64 (57-72) years. The 2 cohorts of interest included 108 patients (31%) with radiation therapy and chemotherapy and 63 patients (16%) with radiation therapy and ICI following neurosurgical metastasis removal (before matching). Median (IQR) follow-up time for the total cohort was 47.9 (28.2-70.1) months with 89 patients (23%) being censored and 295 (77%) dead at the end of follow-up in December 2021. After covariate equalization using propensity score matching (62 patients per group), patients receiving radiation therapy and chemotherapy after neurosurgery had significantly lower overall survival (11.8 months; 95% CI; 9.1-15.2) compared with patients with radiation therapy and ICIs (23.0 months; 95% CI; 20.3-53.8) (P < .001). Patients with NSCLC brain metastases undergoing neurosurgical resection had longer overall survival when treated with radiation therapy and ICIs following neurosurgery compared with those receiving platinum-based chemotherapy and radiation. Radiation and systemic immunotherapy should be regularly evaluated as a treatment option for these patients.

Outcomes From Cytotoxic Chemotherapy Following Progression on Immunotherapy in Metastatic Melanoma: An Institutional Case-Series.

IntroductionThe role of chemotherapy in the management of advanced melanoma is limited due to low response rates and short survival. Improved outcomes to chemotherapy administered after immunotherapy for metastatic melanoma and other solid tumors have been reported. We studied the outcomes of subjects treated at the University of Virginia (UVA) with chemotherapy following progression on prior systemic immunotherapy and compared the results with the existing literature.Materials and MethodsSubjects were identified through an institutional database of patients treated with immunotherapy at UVA. Demographic, pathologic and clinical factors were collected, along with dates of therapy, investigator-assessed best response as per Response Evaluation Criteria for Solid Tumors version 1.1 and dates of death or last follow up. Kaplan-Meier survival estimates and log-rank tests were used to perform time to event analysis of progression free survival and overall survival.ResultsForty-five patients were identified who met the inclusion criteria including 24 men and 21 women with a median age of 61 years. All patients had received at least one line of immunotherapy including 64.4% with prior anti-PD1 treatment. The cytotoxic chemotherapy regimens used included carboplatin with paclitaxel (55.6%), temozolomide (31.1%) and nab-paclitaxel (13.3%). The overall response rate for cytotoxic chemotherapy 22.2% and the disease control rate was 35.6%. The median progression-free survival was 1.7 months and median overall survival was 4.7 months. Nineteen (42.2%) patients survived greater than 6 months and seven (15.5%) patients survived over 12 months. Fourteen patients were able to proceed to further therapy.DiscussionOur results reveal that receipt of immunotherapy prior to chemotherapy for metastatic melanoma does not appear to improve the benefit of chemotherapy. The palliation of symptoms, maintenance of performance status and disease control may be valuable for some patients during this time of robust research and discovery for metastatic melanoma.

Gut Dysbiosis in Ocular Mucous Membrane Pemphigoid.

Mucous Membrane Pemphigoid is an orphan multi-system autoimmune scarring disease involving mucosal sites, including the ocular surface (OcMMP) and gut. Loss of tolerance to epithelial basement membrane proteins and generation of autoreactive T cell and/or autoantibodies are central to the disease process. The gut microbiome plays a critical role in the development of the immune system. Alteration in the gut microbiome (gut dysbiosis) affects the generation of autoreactive T cells and B cell autoantibody repertoire in several autoimmune conditions. This study examines the relationship between gut microbiome diversity and ocular inflammation in patients with OcMMP by comparing OcMMP gut microbiome profiles with healthy controls. DNA was extracted from faecal samples (49 OcMMP patients, 40 healthy controls), amplified for the V4 region of the 16S rRNA gene and sequenced using Illumina Miseq platform. Sequencing reads were processed using the bioinformatics pipeline available in the mothur v.1.44.1 software. After adjusting for participant factors in the multivariable model (age, gender, BMI, diet, proton pump inhibitor use), OcMMP cohort was found to be associated with lower number of operational taxonomic units (OTUs) and Shannon Diversity Index when compared to healthy controls. Within the OcMMP cohort, the number of OTUs were found to be significantly correlated with both the bulbar conjunctival inflammation score (p=0.03) and the current use of systemic immunotherapy (p=0.02). The linear discriminant analysis effect size scores indicated that Streptococcus and Lachnoclostridium were enriched in OcMMP patients whilst Oxalobacter, Clostridia uncultured genus-level group (UCG) 014, Christensenellaceae R-7 group and butyrate-producing bacteria such as Ruminococcus, Lachnospiraceae, Coprococcus, Roseburia, Oscillospiraceae UCG 003, 005, NK4A214 group were enriched in healthy controls (Log10 LDA score < 2, FDR-adjusted p <0.05). In conclusion, OcMMP patients have gut dysbiosis correlating with bulbar conjunctival inflammation and the use of systemic immunotherapies. This provides a framework for future longitudinal deep phenotyping studies on the role of the gut microbiome in the pathogenesis of OcMMP.

Local anesthetics elicit immune-dependent anticancer effects

BackgroundRetrospective clinical trials reported a reduced local relapse rate, as well as improved overall survival after injection of local anesthetics during cancer surgery. Here, we investigated the anticancer effects of...

Immunotherapy questions in melanoma

David McCall, Editor, BioInsights, speaks to Michael Postow, Chief of the Melanoma Service, Associate Attending Physician, Memorial Sloan Kettering Cancer Center. Michael Postow is the Chief of the Melanoma Service and an Associate Attending Physician at Memorial Sloan Kettering Cancer Center. He was involved in the clinical development of the nivolumab + ipilimumab combination and led the first randomized trial of combination immune checkpoint inhibition, resulting in its FDA approval in 2015. He has written papers on immunotherapy toxicities and combining systemic immunotherapies with other treatments such as radiotherapy. He enjoys skiing, outdoor activities, and trying to keep up with his two toddlers.

Primary choroidal melanoma followed by two metachronous ipsilateral ocular metastases

Purpose. To describe two ipsilateral, metachronous, ocular choroidal melanoma metastases.Material and methods. A 64-year-old choroidal melanoma patient was initially treated with palladium-103 ophthalmic plaque brachytherapy which induced local control of the primary cancer. Seven years later, ophthalmic findings of a second, ipsilateral, discrete choroidal melanoma prompted restaging which revealed new hepatic and nodal metastases. Systemic immunotherapy (ipilimumab 3 mg/kg with nivolumab 1 mg/kg IV every 3 weeks 4 doses) resulted in intraocular tumor regression and was followed by maintenance nivolumab 480 mg IV every 4 weeks with follow-up ophthalmic examinations.Results. Three years after initiation of systemic immunotherapy, the patient was found to have a second ipsilateral local recurrence of choroidal melanoma. It presented with retinal detachment, uveitis, and optic neuritis. Then, due to its anterior uveal location, extrascleral tumor extension was amenable to a diagnostic biopsy. Overall, 3 years after onset of metastatic uveal melanoma and 2 months after her second ocular metastasis, the patient died. This was 10 years after the initial diagnosis of choroidal melanoma.Conclusions. Metastatic choroidal melanoma can present twice in the same eye as the primary tumor. Ophthalmic and systemic examinations allowed for immunotherapy to affect initial systemic regression, vision sparing, and globe salvage.

Liver metastasis in uveal melanoma - treatment options and clinical outcome.

Uveal melanoma (UM) is the most prevalent primary intraocular malignancy in adults with a stable incidence rate between five and seven cases per million in Europe and the United States. Although UM and melanoma from other sites have the same origin, UM has different epidemiological, biological, pathological and clinical features including characteristic metastatic hepatotropism. Despite improvements in the treatment of primary tumours, approximately 50% of patients with UM will develop metastases. In 90% of cases the liver is the first site of metastasis, however the mechanisms underlying this hepatic tropism have not been elucidated. Metastatic disease is associated with a very poor prognosis with a median overall survival of 6 to 12 months. Currently, there is no standard systemic treatment available for metastatic UM and once liver metastases have developed, prognosis is relatively poor. In order to prolong survival, close follow-up in all patients with UM is recommended for early detection and treatment. The treatment of metastatic UM includes systemic chemotherapy, immunotherapy and molecular targeted therapy. Liver-directed therapies, such as resection, radioembolization, chemoembolization, immunoembolization, isolated and percutaneous liver perfusion as well as thermal ablation represent available treatment options. However, to date a consensus regarding the optimal method of treatment is still lacking and the importance of setting guidelines in the treatment and management of metastatic UM is becoming a priority. Improvement in knowledge and a better insight into tumour biology, immunology and metastatic mechanism may improve current treatment methods and lead to the development of new strategies paving the way for a personalized approach.

In situ vaccination using unique TLR9 ligand K3-SPG induces long-lasting systemic immune response and synergizes with systemic and local immunotherapy

Although checkpoint inhibitors (CPIs) have changed the paradigm of cancer therapy, low response rates and serious systemic adverse events remain challenging. In situ vaccine (ISV), intratumoral injection of immunomodulators that stimulate innate immunity at the tumor site, allows for the development of vaccines in patients themselves. K3-SPG, a second-generation nanoparticulate Toll-like receptor 9 (TLR9) ligand consisting of K-type CpG oligodeoxynucleotide (ODN) wrapped with SPG (schizophyllan), integrates the best of conventional CpG ODNs, making it an ideal cancer immunotherapy adjuvant. Focusing on clinical feasibility for pancreaticobiliary and gastrointestinal cancers, we investigated the antitumor activity of K3-SPG-ISV in preclinical models of pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC). K3-SPG-ISV suppressed tumor growth more potently than K3-ISV or K3-SPG intravenous injections, prolonged survival, and enhanced the antitumor effect of CPIs. Notably, in PDAC model, K3-SPG-ISV alone induced systemic antitumor effect and immunological memory. ISV combination of K3-SPG and agonistic CD40 antibody further enhanced the antitumor effect. Our results imply that K3-SPG-based ISV can be applied as monotherapy or combined with CPIs to improve their response rate or, conversely, with CPI-free local immunotherapy to avoid CPI-related adverse events. In either strategy, the potency of K3-SPG-based ISV would provide the rationale for its clinical application to puncturable pancreaticobiliary and gastrointestinal malignancies.

Functional Status and Survival in Older Nursing Home Residents With Advanced Non-Small-Cell Lung Cancer: A SEER-Medicare Analysis.

Many older patients with advanced lung cancer have functional limitations and require skilled nursing home care. Function, assessed using activities of daily living (ADL) scores, may help prognostication. We investigated the relationship between ADL impairment and overall survival among older patients with advanced non-small-cell lung cancer (NSCLC) receiving care in nursing homes. Using the SEER-Medicare database linked with Minimum Data Set assessments, we identified patients age 65 years and older with NSCLC who received care in nursing homes from 2011 to 2015. We used Cox regression and Kaplan-Meier survival curves to examine the relationship between ADL scores and overall survival among all patients; among patients who received systemic cancer chemotherapy or immunotherapy within 3 months of NSCLC diagnosis; and among patients who did not receive any treatment. We included 3,174 patients (mean [standard deviation] age, 77 [7.4] years [range, 65-102 years]; 1,664 [52.4%] of female sex; 394 [12.4%] of non-Hispanic Black race/ethnicity), 415 (13.1%) of whom received systemic therapy, most commonly with carboplatin-based regimens (n = 357 [86%] patients). The median overall survival was 3.1 months for patients with ADL score < 14, 2.8 months for patients with ADL score between 14 and 17, 2.3 months for patients with ADL score between 18-19, and 1.8 months for patients with ADL score 20+ (log-rank P < .001). The ADL score was associated with increased risk of death (hazard ratio [HR], 1.20; 95% CI, 1.16 to 1.25 per standard deviation). One standard deviation increase in the ADL score was associated with lower overall survival rate among treated (HR, 1.14; 95% CI, 1.02 to 1.27) and untreated (HR, 1.20; 95% CI, 1.15 to 1.26) patients. ADL assessment stratified mortality outcomes among older nursing home adults with NSCLC, and may be a useful clinical consideration in this population.

Evidence and implementation gaps in management of sentinel node–positive melanoma in the United States

BackgroundMelanoma clinical trials demonstrated that completion lymph node dissection is low value for most sentinel lymph node–positive patients. Contemporaneous trials of adjuvant systemic immunotherapy and BRAF/MEK targeted therapy showed improved recurrence-free survival in high-risk sentinel lymph node–positive patients. To better understand how oncologic evidence is incorporated into practice (implementation), we evaluated factors associated with discontinuation of completion lymph node dissection and adoption of systemic treatment at United States Commission on Cancer–accredited centers. MethodsIn a retrospective cohort study of adults with sentinel lymph node–positive melanoma treated from 2012 to 2017 using the National Cancer Database, we evaluated use of completion lymph node dissection and adjuvant systemic treatment using mixed-effects logistic regression, reporting results as odds ratios with 95% confidence intervals. ResultsAmong 10,240 sentinel lymph node–positive melanoma patients, performance of completion lymph node dissection declined from 60% to 27%. Adjuvant systemic treatment increased from 29% to 43% (37% in stage IIIA patients, 46% in IIIB–C). Completion lymph node dissection was less common with lower extremity tumors (odds ratio = 0.53, 95% confidence interval = 0.44–0.64) and more common with multiple positive sentinel lymph nodes (odds ratio = 2.36, 95% confidence interval = 2.08–2.67), treatment at a high- or moderate-volume center (odds ratiohigh = 1.49, 95% confidence interval = 1.05–2.12; odds ratiomoderate = 1.32, 95% confidence interval = 1.05–1.64), and receipt of systemic therapy (odds ratio = 1.44, 95% confidence interval = 1.27–1.63). The increased likelihood of completion lymph node dissection in patients receiving adjuvant systemic treatment persisted in the most recent study years and in patients with a single positive sentinel lymph node. ConclusionAt a population level, completion lymph node dissection declined and adjuvant systemic treatment increased, reflecting evidence-responsive care. Variation in persistent use of completion lymph node dissection and in provision of adjuvant treatment for lower risk patients highlights residual gaps in both evidence and implementation.

Local Destruction of Tumors for Systemic Immunoresponse: Engineering Antigen-Capturing Nanoparticles as Stimulus-Responsive Immunoadjuvants.

Immunotherapy has established a new paradigm for cancer treatment and made many breakthroughs in clinical practice. However, the rarity of immune response suggests that additional intervention is necessary. In recent years, it has been reported that local tumor destruction (LTD) can cause cancer cell death and induce an immunologic response. Thus, the combination of immunotherapy and LTD methods will be a promising approach to improve immune efficiency for cancer treatment. Herein, a nanobiotechnology platform to achieve high-precision LTD for systemic cancer immunotherapy has been successfully constructed. Possessing radio-sensitizing and photothermal properties, the engineered immunoadjuvant-loaded nanoplatform, which could precisely induce radiotherapy (RT)/photothermal therapy (PTT) to eliminate local tumor and meanwhile lead to the release of tumor-derived protein antigens (TDPAs), has been facilely fabricated by commercialized SPG membrane emulsification technology. Further on, the TDPAs could be captured and form personal nanovaccines in situ to serve as both reservoirs of antigen and carriers of immunoadjuvant, which can effectively improve the immune response. The investigations suggest that the combination of RT/PTT and improved immunotherapy using adjuvant-encapsulated antigen-capturing nanoparticles holds tremendous promise in cancer treatments.

High Plus Low Dose Radiation Strategy in Combination with TIGIT and PD1 Blockade to Promote Systemic Antitumor Responses.

Simple SummaryThis study combines a novel strategy of radiotherapy that utilizes high- and low- dose radiation with immune oncology agents (anti-TIGIT and anti-PD1 monoclonal antibodies) in order to overcome the inhibitory tumor stroma and battle tumors systemically. The findings from this work will impact how checkpoint inhibitors are delivered to maximize their efficacy. Tumors deploy various immune-evasion mechanisms that create a suppressive environment and render effector T-cells exhausted and inactive. Therefore, a rational utilization of checkpoint inhibitors may alleviate exhaustion and may partially restore antitumor functions. However, in high-tumor-burden models, the checkpoint blockade fails to maintain optimal efficacy, and other interventions are necessary to overcome the inhibitory tumor stroma. One such strategy is the use of radiotherapy to reset the tumor microenvironment and maximize systemic antitumor outcomes. In this study, we propose the use of anti-PD1 and anti-TIGIT checkpoint inhibitors in conjunction with our novel RadScopal technique to battle highly metastatic lung adenocarcinoma tumors, bilaterally established in 129Sv/Ev mice, to mimic high-tumor-burden settings. The RadScopal approach is comprised of high-dose radiation directed at primary tumors with low-dose radiation delivered to secondary tumors to improve the outcomes of systemic immunotherapy. Indeed, the triple therapy with RadScopal + anti-TIGIT + anti-PD1 was able to prolong the survival of treated mice and halted the growth of both primary and secondary tumors. Lung metastasis counts were also significantly reduced. In addition, the low-dose radiation component reduced TIGIT receptor (PVR) expression by tumor-associated macrophages and dendritic cells in secondary tumors. Finally, low-dose radiation within triple therapy decreased the percentages of TIGIT+ exhausted T-cells and TIGIT+ regulatory T-cells. Together, our translational approach provides a new treatment alternative for cases refractory to other checkpoints and may bring immunotherapy into a new realm of systemic disease control.

Tumores melanocíticos

The most relevant melanocytic tumors are melanocytic nevi, commonly called «moles», which are the consequence of the migration and later proliferation of cells of neuroectodermal origin to the skin. Though they can be congenital, they are mostly acquired; one of the main determinants of their appearance is sun exposure. Despite the fact that it is an intensely debated issue, it is accepted that skin melanomas (malignant proliferations of melanocytes) only come from melanocytic nevi in one-third of cases; the majority appear de novo. The treatment and prognosis for skin melanomas has undergone a revolution in the past decade due to the advent of targeted therapy and immunotherapy. In localized forms of melanoma, complete extirpation of the lesion with widening continues to be the gold standard treatment, as a cure is possible with this method. In locally advanced forms (for example, lymph node invasion), adjuvant medical treatment has been praised for increasing disease-free time. In stage IV melanomas or those with distant metastases, systemic immunotherapy and targeted anti-BRAF/MEK therapy has entirely supplanted classical chemotherapy, as it significantly prolongs patients’ life expectancy.

Biomarkers in muscle invasive bladder cancer.

Muscle invasive bladder cancer (MIBC) carries a poor prognosis with a 5-year overall survival rate of 40-50%. For localized disease, radical treatment options are cystectomy or radiotherapy with or without a radiosensitiser. Neoadjuvant or adjuvant chemotherapy is often delivered in addition to either. Metastatic disease can be treated with palliative systemic chemotherapy or immunotherapy. Standard clinicopathological information is insufficient to guide treatment decisions in several clinical scenarios in MIBC and there has been substantial effort to identify predictive and prognostic biomarkers. Despite this, no biomarker has been sufficiently qualified in prospective clinical trials to justify routine use. In this chapter we discuss these biomarkers and provide insight into the significant unmet need for robust biomarkers to inform treatment decisions and ultimately improve outcomes for bladder cancer patients.

Major advancement in Ophthalmology in 2021

This year, we are seeing a major boost in the advancement of new targeted gene therapies in the fight against certain orphan ocular genetic diseases that cause blindness. The progressive introduction of computer tools with algorithms for the recognition of diabetic retinopathy should be noted. Progress has been made in other areas of ophthalmology, with particular interest in the fight against myopia, given the worrying and rapidly increasing incidence of this disease, in varying proportions throughout the world. There has also been a major effort to develop new ways of delivering specific ocular treatments without having to rely on patient compliance. Finally, we are discovering new diagnostic and clinical entities related to the side effects of systemic immunotherapy generally used in oncology.

Self-Assembled Nanovesicles with Energy Expenditure, Nitric Oxide Release, Immune Activation for Boosting Systemic Immunotherapy

Self-Assembled Nanovesicles with Energy Expenditure, Nitric Oxide Release, Immune Activation for Boosting Systemic Immunotherapy

Self-assemblies with cascade effect to boost antitumor systemic immunotherapy.

Bio-organic hybrid self-assemblies based on amino acids, conjugated polymers, Fe3+ and enzymes are fabricated with tumor environment-responsive and light-triggered NO release properties. By sequential energy consumption, NO attack and immune activation, FFPG shows boosted antitumor activity toward both primary and distant tumors. The three-level cascade strategy (starvation/NO/immunotherapy) adopted in this work offers a pathway to address the dilemma of low cure rate of malignant tumors.

Injectable thermosensitive hydrogel to enhance the photothermal ablation and systemic immunotherapy of breast tumors.

As the high-frequency tumor in women around the world, breast cancer has high mortality due to metastasis tumors making it difficult to cure. Herein, we report a near-infrared (NIR) activated bio-multifunctional thermosensitive hydrogel (denoted as AMDR) with powerful cell killing and immunogenicity amplifying ability. Based on the molecular engineering strategy, a photothermal agent (M-4) with 52.4% conversion efficiency was synthesized. Accordingly, the designed injectable thermosensitive hydrogel AMDR is simply fabricated by the employment of the M-4 photothermal agent, doxorubicin hydrochloride (DOX) as the antitumor drug, and imiquimod (R837) as the immunologic adjuvant by self-assembly. Under NIR irradiation, the AMDR hydrogel can generate local mild heat to release DOX for synergistic killing of tumor cells with little damage to normal cells. The immunogenic cell death induced by potent in situ killing combined with heat-released R837 can trigger robust immune response to inhibit and kill metastasis tumors. The developed AMDR hydrogel is successfully applied in the treatment of primary tumors and inhibition of distal tumors of tumor-bearing mice. The study provides a novel strategy and platform for complete treatment of breast cancer and also offers ideas for designing high-efficiency photothermal agents.