With the annual increase in the incidence and mortality rates of gastric cancer, it has gradually become one of the significant threats to human health. Approximately 90% of gastric cancer patients are diagnosed with adenocarcinoma. Although the 5-year survival rate for early-stage gastric cancer can exceed 90%, due to its concealed symptoms, less than half of the patients are eligible for radical surgical treatment upon diagnosis. For gastric cancer patients receiving palliative treatment, the current expected survival time is only about one year. In China, the majority of gastric cancer patients, accounting for about 80% of the total, are in the locally advanced stage. For these patients, radical surgery remains the primary treatment option; however, surgery alone is often inadequate in controlling tumor progression. In the pivotal MAGIC study, the recurrence rate was as high as 75%, and similar results were obtained in the French ACCORD07-FFCD9703 study. Numerous clinical trials are currently exploring preoperative neoadjuvant therapy for patients with locally advanced gastric cancer. Data indicates that preoperative neoadjuvant therapy can not only reduce the size of the local tumor but also shrink surrounding lymph nodes, thereby downstaging the tumor and improving the R0 resection rate. Additionally, it can decrease tumor cell activity and eliminate potential micrometastases. The emergence of various immunotherapies has ushered in a new era for neoadjuvant treatment options for gastric cancer.

Immune checkpoint inhibitors (ICIs) are increasingly used in the treatment of cancer. However, immune-related adverse events are prevalent in patients receiving ICI therapy. A serious immune-related adverse event is ICI-myocarditis, which is complex to diagnose given that the significance of early symptoms and biomarker trajectories, such as high-sensitivity troponin T (hs-TnT) are unclear.

The purpose of the study was to evaluate kinetics of hs-TnT in cancer patients receiving ICI and to identify patients at risk of developing ICI-myocarditis.

This prospective, observational, single-center study included 164 patients receiving ICI therapy. Patients' history, demographics, and clinical characteristics, as well as survival statistics, were collected from electronic patient records and used to analyze associations between elevated hs-TnT (≥14 ng/L) and a significant rise in hs-TnT (100% rise from baseline, with an absolute value ≥2x upper limit of normal (ie, ≥28 ng/L) with ICI-myocarditis.

We included 164 patients with a mean follow-up time of 1.60 ± 0.91 years. Melanoma was the most common type of cancer in the patient population, and most patients received treatment with programmed cell death protein 1 (PD-1). Twenty-six patients (16%) exhibited significant hs-TnT elevations, while 8 patients (5%) developed ICI-myocarditis. In 18 of 26 (69%) patients, ICI-myocarditis could not be diagnosed with certainty, while 10 of 26 (38%) patients had no other signs of symptoms of cardiac damage. All 8 myocarditis cases were preceded by significantly higher hs-TnT elevations than asymptomatic patients. Despite a high ICI-myocarditis incidence in our study population, cardiac mortality remained low (4%).

Significant hs-TnT elevations occur more often than previously reported, are often asymptomatic, and do not always lead to myocarditis diagnosis.

Based on the demonstrated clinical activity of immune-checkpoint blockade (ICB) in advanced dedifferentiated liposarcoma (DDLPS) and undifferentiated pleomorphic sarcoma (UPS), we conducted a randomized, non-comparative phase 2 trial ( NCT03307616 ) of neoadjuvant nivolumab or nivolumab/ipilimumab in patients with resectable retroperitoneal DDLPS (n = 17) and extremity/truncal UPS (+ concurrent nivolumab/radiation therapy; n = 10). The primary end point of pathologic response (percent hyalinization) was a median of 8.8% in DDLPS and 89% in UPS. Secondary end points were the changes in immune infiltrate, radiographic response, 12- and 24-month relapse-free survival and overall survival. Lower densities of regulatory T cells before treatment were associated with a major pathologic response (hyalinization > 30%). Tumor infiltration by B cells was increased following neoadjuvant treatment and was associated with overall survival in DDLPS. B cell infiltration was associated with higher densities of regulatory T cells before treatment, which was lost upon ICB treatment. Our data demonstrate that neoadjuvant ICB is associated with complex immune changes within the tumor microenvironment in DDLPS and UPS and that neoadjuvant ICB with concurrent radiotherapy has significant efficacy in UPS.

To assess the relationship between prior exposure to immune checkpoint inhibitors (ICIs) and the risk of postoperative complications in cancer patients.

Single-center retrospective cohort study.

The main exposure was treatment with an FDA-approved ICI within 6 months before surgery.

Exposure to ICIs and covariates was determined from the electronic health record. The primary outcome was a composite of postoperative complications, including prolonged pressor or oxygen dependence, kidney injury, or myocardial injury. Secondary outcomes included each subcomponent of the primary outcome. Of 7674 subjects with cancer admitted to the ICU after surgery, 247 were exposed to one or more ICIs in the 6 months before surgery. After propensity score matching, 197 ICI-exposed subjects were matched to 777 nonexposed. The composite outcome occurred in 70 of 197 (35.5%) ICI-exposed subjects and 251 of 777 (32.3%) nonexposed. There was no difference between exposed and nonexposed groups in the primary composite outcome (odds ratio [OR], 1.12; 95% CI, 0.80-1.58) by conditional logistic regression. Risk of the secondary outcome of prolonged pressor dependence was significantly higher in ICI-exposed subjects (OR, 1.64; 95% CI, 1.01-2.67). Risks of oxygen dependence (OR, 1.13; 95% CI, 0.75-1.73), kidney injury (OR, 1.15; 95% CI, 0.77-1.71), and myocardial injury (OR, 1.76; 95% CI, 1.00-3.10) were not significantly different. There was no difference between groups in the time to hospital discharge alive (p = 0.62).

Exposure to ICIs within 6 months before high-risk surgery was not associated with the composite outcome of cardiopulmonary instability or organ injury in patients with cancer. The potential for an association with the secondary outcomes of cardiac instability and injury is worthy of future study.

Adjuvant and neoadjuvant therapies that reduce the risk of renal cell carcinoma (RCC) recurrence remain an area of unmet need. Advances have been made in metastatic RCC recently by leveraging PD-1/PD-L1 immune checkpoint inhibitors (ICIs). These agents are currently being investigated in the adjuvant and neoadjuvant settings to determine if intervention early in the disease trajectory offers a clinically meaningful benefit. While a disease-free survival benefit has been demonstrated with pembrolizumab, results from other ICI studies have not been positive to date. More mature data from these studies are needed to determine whether there is a survival benefit to ICIs in the curative-intent setting. The success of ICIs has also ushered a new wave of studies combining ICIs with other agents such as targeted therapies and vaccines, which are in early stages of investigation. We review the current state of adjuvant/neoadjuvant therapy in RCC and highlight opportunities for ongoing study.

To evaluate whether relative Hounsfield unit attenuation index (rHUAI) on contrast-enhanced computed tomography (CECT) can predict tumor response in advanced hepatocellular carcinoma (HCC) patients who received sequential combined treatment of immune checkpoint inhibitor (ICI) and anti-angiogenesis therapy.

One hundred seventeen advanced HCC patients who underwent the sequential combined treatment in a tertiary hospital between March 2020 and December 2021 were allocated to prediction and validation cohorts (with a ratio of 2:1) based on the time of initial ICI treatment. rHUAI from the arterial to the portal-venous phase (rHU_ap) and from the portal-venous to the delayed phase (rHU_pd) was calculated. The optimal cut-off values (COVs) of rHU_ap and rHU_pd for predicting tumor response were identified using Youden's index. Univariate and multivariable analyses were performed to assess the relationship between the COVs and tumor response. The validity of COVs was verified in the validation cohort using the chi-square test and Cramer's V coefficient (V).

The optimal COVs of the two observers were 0.5316 and 0.3265 for rHU_ap, and -0.0208 and -0.0048 for rHU_pd, respectively. Multivariable analysis suggested that the COVs were independently associated with tumor response in the prediction cohort (rHU_ap, Odds ratio: 7.727 and 7.808, 95 % CI: 2.516-23.728 and 2.399-25.410, p value < 0.001 and 0.001; rHU_pd, Odds ratio: 0.034 and 0.011, 95 % CI: 0.002-0.600 and 0.001-0.209, p value of 0.021 and 0.003). In the validation cohort, the optimal COVs of rHU_ap had a moderate to a strong association with tumor response (V = 0.362-0.545, p < 0.05). The association between COVs of rHU_pd and tumor response was slight to strong (V = 0.24-0.545, p = 0.001 to 0.134).

rHUAI obtained from CECT has the potential as a non-invasive tool for predicting tumor response in advanced HCC patients who have received combined ICI and anti-angiogenesis treatment.

Stage III non-small cell lung cancer (NSCLC) is a heterogeneous disease with different subtypes, multidisciplinary teams-led management, and a poor prognosis. Currently, the clinical benefits of stage III NSCLC in the neoadjuvant setting are still unclear. We performed a meta-analysis of published data on neoadjuvant chemoimmunotherapy in stage III NSCLC to systematically evaluate its efficacy and safety.

We searched the databases to identify eligible studies of neoadjuvant chemoimmunotherapy for stage III NSCLC. The primary outcomes mainly included pathological and radiological response outcomes, the feasibility of surgery, and the safety of the regimen. The pathological and radiological response included the rate of major pathologic response (MPR), complete pathologic response (pCR), radiological response outcomes, and R0 resection; The feasibility included the rate of surgical resection, conversion to thoracotomy, surgical complications, pathological downstaging of clinical disease stage. The safety included the incidence of treatment-related adverse events (TRAEs) and severe adverse events (SAEs). R 4.1.3 software was conducted for data analysis, and p < 0.05 was considered statistically significant.

Nine trials containing a total of 382 populations were eligible for the meta-analysis, with the pooled surgical resection rate of 90%. Owing to the large heterogeneity of the single-rate meta-analysis, the random effect model was adopted. The estimated pooled prevalence of MPR was 56% (95%CI 0.39-0.72) and of pCR was 39% (95%CI 0.28-0.51). The pooled rate of TRAEs was 65% (95%CI 0.17-0.99) and SAEs was 24% (95%CI 0.05-0.49).

Compared to neoadjuvant chemotherapy or immunotherapy, neoadjuvant chemoimmunotherapy achieved more pathological and radiological relief, and has a high surgical resection rate and low risk of conversion to thoracotomy and surgical complications, with poor tolerance of toxicity but rarely developing life-threatening adverse events. In conclusion, neoadjuvant chemoimmunotherapy is suggested to be beneficial for stage III NSCLC.

The goal of this guideline/procedure standard is to assist nuclear medicine physicians, other nuclear medicine professionals, oncologists or other medical specialists for recommended use of [18F]FDG PET/CT in oncological patients undergoing immunotherapy, with special focus on response assessment in solid tumors.

In a cooperative effort between the EANM, the SNMMI and the ANZSNM, clinical indications, recommended imaging procedures and reporting standards have been agreed upon and summarized in this joint guideline/procedure standard.

The field of immuno-oncology is rapidly evolving, and this guideline/procedure standard should not be seen as definitive, but rather as a guidance document standardizing the use and interpretation of [18F]FDG PET/CT during immunotherapy. Local variations to this guideline should be taken into consideration.

The European Association of Nuclear Medicine (EANM) is a professional non-profit medical association founded in 1985 to facilitate worldwide communication among individuals pursuing clinical and academic excellence in nuclear medicine. The Society of Nuclear Medicine and Molecular Imaging (SNMMI) is an international scientific and professional organization founded in 1954 to promote science, technology and practical application of nuclear medicine. The Australian and New Zealand Society of Nuclear Medicine (ANZSNM), founded in 1969, represents the major professional society fostering the technical and professional development of nuclear medicine practice across Australia and New Zealand. It promotes excellence in the nuclear medicine profession through education, research and a commitment to the highest professional standards. EANM, SNMMI and ANZSNM members are physicians, technologists, physicists and scientists specialized in the research and clinical practice of nuclear medicine. All three societies will periodically put forth new standards/guidelines for nuclear medicine practice to help advance the science of nuclear medicine and improve service to patients. Existing standards/guidelines will be reviewed for revision or renewal, as appropriate, on their fifth anniversary or sooner, if indicated. Each standard/guideline, representing a policy statement by the EANM/SNMMI/ANZSNM, has undergone a thorough consensus process, entailing extensive review. These societies recognize that the safe and effective use of diagnostic nuclear medicine imaging requires particular training and skills, as described in each document. These standards/guidelines are educational tools designed to assist practitioners in providing appropriate and effective nuclear medicine care for patients. These guidelines are consensus documents based on current knowledge. They are not intended to be inflexible rules or requirements of practice, nor should they be used to establish a legal standard of care. For these reasons and those set forth below, the EANM, SNMMI and ANZSNM caution against the use of these standards/guidelines in litigation in which the clinical decisions of a practitioner are called into question. The ultimate judgment regarding the propriety of any specific procedure or course of action must be made by medical professionals considering the unique circumstances of each case. Thus, there is no implication that an action differing from what is laid out in the guidelines/procedure standards, standing alone, is below standard of care. To the contrary, a conscientious practitioner may responsibly adopt a course of action different from that set forth in the standards/guidelines when, in the reasonable judgment of the practitioner, such course of action is indicated by the condition of the patient, limitations of available resources or advances in knowledge or technology subsequent to publication of the guidelines/procedure standards. The practice of medicine involves not only the science, but also the art of dealing with the prevention, diagnosis, alleviation and treatment of disease. The variety and complexity of human conditions make it impossible for general guidelines to consistently allow for an accurate diagnosis to be reached or a particular treatment response to be predicted. Therefore, it should be recognized that adherence to these standards/ guidelines will not ensure a successful outcome. All that should be expected is that practitioners follow a reasonable course of action, based on their level of training, current knowledge, clinical practice guidelines, available resources and the needs/context of the patient being treated. The sole purpose of these guidelines is to assist practitioners in achieving this objective. The present guideline/procedure standard was developed collaboratively by the EANM, the SNMMI and the ANZSNM, with the support of international experts in the field. They summarize also the views of the Oncology and Theranostics and the Inflammation and Infection Committees of the EANM, as well as the procedure standards committee of the SNMMI, and reflect recommendations for which the EANM and SNMMI cannot be held responsible. The recommendations should be taken into the context of good practice of nuclear medicine and do not substitute for national and international legal or regulatory provisions.

Response rates to immune checkpoint blockade (ICB) remain low in oesophageal adenocarcinoma (OAC). Combining ICB with immunostimulatory chemotherapies to boost response rates is an attractive approach for converting 'cold' tumours into 'hot' tumours. This study profiled immune checkpoint (IC) expression on circulating and tumour-infiltrating T cells in OAC patients and correlated these findings with clinical characteristics. The effect of first-line chemotherapy regimens (FLOT and CROSS) on anti-tumour T cell immunity was assessed to help guide design of ICB and chemotherapy combinations in the first-line setting. The ability of ICB to enhance lymphocyte-mediated cytolysis of OAC cells in the absence and presence of post-FLOT and post-CROSS chemotherapy tumour cell secretome was assessed by a CCK-8 assay. Expression of ICs on T cells positively correlated with higher grade tumours and a subsequent poor response to neoadjuvant treatment. First-line chemotherapy regimens substantially altered IC expression profiles of T cells increasing PD-1, A2aR, KLRG-1, PD-L1, PD-L2 and CD160 and decreasing TIM-3 and LAG-3. In addition, pro-inflammatory T cell cytokine profiles were enhanced by first-line chemotherapy regimens. T cell activation status was significantly altered; both chemotherapy regimens upregulated co-stimulatory markers ICOS and CD69 yet downregulated co-stimulatory marker CD27. However, ICB attenuated chemotherapy-induced downregulation of CD27 on T cells and promoted differentiation of effector memory T cells into a terminally differentiated state. Importantly, dual nivolumab-ipilimumab treatment increased lymphocyte-mediated cytolysis of OAC cells, an effect further enhanced in the presence of post-FLOT tumour cell secretome. These findings justify a rationale to administer ICBs concurrently with first-line chemotherapies.

The neoadjuvant and adjuvant anti-PD-1/PD-L1 treatment has been increasingly noticed. To summarize the global landscape of these clinical trials will provide essential data for all the stakeholders of drug development. Based on the Trialtrove database, a total of 668 clinical trials initiated by the end of 2020 were retrospectively analyzed. We found that a rising capability of global neoadjuvant and adjuvant anti-PD-1/PD-L1 clinical development has been achieved. High prevalent cancer types were extensively studied though the priorities in China and the United States were different. However, a lack of phase III trials and industry-sponsored trials was addressed. The confirmatory neoadjuvant trials were particularly insufficient, and the combination strategy mainly focused on chemotherapy. Thus, more public funding and accelerated regulatory strategies are needed in this field. Efforts should be made to confirm the benefit of neoadjuvant treatment and explore novel combination strategies.

With the rapid development of immunotherapy, the efficacy and feasibility of neoadjuvant immunotherapy for early resectable non-small-cell lung cancer (NSCLC) has been demonstrated. However, there are still difficulties and controversies in evaluating the efficacy of neoadjuvant immunotherapy. In our report, we described a 43-year-old female patient who was diagnosed with stage IIIA (cT1N2M0) pulmonary adenocarcinoma. After two cycles of neoadjuvant immunotherapy (sintilimab) combined with chemotherapy, according to imaging evaluation, the efficacy of the primary lesion was evaluated as stable disease and the mediastinal lymph nodes were evaluated as partial response. However, the postoperative pathological evaluation showed the primary lesion was pathological complete response and the mediastinal lymph nodes were major pathological response. This indicated that neoadjuvant chemo-immunotherapy was effective for both primary and mediastinal lymph nodes, but regression of the lesions was not synchronous. This study provided a complete process of neoadjuvant treatment, illustrating the effectiveness and safety of neoadjuvant chemo-immunotherapy to a certain extent. It is also suggested that the evaluation of neoadjuvant immunotherapy should be combined with imaging and pathology, and the primary tumor and lymph nodes should be evaluated, respectively.

Introduction: Regional or distant metastases from melanoma may be surgically resected but remain at high-risk of recurrence. Over the last few years, several treatments have been approved to mitigate this risk. These include anti-PD-1 agents, specifically pembrolizumab and nivolumab.Areas covered: Herein, we will discuss the landscape of pembrolizumab safety and efficacy used in the adjuvant setting for high-risk, resected melanoma. We place this in context with other available adjuvant therapies, and discuss subgroup analyses.Expert opinion: Anti-PD-1 therapy with either pembrolizumab or nivolumab has become a standard of care for patients with resected stage III or IV melanoma. In our practice, we generally offer these agents (which have comparable safety and efficacy profiles) to patients with resected stage IIIb-IV melanoma regardless of BRAF mutation status.

Even patients after standard surgery and adjuvant chemotherapy still have a high risk of recurrence and metastasis. With the success of immunotherapy in advanced non-small cell lung cancer (NSCLC), the application of immunotherapy in locally advanced NSCLC has being investigated to reduce the recurrence and metastasis. Pre-clinical studies and several phase II clinical studies had provided theoretical support and clinical evidence for neoadjuvant immunotherapy for NSCLC. This review describes the mechanism of neoadjuvant immuno-chemotherapy, summarizes up-to-date clinical studies, and analyzes efficiency and feasibility of neoadjuvant immune monotherapy or immuno-chemotherapy. Results from four studies (NCT02259621, NEOSTAR, LCMC3 and ChiCTR-OIC-17013726) showed efficiency and feasibility of neoadjuvant anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) monotherapy. Neoadjuvant nivolumab plus ipilimumab achieved higher major pathological response rate than nivolumab monotherapy. However, the combination of nivolumab plus ipilimumab led to more severe adverse events as is seen in the NEOSTAR trial. Results from NCT02716038, SAKK 16/14 and NADIM studies suggest that the pathological response rate of neoadjuvant immune-chemotherapy is higher than neoadjuvant immune checkpoint inhibitor monotherapy. This review also elaborates the mechanism of chemotherapy combined with immunotherapy, and discusses the efficacy evaluation after neoadjuvant immunotherapy.
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Immune therapy has emerged as a powerful treatment of metastatic urothelial carcinoma. Over 20 ongoing studies are exploring this strategy in the neoadjuvant setting in patients with localized muscle-invasive bladder cancer.

To summarize the rationale and the clinical outcomes regarding the use of immune checkpoint blockade in the neoadjuvant setting before radical cystectomy.

A systematic review of the literature in the MEDLINE database was performed. The central search strategy used the terms bladder cancer, urothelial carcinoma, mice, human, immunotherapy, neoadjuvant therapy, atezolizumab, pembrolizumab, durvalumab, nivolumab, avelumab, ipilimumab, and tremelimumab. The search was limited to publications between January 2008 and February 2020. Publicly available relevant abstracts from recent meetings were also included.

Phase II trials investigating neoadjuvant immune checkpoint blockade as a single agent before radical cystectomy reported a rate of pathological complete response (CR), ranging from 31% with an anti-PD-L1 monoclonal antibody (mAb) atezolizumab (n = 27/88) to 37% with anti-PD-1 mAb pembrolizumab (n = 42/114). Overall, 92% (n = 87/95) and 98% (n = 112/114) of the patients underwent radical cystectomy. Neoadjuvant immune checkpoint blockade did not delay planned surgery. Checkpoint inhibitor monotherapy was well tolerated, with no unexpected toxicity in the presurgical setting. Early phase I/II trials investigating neoadjuvant combination chemotherapy strategies with immune checkpoint blockers reported enhanced antitumor efficacy, with a pathological CR ranging from 33% to 50%.

Although limited clinical data are available on long-term survival, neoadjuvant immune checkpoint blockade demonstrated effective antitumor efficacy for localized muscle-invasive bladder cancer. Phase III trials are currently investigating this strategy in the presurgical setting.

Immunotherapy prior to surgery has been evaluated for patients with muscle-invasive bladder cancer. Although long-term survival benefit is unknown, such treatment strategy revealed a promising antitumor response rate for patients who underwent radical cystectomy. Ongoing prospective clinical trials will define the potential advantage of this approach over current cisplatin-based chemotherapeutic regimens alone or in combination.

Treatment of multiple malignant solid tumours with programmed death (PD)-1/PD ligand (PD-L) 1 inhibitors has been reported. However, the efficacy and immune adverse effects of combination therapies are controversial. This meta-analysis was performed with PubMed, Web of Science, Medline, EMBASE and Cochrane Library from their inception until January 2020. Random-effect model was adopted because of relatively high heterogeneity. We also calculated hazard ratio (HR) of progression-free survival (PFS), overall survival (OS) and risk ratio (RR) of adverse events (AEs), the incidence of grade 3-5 AEs by tumour subgroup, therapeutic schedules and therapy lines. Nineteen articles were selected using the search strategy for meta-analysis. Combined PD-1/PD-L1 inhibitors prolonged OS and PFS (HR 0.72, P < 0.001) and (HR 0.66, P < 0.001). In addition, incidence of all-grade and grade 3-5 AEs was not significant in the two subgroup analyses (HR 1.01, P = 0.31) and (HR 1.10, P = 0.07), respectively. Our meta-analysis indicated that combination therapy with PD-1/PD-L1 inhibitors had greater clinical benefits and adverse events were not increased significantly.

We developed a custom-designed liposome carrier for codelivery of a potent immunogenic cell death (ICD) stimulus plus an inhibitor of the indoleamine 2,3-dioxygenase (IDO-1) pathway to establish a chemo-immunotherapy approach for solid tumors in syngeneic mice. The carrier was constructed by remote import of the anthraquinone chemotherapeutic agent, mitoxantrone (MTO), into the liposomes, which were further endowed with a cholesterol-conjugated indoximod (IND) prodrug in the lipid bilayer. For proof-of-principle testing, we used IV injection of the MTO/IND liposome in a CT26 colon cancer model to demonstrate the generation of a robust immune response, characterized by the appearance of ICD markers (CRT and HMGB-1) as well as evidence of cytotoxic cancer cell death, mediated by perforin and granzyme B. Noteworthy, the cytotoxic effects involved natural killer (NK) cell, which suggests a different type of ICD response. The immunotherapy response was significantly augmented by codelivery of the IND prodrug, which induced additional CRT expression, reduced number of Foxp3+ Treg, and increased perforin release, in addition to extending animal survival beyond the effect of an MTO-only liposome. The outcome reflects the improved pharmacokinetics of MTO delivery to the cancer site by the carrier. In light of the success in the CT26 model, we also assessed the platform efficacy in further breast cancer (EMT6 and 4T1) and renal cancer (RENCA) models, which overexpress IDO-1. Encapsulated MTO delivery was highly effective for inducing chemo-immunotherapy responses, with NK participation, in all tumor models. Moreover, the growth inhibitory effect of MTO was enhanced by IND codelivery in EMT6 and 4T1 tumors. All considered, our data support the use of encapsulated MTO delivery for chemo-immunotherapy, with the possibility to boost the immune response by codelivery of an IDO-1 pathway inhibitor.

No clinically available biomarkers can predict pathological complete response (pCR) for esophageal squamous cell carcinomas (ESCCs) with neoadjuvant chemoradiotherapy (nCRT). Considering that antitumor immunity status is an important determinant for nCRT, we performed an integrative analysis of immune-related gene profiles from pretreatment biopsies and constructed the first individualized immune signature for pCR and outcome prediction of ESCCs through a multicenter analysis. During the discovery phase, 14 differentially expressed immune-related genes (DEIGs) with greater than a twofold change between pCRs and less than pCRs ( Collapse

The incidence of melanoma in the United States has been increasing over the past several decades. Prognosis largely depends on disease stage, with 5-year melanoma-specific survival ranging from as high as 99% in patients with stage I disease to less than 10% for some patients with stage IV (distant metastatic) disease. Fortunately, in the last 5-10 years, there have been remarkable treatment advances for patients with high-risk resectable melanoma, including approval of targeted and immune checkpoint blockade therapies. In addition, results of recent clinical trials have confirmed the importance of sentinel lymph node biopsy and continue to refine the approach to regional lymph node basin management. Lastly, the melanoma staging system was revised in the eighth edition AJCC Cancer Staging Manual, which was implemented on January 1, 2018. Here we discuss these changes and the clinicopathological features that confer high risk for locoregional and distant disease relapse and poor survival. Implications regarding the management of melanoma in the metastatic and adjuvant settings are discussed, as are future directions for neoadjuvant therapies.

Mounting evidence demonstrates that combining radiation therapy (RT) with immunotherapy can reduce tumor burden in a subset of patients. However, conventional systemic delivery of immunotherapeutics is often associated with significant adverse effects, which force treatment cessation. The aim of this study was to investigate a minimally invasive therapeutics delivery approach to improve clinical response while attenuating toxicity.

We used a nanofluidic drug-eluting seed (NDES) for sustained intratumoral delivery of combinational antibodies CD40 and PDL1. To enhance immune and tumor response, we combined the NDES intratumoral platform with RT to treat the 4T1 murine model of advanced triple negative breast cancer. We compared the efficacy of NDES against intraperitoneal administration, which mimics conventional systemic treatment. Tumor growth was recorded, and local and systemic immune responses were assessed via imaging mass cytometry and flow cytometry. Livers and lungs were histologically analyzed for evaluation of toxicity and metastasis, respectively.

The combination of RT and sustained intratumoral immunotherapy delivery of CD40 and PDL1 via NDES (NDES CD40/PDL1) showed an increase in both local and systemic immune response. In combination with RT, NDES CD40/PDL1 achieved significant tumor burden reduction and liver inflammation mitigation compared with systemic treatment. Importantly, our treatment strategy boosted the abscopal effect toward attenuating lung metastatic burden.

Overall, our study demonstrated superior efficacy of combination treatment with RT and sustained intratumoral immunotherapy via NDES, offering promise for improving therapeutic index and clinical response.

In cancer, lymph nodes (LNs) coordinate tumor antigen presentation necessary for effective antitumor immunity, both at the levels of local cellular interactions and tissue-level organization. In this review, we examine how LNs may be engineered to improve the therapeutic outcomes of cancer immunotherapy. At the cellular scale, targeting the LNs impacts the potency of cancer vaccines, immune checkpoint blockade, and adoptive cell transfer. On a tissue level, macro-scale biomaterials mimicking LN features can function as immune niches for cell reprogramming or delivery in vivo, or be utilized in vitro to enable preclinical testing of drugs and vaccines. We additionally review strategies to induce ectopic lymphoid sites reminiscent of LNs that may improve antitumor T cell priming.

We recently reported a 17.5% objective RECIST 1.1 response rate in a phase II study of pembrolizumab in patients with advanced sarcoma (SARC028). The majority of responses occurred in undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLPS). We sought to determine whether we can identify immune features that correlate with clinical outcomes from tumor tissues obtained pre- and on-treatment.

Pretreatment (n = 78) and 8-week on-treatment (n = 68) tumor biopsies were stained for PD-L1 and multiplex immunofluorescence panels. The density of positive cells was quantified to determine associations with anti-PD-1 response.

Patients that responded to pembrolizumab were more likely to have higher densities of activated T cells (CD8+ CD3+ PD-1+) and increased percentage of tumor-associated macrophages (TAM) expressing PD-L1 pre-treatment compared with non-responders. Pre-treatment tumors from responders also exhibited higher densities of effector memory cytotoxic T cells and regulatory T cells compared with non-responders. In addition, higher density of cytotoxic tumor-infiltrating T cells at baseline correlated with a better progression-free survival (PFS).

We show that quantitative assessments of CD8+ CD3+ PD-1+ T cells, percentage of TAMs expressing PD-L1, and other T-cell densities correlate with sarcoma response to pembrolizumab and improved PFS. Our findings support that multiple cell types present at the start of treatment may enhance tumor regression following anti-PD-1 therapy in specific advanced sarcomas. Efforts to confirm the activity of pembrolizumab in an expansion cohort of patients with UPS/DDLPS are underway.

Cancer immunotherapies that target the programmed cell death 1 (PD-1):programmed death-ligand 1 (PD-L1) immune checkpoint pathway have ushered in the modern oncology era. Drugs that block PD-1 or PD-L1 facilitate endogenous antitumor immunity and, because of their broad activity spectrum, have been regarded as a common denominator for cancer therapy. Nevertheless, many advanced tumors demonstrate de novo or acquired treatment resistance, and ongoing research efforts are focused on improving patient outcomes. Using anti-PD-1 or anti-PD-L1 treatment against earlier stages of cancer is hypothesized to be one such solution. This Review focuses on the development of neoadjuvant (presurgical) immunotherapy in the era of PD-1 pathway blockade, highlighting particular considerations for biological mechanisms, clinical trial design, and pathologic response assessments. Findings from neoadjuvant immunotherapy studies may reveal pathways, mechanisms, and molecules that can be cotargeted in new treatment combinations to increase anti-PD-1 and anti-PD-L1 efficacy.

Anticancer immunotherapies involving the use of immune-checkpoint inhibitors or adoptive cellular transfer have emerged as new therapeutic pillars within oncology. These treatments function by overcoming or relieving tumour-induced immunosuppression, thereby enabling immune-mediated tumour clearance. While often more effective and better tolerated than traditional and targeted therapies, many patients have innate or acquired resistance to immunotherapies. Cancer immunoediting is the process whereby the immune system can both constrain and promote tumour development, which proceeds through three phases termed elimination, equilibrium and escape. Throughout these phases, tumour immunogenicity is edited, and immunosuppressive mechanisms that enable disease progression are acquired. The mechanisms of resistance to immunotherapy seem to broadly overlap with those used by cancers as they undergo immunoediting to evade detection by the immune system. In this Review, we discuss how a deeper understanding of the mechanisms underlying the cancer immunoediting process can provide insight into the development of resistance to immunotherapies and the strategies that can be used to overcome such resistance.

Adjuvant immunotherapies targeting CTLA4 or PD-1 recently demonstrated efficacy in the treatment of earlier stages of human cancer. We previously demonstrated using mouse spontaneous metastasis models that neoadjuvant immunotherapy and surgery was superior, compared to surgery and adjuvant immunotherapy, in eradicating the lethal metastatic disease. However, the optimal scheduling between neoadjuvant immunotherapy and surgery and how it impacts on efficacy and development of immune-related adverse events (irAEs) remains undefined. Using orthotopic 4T1.2 and E0771 mouse models of spontaneously metastatic mammary cancer, we varied the schedule and duration of neoadjuvant immunotherapies and surgery and examined how it impacted on long-term survival. In two tumor models, we demonstrated that a short duration (4-5 days) between first administration of neoadjuvant immunotherapy and resection of the primary tumor was necessary for optimal efficacy, while extending this duration (10 days) abrogated immunotherapy efficacy. However, efficacy was also lost if neoadjuvant immunotherapy was given too close to surgery (2 days). Interestingly, an additional 4 adjuvant doses of treatment following a standard 2 doses of neoadjuvant immunotherapy, did not significantly improve overall tumor-free survival regardless of the combination treatment (anti-PD-1+anti-CD137 or anti-CTLA4+anti-PD-1). Furthermore, biochemical immune-related adverse events (irAEs) increased in tumor-bearing mice that received the additional adjuvant immunotherapy. Overall, our data suggest that shorter doses of neoadjuvant immunotherapy scheduled close to the time of surgery may optimize effective anti-tumor immunity and reduce severe irAEs.

The eighth edition of the American Joint Committee on Cancer (AJCC) melanoma staging system was implemented in the United States on 1 January 2018. Areas covered: This article provides an overview of important changes in the eighth edition AJCC staging system from the seventh edition based on analyses of a large international melanoma database. The clinical implications of these changes for melanoma treatment are also discussed. Expert commentary: A standardized and contemporary cancer staging system that facilitates accurate risk stratification is essential to guide patient treatment. The eighth edition of the AJCC staging system is currently the most widely accepted approach to melanoma staging and classification at initial diagnosis.

Management of metastatic genitourinary malignancies has recently been transformed through the use of immune checkpoint inhibitors. The best way to integrate them into local treatment paradigms is still under investigation.

To systematically evaluate evidence regarding the use of immunotherapy in the treatment of local disease, in both the perioperative and the metastatic setting.

We performed a critical review of PubMed and ClinicalTrials.gov according to the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) statement. Prospective and retrospective studies between 2011 and 2018 were included. Twenty-four publications were selected for inclusion, including 10 on urothelial carcinoma, seven on renal cell carcinoma, six on prostate cancer, and one on germ-cell cancer.

Prospective early-phase trials investigating neoadjuvant immunotherapy prior to cystectomy in urothelial carcinoma suggest a high rate of pathological complete response, from 29% with atezolizumab to 39.5% with pembrolizumab. Several neoadjuvant and adjuvant trials are still ongoing in bladder, renal, and prostate cancers, before or after surgery. The combination of immunotherapy and radiotherapy is being explored and could offer an interesting strategy for definitive treatment modality with curative intent. Finally, in metastatic disease, delayed local treatment could be discussed after immunotherapy in selected patients with an excellent radiographic response.

Little evidence exists on the oncological impact of immunotherapy on the local treatment of genitourinary malignancies, but preliminary results are encouraging and many prospective trials are ongoing.

In this study, we review recent advances in immunotherapy and its role in local treatment. Immunotherapy is evaluated before or after surgery, or in combination with radiotherapy for localized disease. Ongoing trials will bring clarity on the local downstaging effect of immunotherapy and its association with oncological and functional outcomes.

PD-1/PD-L1 checkpoint therapy for cancer is commonly considered to act by reactivating T cells in the tumor microenvironment. Here, we present data from 2 mouse tumor models demonstrating an essential involvement of tumor-draining lymph nodes in PD-1 and PD-L1 therapeutic efficacy. Immune activation induced by checkpoint treatment was predominantly observed in the tumor-draining, but not nondraining, lymph nodes and was reflected in local accumulation of CD8+ T cells. Surgical resection of these lymph nodes, but not contralateral lymph nodes, abolished therapy-induced tumor regressions and was associated with decreased immune infiltrate in the tumor microenvironment. Moreover, inhibitor FTY720, which locks lymphocytes in lymph organs, also abrogated checkpoint therapy, suggesting that the tumor-draining lymph nodes function as sites of T cell invigoration required for checkpoint blockade therapy. Now that PD-1/PD-L1 checkpoint treatment is applied in earlier clinical stages of cancer, our preclinical data advocate for enrolling patients with their tumor-draining lymph nodes still in place, to optimally engage the antitumor immune response and thereby enhance clinical benefit.