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Drug resistance presents a significant challenge in cancer treatment. By far, there is no effective method to solve this issue. Therapeutic cancer vaccine, which uses tumor antigens, e.g. neoantigens, to activate the hosts’ immune system to eliminate tumor cells, may be effective for overcoming tumor resistance. So, it is hypothesized that resistant tumors may have much more abundant tumor mutations in comparison to naive tumors, and the corresponding vaccine may overcome drug resistance. The proteomics data confirmes that cell lysates from resistant tumors to gemcitabine (GEM), a model drug, contain abundant tumor‐associated antigens, tumor‐specific antigens, damage‐associated molecular patterns, and neoantigens, which can activate immune responses. Herein, to enhance antigen presentation, a mesoporous silicon nanovaccine is developed, which is loaded with antigens from GEM treated GEM‐resistant triple‐negative breast cancer 4T1 cells. When mice bearing GEM‐resistant tumors are vaccinated, the nanovaccine displays efficacy against GEM‐resistant tumors. Moreover, when combined with immunotherapy, the efficacy of the developed nanovaccine on GEM‐resistant tumors are further improved by increasing intratumoral T‐cell infiltrations. The work presents a new strategy for overcoming drug resistance using cancer nanovaccine, which broadens clinical application prospects. [ABSTRACT FROM AUTHOR]

Background: Photodynamic therapy (PDT) is an antitumor therapy and has traditionally been regarded as a localized therapy in itself. However, recent reports have shown that it not only exerts a direct cytotoxic effect on cancer cells but also enhances body's tumor immunity. We hypothesized that the immunological response induced by PDT could potentially enhance the efficacy of programmed death‐1 (PD‐1) / programmed death‐ligand 1 (PD‐L1) blockade. Methods: The cytotoxic effects of PDT on colon 26 cells were investigated in vitro using the WST assay. We investigated whether the antitumor effect of anti‐PD‐1 antibodies could be amplified by the addition of PDT. We performed combination therapy by randomly allocating tumor‐bearing mice to four treatment groups: control, anti‐PD‐1 antibodies, PDT, and a combination of anti‐PD‐1 antibodies and PDT. To analyze the tumor microenvironment after treatment, the tumors were resected and pathologically evaluated. Results: The viability rate of colon 26 cells decreased proportionally with the laser dose. In vivo experiments for combined PDT and anti‐PD‐1 antibody treatment, combination therapy showed an enhanced antitumor effect compared with the control. Immunohistochemical findings of the tumor microenvironment 10 days after PDT indicated that the number of CD8+ cells, the area of Iba‐1+ cells and the area expressing PD‐L1 were significantly higher in tumors treated with combination therapy than in tumors treated with anti‐PD‐1 antibody alone, PDT alone, or the control. Conclusions: PDT increased immune cell infiltration into the tumor microenvironment. The immunological response induced by PDT may enhance the efficacy of PD‐1/PD‐L1 blockade. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy is an attractive strategy because it stimulates immune cells to target malignant cells by regulating the intrinsic activity of the immune system. However, due to lacking many immunologic markers, it remains difficult to treat glioma, a representative "cold" tumor. Herein, to wake the "hot" tumor immunity of glioma, Porphyromonas gingivalis (Pg) is customized with a coating to create an immunogenic tumor microenvironment and further prove the effect in combination with the immune checkpoint agent anti‐PD‐1, exhibiting elevated therapeutic efficacy. This is accomplished not by enhancing the delivery of PD‐1 blockade to enhance the effect of immunotherapy, but by introducing bacterial photothermal therapy to promote greater involvement of M1 cells in the immune response. After reaching glioma, the bacteria further target glioma cells and M2 phenotype macrophages selectively, enabling precise photothermal conversion for lysing tumor cells and M2 phenotype macrophages, which thereby enhances the positive feedback loop of cancer cells‐M1 macrophages‐T cells. Collectively, the bacteria synergized with PD‐1 blockade strategy may be the key to overcoming the immunosuppressive glioma microenvironment and improving the outcome of immunotherapy toward glioma. [ABSTRACT FROM AUTHOR]

In situ vaccination is a desirable strategy for cancer immunotherapy due to its convenience and capacity to target tumor antigens. Here, an in situ nanovaccine based on a cationic peptide with cholesterol‐modified, DP7‐C, for cancer immunotherapy is rationally designed, and developed a cancer nanovaccine that is easy to preparate. The nanovaccine includes cocktail small interfering RNAs (siRNAs) and immunologic adjuvant CpG ODNs, has synergistic effect in the cancer treatment. This nanovaccine can induce tumor cell death, promote antigen presentation and relieve immune suppression in the tumor microenvironment (TME). Moreover, this nanovaccine is administered to CT26 (hot) and B16F10 (cold) tumor model mice, in which it targeted the primary tumors and induced systemic antitumor immunity to inhibit metastasis. It is validated that the nanovaccine can convert cold tumors into hot tumors. Furthermore, the nanovaccine increased the immune response to anti‐PD‐1 therapy by modulating the TME in both CT26‐ and B16F10‐tumor‐bearing mice. The siRNA cocktail/CpG ODN/self‐assembling peptide nanovaccine is a simple and universal tool that can effectively generate specific tumor cell antigens and can be combined with immuno‐oncology agents to enhance antitumor immune activity. The versatile methodology provides an alternative approach for developing cancer nanovaccines. [ABSTRACT FROM AUTHOR]

Objective: The effectiveness and security of radiofrequency ablation (RFA) in combination with toripalimab (anti‐PD‐1) for the treatment of recurrent hepatocellular carcinoma (HCC) was studied in this article. Methods: Total of 40 patients were enrolled in the study between September 2019 and November 2021. Data follow‐up ends in April 2022. The study's main focus is on recurrence free survival (RFS), while the secondary objectives was safety. Chi‐square tests, Kaplan‐Meier, and Cox proportional hazards models were utilized to analyze the data. Results: The median follow‐up period was 21.40 months, and the median RFS was 15.40 months in the group that received combination therapy, which was statistically significantly different (HR: 0.44, p = 0.04) compared with the RFA group (8.2 months). RFS rates (RFSr) at 6, 12 and 18 months in the combination therapy groups and RFA groups were 80% vs 65%, 62.7% vs 35% and 48.7% vs 18.8%, respectively. Between the two groups, significant difference of RFSr was found at 18 months (p = 0.04). No statistical differences were observed between the two groups in terms of safeness (p > 0.05). The subgroup analysis indicated that the combination of RFA and anti‐PD‐1 led to better RFS than RFA alone. Moreover, patients benefited more from combination therapy in the groups younger than 60 years (HR: 0.26, p = 0.018), male (HR: 0.32, p = 0.028) and Child‐Pugh grade A (HR: 0.38, p = 0.032). Conclusions: Combining RFA with anti‐PD‐1 showed improved RFS and was deemed safe for patients with recurrent HCC who had previously undergone RFA treatment alone. [ABSTRACT FROM AUTHOR]

To explore the effects of anti‐programmed death‐1 (PD‐1) therapy on advanced colorectal cancer (CRC) based on the intestinal microecology. Ninety‐two patients with advanced CRC were selected. Patients were treated with Apatinib alone or anti PD‐1 treatment combined with Apatinib. The lactulose/mannitol (L/M) value of the urine was detected by high performance liquid chromatography. The changes of intestinal microflora were determined by real‐time fluorescence quantitative PCR. The risk factors were analyzed through multivariate logistic regression analysis. The curative effect of anti PD‐1 treatment combined with the Apatinib treatment (82.61%) was much higher than that of the Apatinib treatment alone (63.04%, p < 0.05). After treatment, the contents of Bifidobacterium, Lactobacillus, and Enterococcus faecalis were higher with lower levels of Escherichia coli in the observation group than the control (p < 0.05). The level of D‐lactic acid and urinary L/M value of the urine in the observation group was lower than that in control after treatment (p < 0.001). The patients had a 3‐year survival rate of 91.30%. Age >60 years old, histological types of mucinous adenocarcinoma and signet ring cell carcinoma, vascular tumor thrombus, nerve invasion, TNM stage of Ⅲ−Ⅳ were independent risk factors, and anti PD‐1 treatment was the protective factor (p < 0.05). In advanced CRC patients receiving anti PD‐1 treatment combined with the Apatinib treatment, the progression of advanced CRC was effectively controlled by maintaining the intestinal microflora balance. Anti PD‐1 therapy can improve the living quality of CRC patients. [ABSTRACT FROM AUTHOR]

Immune checkpoint blockade reaches remarkable clinical responses. However, even in the most favorable cases, half of these patients do not benefit from these therapies in the long term. It is hypothesized that the activation of host immunity by co‐delivering peptide antigens, adjuvants, and regulators of the transforming growth factor (TGF)‐β expression using a polyoxazoline (POx)‐poly(lactic‐co‐glycolic) acid (PLGA) nanovaccine, while modulating the tumor‐associated macrophages (TAM) function within the tumor microenvironment (TME) and blocking the anti‐programmed cell death protein 1 (PD‐1) can constitute an alternative approach for cancer immunotherapy. POx‐Mannose (Man) nanovaccines generate antigen‐specific T‐cell responses that control tumor growth to a higher extent than poly(ethylene glycol) (PEG)‐Man nanovaccines. This anti‐tumor effect induced by the POx‐Man nanovaccines is mediated by a CD8+‐T cell‐dependent mechanism, in contrast to the PEG‐Man nanovaccines. POx‐Man nanovaccine combines with pexidartinib, a modulator of the TAM function, restricts the MC38 tumor growth, and synergizes with PD‐1 blockade, controlling MC38 and CT26 tumor growth and survival. This data is further validated in the highly aggressive and poorly immunogenic B16F10 melanoma mouse model. Therefore, the synergistic anti‐tumor effect induced by the combination of nanovaccines with the inhibition of both TAM‐ and PD‐1‐inducing immunosuppression, holds great potential for improving immunotherapy outcomes in solid cancer patients. [ABSTRACT FROM AUTHOR]

Combinational immunotherapy of dendritic cell (DC) vaccines and anti‐programmed cell death protein 1 antibodies (aPD1) has been regarded as a promising strategy for cancer treatment because it not only induces tumor‐specific T cell immune responses, but also prevents failure of T cell functions by the immune suppressive milieu of tumors. Microneedles have emerged as an innovative platform for efficient transdermal immunotherapies. However, co‐delivery of DC vaccines and aPD1 via microneedles has not been studied since conventional microneedle platforms are unsuitable for fragile therapeutics like living cells and antibodies. This study employs our newly invented cryomicroneedles (cryoMNs) to co‐deliver DC vaccines and aPD1 for the combinational immunotherapy. CryoMNs are fabricated by stepwise cryogenic micromoulding of cryogenic medium with pre‐suspended DCs and aPD1, which are further integrated with a homemade handle for convenient application. The viability of DCs in cryoMNs remains above 85%. CryoMNs are mechanically strong enough to insert into porcine and mouse skin, successfully releasing DCs and aPD1 inside skin tissue after melting. Co‐delivery of ovalbumin (OVA)‐pulsed DCs (OVA‐DCs) and aPD1 via cryoMNs induced higher antigen‐specific cellular immune responses compared with the mono‐delivery of OVA‐DCs or aPD1. Finally, administration with cryoMNs co‐encapsulated with OVA‐DCs and aPD1 increases the infiltration of effector T cells in the tumor, resulting in stronger anti‐tumor therapeutic efficacy in both prophylactic and therapeutic melanoma models compared with administration with cryoMNs loaded with OVA‐DCs or aPD1. This study demonstrates the great potential of cryoMNs as a co‐delivery system of therapeutic cells and biomacromolecules for combinational therapies. [ABSTRACT FROM AUTHOR]

Combining immune checkpoint inhibitors with vascular endothelial growth factor/vascular endothelial growth factor receptor inhibitors is effective in treating a number of solid tumors; however, evidence in advanced gastric/gastroesophageal junction (G/GEJ) cancer is limited. This retrospective study included consecutive patients who received a programmed cell death protein 1 (PD‐1) inhibitor plus the vascular endothelial growth factor receptor 2 inhibitor apatinib, second‐line or later to treat unresectable advanced or metastatic, histologically proven, human epidermal growth factor receptor 2–negative G/GEJ cancer in a single center between November 1, 2018, and March 31, 2021. Treatment was continued until the disease progressed or the toxicity became intolerable. We examined data from 52 patients. The primary tumor site was the stomach in 29 patients and the GEJ in 23 patients. PD‐1 inhibitors administered included camrelizumab (n = 28), sintilimab (n = 18), pembrolizumab (n = 3), and tislelizumab (n = 1), and all patients were given 200 mg every 3 weeks, and toripalimab (240 mg every 3 weeks) and nivolumab (200 mg every 2 weeks) were given to 1 patient each. For 28 days, apatinib 250 mg was administered orally once a day. The objective response rate was 15.4% (95% confidence interval [CI], 6.9‐28.1), and the disease control rate was 61.5% (95%CI, 47.0‐74.7). After 14.8 months of median follow‐up, the median progression‐free survival was 4.2 months (95%CI, 2.6‐4.8), and the overall survival was 9.3 months (95%CI, 7.9‐12.9). Twelve patients underwent grade 3‐4 treatment‐related adverse events (23.1%). There was no unexpected toxicity or death. This trial demonstrated combination therapy with an anti–PD‐1 antibody and apatinib was effective and safe in patients with previously treated unresectable advanced or metastatic G/GEJ cancer. [ABSTRACT FROM AUTHOR]

This article discusses the results of a single-center observational study on the combination therapy of lenvatinib and pembrolizumab in heavily pretreated patients with metastatic melanoma. The study included 18 adults who had previously failed anti-PD-1 +/- anti-CTLA-4 treatment. The primary endpoint was the objective response rate (ORR), and secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety profiles. The study found that the ORR was 27.7%, and the disease control rate (DCR) was 38.9%. The medians of PFS and OS were 3.1 months and 9.3 months, respectively. The study suggests that the combination therapy may be a therapeutic option for patients who have failed standard therapies, but further research is needed. [Extracted from the article]

β‐TrCP is an E3 ubiquitin ligase that plays important roles in multiple human cancers including esophageal squamous cell carcinoma (ESCC). Analysis of ESCC patient samples reveal that only protein level but not transcript level of β‐TrCP associated with patient prognosis, suggesting regulators of β‐TrCP protein stability play an essential role in ESCC progression and may be novel targets to develop ESCC therapies. Although β‐TrCP stability is known to be mediated by the ubiquitin‐proteasome system, it is unclear which enzymes play a major role to determine β‐TrCP stability in the context of ESCC. In this study, OTUD6B is identified as a potent deubiquitinase of β‐TrCP that suppress ESCC progression through the OTUD6B‐β‐TrCP‐SNAIL axis. Low OTUD6B expression is associated with a poor prognosis of ESCC patients. Importantly, all‐trans retinoic acid (ATRA) is found to promote OTUD6B translation and thus suppress ESCC tumor growth and enhance the response of ESCC tumors to anti‐PD‐1 immunotherapies. These findings demonstrate that OTUD6B is a crucial deubiquitinase of β‐TrCP in ESCC and suggest combination of ATRA and anti‐PD‐1 immune checkpoint inhibitor may benefit a cohort of ESCC patients. [ABSTRACT FROM AUTHOR]

The optimum fractionation of radiation to combine with immune checkpoint blockade is controversial. This study aimed to investigate the fractionated radiation to maximize immunity during combination therapy. To evaluate the abscopal effect, C57BL/6 hPD-1 knock-in mice bearing two syngeneic contralateral MC38 murine colon cancer tumors were treated with four distinct regimens of radiotherapy. Three fractions of 8 Gy were chosen as the optimal fractionation to combine with anti-PD-1 as the optimal fractionation for maximizing immunity. Anti-PD-1 administration enhanced both local and systemic antitumor immunity in a cytotoxic T cell-dependent manner. Meanwhile, the spleen exhibited decreased myeloid-derived suppressor cells (MDSCs) under combination treatment. Furthermore, RNA-sequencing revealed significantly increased tumor necrosis factor (TNF) receptors and cytokines associated with lymphocyte infiltration in the combining group. Here we demonstrate that the hypofractionation of 8 Gy × 3f was the optimum-fractionated dosage to maximize immunity, and the combination of anti-PD-1 showed promising results in boosting abscopal effect. Underlying mechanisms may include the activation of T cells and the reduction of MDSCs, which is achieved through the action of TNF and related cytokines. This study indicates a radioimmunotherapy dosage painting method that can be developed to overcome present limitations in tumor immunosuppression. [ABSTRACT FROM AUTHOR]

Little is known about the long-term outcomes of anti-PD-1 treated patients with melanoma beyond 5 years, especially for patients treated off clinical trials. This retrospective cohort study includes patients with unresectable stage III/IV nonuveal melanoma treated with anti-PD-1 off-trial at Memorial Sloan Kettering Cancer Center between 2014 and 2017 who survived at least 5 years following their first anti-PD-1 dose (N = 139). We characterized overall survival (OS), melanoma-specific survival (MSS) estimates, treatment-free survival rates, and subsequent treatment courses. Median follow-up among 5-plus year survivors (N = 125) was 78.4 months (range 60.0-96.3). OS at year 7 (2 years post 5-year landmark) was 90.1% (95% CI: 83.0%-94.3%). Fourteen deaths occurred, seven due to melanoma. MSS at year 7 (2 years post 5-year landmark) was 95.0% (95% CI: 33.5%-95.2%). In patients who completed anti-PD-1 based therapy and did not require subsequent treatment by 5 years (N = 80), the probability of not requiring additional treatment for an additional 2 years was 95.7% (95% CI: 91.0%-100%). Patients treated with anti-PD-1 regimens off clinical trials who survive at least 5 years from initial anti-PD-1 treatment can be reassured of their excellent long-term prognosis, particularly if they did not require additional melanoma treatment during the first 5 years. [ABSTRACT FROM AUTHOR]

Melanoma is a highly immunogenic cancer, and circannual rhythms influence the activity of the immune system. We retrospectively collected information on all cases with metastatic melanoma (ocular melanoma excluded) that initiated treatment with BRAF‐inhibitor‐based therapy (BRAFi) or anti‐PD‐1 monotherapy (PD‐1). Cases were divided in two groups based on treatment initiation in the summer half‐year (April to September) or winter half‐year (October to March). We collected a total of 1054 (BRAF‐i) and 1205 (PD‐1) patient cases. Median follow‐up was 39.7 (BRAFi) and 47.5 (PD‐1) months. We did not observe differences in outcomes across patients who were treated in summer versus winter in the BRAFi cohort. Furthermore, we did not observe significant differences in ORR, CRR, and PFS in the PD‐1 cohort. However, in patients with BRAF wild‐type disease of the PD‐1 cohort, treatment initiation in summer was associated with an improved OS (mOS 39.7 months [summer] versus 21.3 months [winter]; HR 0.70, 95% CI 0.57–0.86, p =.0007). This result remained robust to multivariable proportional hazards adjustment (HR 0.70, 95% CI 0.57–0.87, p =.001). Initiation of immunotherapy in summer is associated with prolonged survival in patients with BRAF wild‐type melanoma living in Denmark. [ABSTRACT FROM AUTHOR]

Summary: Nucleophosmin1 (NPM1) is one of the most commonly mutated genes in AML and is often associated with a favourable prognosis. Immune responses play an increasing role in AML treatment decisions; however, the role of immune checkpoint inhibition is still not clear. To address this, we investigated specific immune responses against NPM1, and three other leukaemia‐associated antigens (LAA), PRAME, Wilms' tumour 1 and RHAMM in AML patients. We investigated T cell responses against leukaemic progenitor/stem cells (LPC/LSC) using colony‐forming immunoassays and flow cytometry. We examined whether immune checkpoint inhibition with the anti‐programmed death 1 antibody increases the immune response against stem cell‐like cells, comparing cells from NPM1 mutated and NPM1 wild‐type AML patients. We found that the anti‐PD‐1 antibody, nivolumab, increases LAA stimulated cytotoxic T lymphocytes and the cytotoxic effect against LPC/LSC. The effect was strongest against NPM1mut cells when the immunogenic epitope was derived from the mutated region of NPM1 and these effects were enhanced through the addition of anti‐PD‐1. The data suggest that patients with NPM1 mutated AML could be treated with the immune checkpoint inhibitor anti‐PD‐1 and that this treatment combined with NPM1‐mutation specific directed immunotherapy could be even more effective for this unique group of patients. [ABSTRACT FROM AUTHOR]

Routine [18F]2‐fluoro‐2‐deoxy‐d‐glucose positron emission tomography (FDG‐PET) may help predict clinical outcomes after response to immunotherapy. With a European Medicines Agency‐recommended treatment length until disease progression or unacceptable toxicity, the optimal duration of immunotherapy remains to be defined. In a retrospective study, we retrieved from the Danish Metastatic Melanoma Database (DAMMED), all patients that were annotated as a partial or complete response based on the computed tomography (CT) of serial FDG‐PET‐CT scans. Patients treated with an anti‐Programmed Death (PD)‐1‐containing regimen for <18 months, and ≥4 months without disease progression after halting anti‐PD‐1 were included. Cases were divided into an "elective" and a "toxicity" group based on the reason for treatment discontinuation. A total of 140 patients were included. At 29.3 months of median follow‐up, a higher proportion of patients remained alive in the "elective" group (93% vs 75%, P =.0031) with an improved melanoma‐specific (HR 0.07, 95% CI 0.02‐0.32, P =.0041) survival (MSS). Patients without FDG‐avid lesions at the time of treatment discontinuation had an improved MSS (HR 0.03, 95% CI 0.01‐0.17, P =.0002), and the absence of FDG‐avid lesions was the only independent predictive feature of improved MSS in multivariate analysis. In conclusion, patients with metastatic melanoma who obtain an early response and early discontinue immunotherapy have an excellent prognosis, especially in the absence of FDG‐PET avid lesions when discontinuing treatment. These data support the option of early discontinuation, limiting possible overtreatment and thereby toxicity, health and economic expenses and improving logistics. [ABSTRACT FROM AUTHOR]

There is no consensus on the optimal treatment duration of anti‐PD‐1 for advanced melanoma. The aim of our study was to gain insight into the outcomes of anti‐PD‐1 discontinuation, the association of treatment duration with progression and anti‐PD‐1 re‐treatment in relapsing patients. Analyses were performed on advanced melanoma patients in the Netherlands who discontinued first‐line anti‐PD‐1 monotherapy in the absence of progressive disease (n = 324). Survival was estimated after anti‐PD‐1 discontinuation and with a Cox model the association of treatment duration with progression was assessed. At the time of anti‐PD‐1 discontinuation, 90 (28%) patients had a complete response (CR), 190 (59%) a partial response (PR) and 44 (14%) stable disease (SD). Median treatment duration for patients with CR, PR and SD was 11.2, 11.5 and 7.2 months, respectively. The 24‐month progression‐free survival and overall survival probabilities for patients with a CR, PR and SD were, respectively, 64% and 88%, 53% and 82%, 31% and 64%. Survival outcomes of patients with a PR and CR were similar when anti‐PD‐1 discontinuation was not due to adverse events. Having a PR at anti‐PD‐1 discontinuation and longer time to first response were associated with progression [hazard ratio (HR) = 1.81 (95% confidence interval, CI = 1.11‐2.97) and HR = 1.10 (95% CI = 1.02‐1.19; per month increase)]. In 17 of the 27 anti‐PD‐1 re‐treated patients (63%), a response was observed. Advanced melanoma patients can have durable remissions after (elective) anti‐PD‐1 discontinuation. What's new? Reasons for discontinuing treatment with the anti‐PD‐1 antibodies nivolumab and pembrolizumab can vary significantly among melanoma patients. Moreover, the optimal treatment duration for these drugs remains unclear. In this observational study on anti‐PD‐1 discontinuation, most patients with advanced melanoma who had complete or partial response at anti‐PD‐1 discontinuation experienced ongoing response, with potential survival benefits. Shorter time to first response of anti‐PD‐1 monotherapy and partial response at discontinuation were associated with later progression of disease. Elective discontinuation, by contrast, was linked to a reduced likelihood of subsequent progression. Anti‐PD‐1 retreatment exhibited clinical activity against melanoma, warranting further investigation. [ABSTRACT FROM AUTHOR]

A considerable proportion of cancer patients are resistant or only partially responsive to immune checkpoint blockade immunotherapy. Tumor‐Associated Macrophages (TAMs) infiltrating the tumor stroma suppress the adaptive immune responses and, hence, promote tumor immune evasion. Depletion of TAMs or modulation of their protumoral functions is actively pursued, with the purpose of relieving this state of immunesuppression. We previously reported that trabectedin, a registered antitumor compound, selectively reduces monocytes and TAMs in treated tumors. However, its putative effects on the adaptive immunity are still unclear. In this study, we investigated whether treatment of tumor‐bearing mice with trabectedin modulates the presence and functional activity of T‐lymphocytes. In treated tumors, there was a significant upregulation of T cell‐associated genes, including CD3, CD8, perforin, granzyme B, and IFN‐responsive genes (MX1, CXCL10, and PD‐1), indicating that T lymphocytes were activated after treatment. Notably, the mRNA levels of the Pdcd1 gene, coding for PD‐1, were strongly increased. Using a fibrosarcoma model poorly responsive to PD‐1‐immunotherapy, treatment with trabectedin prior to anti‐PD‐1 resulted in improved antitumor efficacy. In conclusion, pretreatment with trabectedin enhances the therapeutic response to checkpoint inhibitor‐based immunotherapy. These findings provide a good rational for the combination of trabectedin with immunotherapy regimens. [ABSTRACT FROM AUTHOR]

Although the optimal treatment method for metastatic oral cancer remains largely unknown, the present case suggests that immunotherapy is a potentially promising alternative for metastatic oral cancer in which other therapies are no longer effective. [ABSTRACT FROM AUTHOR]

Background: There is a concern that influenza vaccination may increase the incidence of immune‐related adverse events in patients receiving immune checkpoint inhibitors (ICIs). The aim of this systematic review was to summarize the available data on the safety and efficacy of influenza vaccination in cancer patients receiving ICIs. Methods: Studies reporting safety and efficacy outcomes of influenza vaccination in cancer patients receiving ICIs were included. Only descriptive statistics were conducted to obtain a pooled rate of immune‐related adverse events in vaccinated patients. Results: Ten studies assessing the safety and eight assessing the efficacy of influenza vaccination in cancer patients receiving ICIs were identified, for a total of 1124 and 986 vaccinated patients, respectively. Most patients had melanoma or lung cancer and received a single agent anti‐PD‐1, but also other tumour types and immunotherapy combinations were represented. No severe vaccination‐related toxicities were reported. The pooled incidence of any grade immune checkpoint inhibitor–related adverse events was 28.9%. In the 6 studies specifying the incidence of grade 3‐4 toxicities, the pooled incidence was 7.5%. No grade 5 toxicities were reported. No pooled descriptive analysis was conducted in studies reporting efficacy outcomes due to the heterogeneity of endpoints and data reporting. Nevertheless, among the eight studies included, seven reported positive efficacy outcomes of influenza vaccination. Conclusion: The results of this systematic review support the safety and efficacy of influenza vaccination in cancer patients receiving ICIs. These results are particularly relevant in the context of the SARS‐CoV‐2 pandemic. [ABSTRACT FROM AUTHOR]

The analysis by Broman and colleagues in this issue contributes to a still rapidly developing evidence base of patients with melanoma and a positive sentinel node who are followed with active surveillance. It reveals substantial adoption of randomized clinical trial findings that support active surveillance for these patients and, with limited follow‐up, suggests that loss of regional basin control is a very uncommon event in this era of effective adjuvant therapy. [ABSTRACT FROM AUTHOR]

Background: Anti‐programmed cell death protein 1 (PD‐1) antibodies are a standard treatment for metastatic melanoma patients. However, the understanding of the efficacy of anti‐PD‐1 for acral melanoma (AM) and mucosal melanoma (MM) is limited as these subtypes are relatively rare compared to cutaneous melanoma (CM). Methods: This single institution, retrospective cohort study included patients with advanced AM and MM who underwent anti‐PD‐1 therapy for metastatic melanoma between 2012 and 2018. Objective responses were determined using the investigator‐assessed Response Evaluation Criteria in Solid Tumors version 1.1. Progression‐free survival (PFS) and overall survival (OS) were assessed using the Kaplan–Meier method. A Cox regression analysis was performed to identify the factors associated with survival outcomes. Results: Ninety‐seven patients were identified, 38 (39%) with AM and 59 (61%) with MM. The objective response rates (ORRs) were 21.0% and 15.2% in patients with AM and MM, respectively. The median PFS and OS were 3.6 and 25.7 months for AM patients, and 3.0 and 20.1 months for MM patients, respectively. Elevated serum lactate dehydrogenase (LDH) (AM: hazard ratio [HR], 0.22; 95% confidence interval [CI], 0.06–0.87; p = 0.03, MM: HR, 0.20; 95% CI, 0.08–0.53; p = 0.001) was significantly associated with shorter OS for both subtypes. Conclusions: The ORR, PFS, and OS with anti‐PD‐1 therapy were poor in patients with AM and MM compared to those previously reported clinical trials for nonacral CM. High serum LDH was associated with significantly shorter OS. [ABSTRACT FROM AUTHOR]

BRAF + MEK inhibition is preferentially applied as first‐line therapy in BRAF V600‐mutated melanoma patients with unfavourable prognostic features, due to the ability of targeted therapy (TT) to induce rapid symptom control, decrease tumour burden and normalize lactate dehydrogenase (LDH) levels. In addition, short‐term TT transiently increases tumour antigen presentation and tumour influx of T cells. Therefore, it might be favourable to switch TT to checkpoint inhibition (CPI) before progression (PD). We retrospectively analysed melanoma patients treated first line with TT (TT1) and who subsequently switched to CPI during response to TT (sDR group) or at progression upon TT (sPD group). We identified 74 patients (n = 37 sDR group and n = 37 sPD group). ORR to CPI was 27.0% in the sDR group versus 24.3% in the sPD group (p =.790). Median was PFS 2.5 months versus 1.2 months (p =.145), and median OS was 30.6 versus 14.1 months (p =.007). After adjusting for baseline differences and known prognostic factors, hazard ratios (HRs) favouring sDR were 0.89 for PFS upon CPI (p =.956) and 0.48 for OS (p =.055). Thus, patients switching to CPI during ongoing clinical benefit from TT do not have an inferior outcome. Due to baseline imbalances and small patient population, a favourable trend for the sDR group can be hypothesized only. [ABSTRACT FROM AUTHOR]

Background: This study evaluated the efficacy and safety of retreatment with anti‐programmed death 1 (anti‐PD‐1) antibodies in patients with advanced non‐small cell lung cancer (NSCLC) after prior treatment with anti‐programmed death‐ligand 1 (anti‐PD‐L1) antibodies. Methods: Data (N = 15) on patients' characteristics, number of cycles, regimens, their best response and immune‐related adverse events (irAEs) were recorded retrospectively. Results: NSCLC was initially treated with anti‐PD‐L1 antibody atezolizumab (N = 14) or durvalumab (N = 1). No patients had a high (≥50%) tumor expression of PD‐L1. The median cycles for atezolizumab were five (range 1–15), and median progression‐free survival was 2.8 and 6.0 months for atezolizumab and durvalumab, respectively. Five (33.3%) and nine (60.0%) patients showed stable and progressive disease as their best response, respectively. No differences in irAEs between anti‐PD‐L1 and anti‐PD‐1 antibodies occurred. Conclusion: Patients treated with anti‐PD‐L1 antibodies for NSCLC received limited benefits from retreatment with anti‐PD‐1 antibodies. [ABSTRACT FROM AUTHOR]

The pervasive use of therapeutic antibodies targeting programmed cell death protein 1 (PD‐1) to boost anti‐tumor immunity has positioned this approach to become the standard‐of‐care for some solid tumor malignancies. However, little is known as to how blockade of PD‐1 may alter the function or phenotype of tumor‐infiltrating lymphocytes (TIL). We used our ongoing Phase II clinical trial of pembrolizumab for patients with rare solid tumors from various types (NCT02721732) with matched core biopsies taken at baseline and after initial dose of anti‐PD‐1 (15–21 days post‐dose) to elucidate this question. One fresh core needle biopsy was used to propagate TIL ex vivo to analyze phenotype and function using flow cytometry in both CD8+ and CD4+ TIL populations. An enriched CTLA‐4 expression in the CD4+ TIL population was observed in TIL expanded from the on‐treatment samples compared to TIL expanded from the matched baseline (n = 22, p = 0.0007) but was not observed in patients who experienced tumor regression. Impact on functionality was evaluated by measuring secretion of 65 soluble factors by expanded TIL from 26 patients at baseline and on‐treatment. The CD8+ TIL population demonstrated a diminished cytokine secretion profile post‐pembrolizumab. Overall, our study assesses the ramifications of one dose of anti‐PD‐1 on TIL in rare solid tumor types. [ABSTRACT FROM AUTHOR]

Objectives: Investigation of variable response rates to cancer immunotherapies has exposed the immunosuppressive tumor microenvironment (TME) as a limiting factor of therapeutic efficacy. A determinant of TME composition is the tumor location, and clinical data have revealed associations between certain metastatic sites and reduced responses. Preclinical models to study tissue‐specific TMEs have eliminated genetic heterogeneity, but have investigated models with limited clinical relevance. Methods: We investigated the TMEs of tumors at clinically relevant sites of metastasis (liver and lungs) and their impact on αPD‐1/αCTLA4 and trimAb (αDR5, α4‐1BB, αCD40) therapy responses in the 67NR mouse breast cancer and Renca mouse kidney cancer models. Results: Tumors grown in the lungs were resistant to both therapies whereas the same tumor lines growing in the mammary fat pad (MFP), liver or subcutaneously could be completely eradicated, despite greater tumor burden. Assessment of tumor cells and drug delivery in 67NR lung or MFP tumors revealed no differences and prompted investigation into the immune TME. Lung tumors had a more immunosuppressive TME with increased myeloid‐derived suppressor cell infiltration, decreased T cell infiltration and activation, and decreased NK cell activation. Depletion of various immune cell subsets indicated an equivalent role for NK cells and CD8+ T cells in lung tumour control. Thus, targeting T cells with αPD‐1/αCTLA4 or trimAb was not sufficient to elicit a robust antitumor response in lung tumors. Conclusion: Taken together, these data demonstrate that tissue‐specific TMEs influence immunotherapy responses and highlight the importance in defining tissue‐specific response patterns in patients. [ABSTRACT FROM AUTHOR]

Despite its anticipated clinical potential, anti‐PD‐1 immunotherapy has only yielded poor outcomes in recent clinical trials for glioblastoma patients. Strategies combining anti‐PD‐1 antibody with other treatment modalities are being explored to alter the immunosuppressive microenvironment that appears to characterize these anti‐PD‐1‐insensitive tumors. Here, we evaluated whether introducing wild‐type p53 gene via a tumor‐targeting nanomedicine (termed SGT‐53) could provide immune stimulation and augment anti‐PD‐1 therapy in mouse syngeneic GL261 tumor models (either subcutaneous or intracranial). In both models, anti‐PD‐1 monotherapy had no demonstrable therapeutic effect. However, combining anti‐PD‐1 with our investigational nanomedicine SGT‐53 was very effective in inhibiting tumor growth, inducing tumor cell apoptosis and increasing intratumoral T‐cell infiltration. A significant survival benefit was observed in mice bearing intracranial glioblastoma receiving combination treatment. Importantly, SGT‐53 upregulated PD‐L1 expression both in vitro and in vivo. Transcriptome analysis revealed modulation of genes linked to either cancer progression or immune activation after combination treatment. Our data suggest that SGT‐53 can boost antitumor immunity and sensitize glioblastoma to anti‐PD‐1 therapy by converting immunologically "cold" tumors into "hot" tumors. Combining SGT‐53 with anti‐PD‐1 might benefit more patients from anti‐PD‐1 immunotherapy and our data support evaluation of this combination in patients with glioblastoma. What's new? Antibodies targeting the programmed cell death protein 1 (anti‐PD‐1) pathway represent a promising immunotherapeutic strategy against glioblastoma. Nonetheless, in recent trials, significant numbers of glioblastoma patients failed to respond to anti‐PD‐1. Here, the authors explored the possibility of overcoming this insensitivity by combining anti‐PD‐1 with SGT‐53, a tumor‐targeting nanomedicine that restores p53 function. In glioblastoma mouse models, the combined immunotherapy approach effectively inhibited tumor growth and increased intratumoral infiltration of immune effector cells. Increased immunogenicity was associated with significant survival benefits. The data provide a strong mechanistic rationale for combining SGT‐53 nanomedicine and anti‐PD‐1 immunotherapy in the treatment of glioblastoma. [ABSTRACT FROM AUTHOR]

Background: The application of anti‐programmed death‐1 (PD‐1) therapies for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) has found promising results. It is the first "second‐line therapy" in this setting to impact on prognosis. The studies demonstrated overall response rates in the range of 20%. Therefore, HNSCC showed 60%‐80% progression at first evaluation with better overall survival, suggesting regained efficacy of treatments given thereafter. Methods: We report three clinical cases treated with anti‐PD‐1 after platinum‐based chemotherapy. Results: Our case reports achieved an unforeseen response to conventional therapies supporting the hypothesis of restored responses to conventional therapies after immunotherapy. Conclusions: We believe that the inhibition of the PD‐1/PD‐ligand 1 checkpoint may synergize with both chemotherapy or radiotherapy through immunologic interplay, reversing the HNSCC‐induced immune suppression. [ABSTRACT FROM AUTHOR]

Like in many tumor types, immunotherapy is currently under investigation to assess its potential efficacy in glioblastoma patients. Trials are under way to assess the efficacy of new immune checkpoint inhibitors including anti‐PD‐1 or CTLA4. We here investigate the expression and efficacy of a novel immune‐checkpoint inhibitor, called LAG‐3. We show that LAG‐3 is expressed in human glioblastoma samples and in a mouse glioblastoma model we show that knock out or LAG‐3 inhibition with a blocking antibody is efficacious against glioblastoma and can be used in combination with other immune checkpoint inhibitors toward complete eradication of the model glioblastoma tumors. From a mechanistic standpoint we show that LAG‐3 expression is an early marker of T cell exhaustion and therefore early treatment with LAG‐3 blocking antibody is more efficacious than later treatment. These data provide insight and support the design of trials that incorporate LAG‐3 in the treatment of glioblastoma. What's new? Glioblastoma derives some of its lethality from its ability to escape destruction by the immune system. Researchers have begun investigating immune checkpoint inhibitors as a tool to combat glioblastoma. Here, the authors report on a novel immune‐checkpoint inhibitor, LAG‐3. In a mouse model of glioblastoma, they successfully improved survival by eliminating LAG‐3, either by genetic knockout or using antibodies against it. They show that TILs from human glioblastoma samples express LAG‐3, and that high LAG‐3 expression correlates with reduced interferon release. The authors propose that anti‐LAG‐3, alone or in combination with other anti‐PD‐1 treatment, could improve glioblastoma treatment. [ABSTRACT FROM AUTHOR]

Introduction: Randomized prospective studies on patients with metastatic non‐small‐cell lung cancers (NSCLCs) showed that anti‐programmed death‐1 (PD‐1) agents notably improved 2‐year overall survival (OS) rates, compared to docetaxel. NSCLC patients now receive nivolumab and irradiation, concurrently or not. However, little is known about the safety of this combination, even though the preclinical model suggested a possible synergic effect. We analyzed NSCLC patients treated with radiotherapy and nivolumab according to former's timing. Methods: We retrospectively reviewed records of a large series of metastatic NSCLC patients from three French centers, irradiated during the 6 months preceding, concomitantly, or 3 months after nivolumab administration to assess nivolumab tolerance and outcomes. Results: Among 104 patients included (37 women; 67 men; median age 60.3 years; 67% with performance status <2; 93.2% were current or past smokers) and their 144 intra‐ or extracranial irradiation courses, any‐grade adverse events (AEs) were observed in 62 (59.6%), with 10 (9.6%) experiencing at least one grade 3/4 toxicity and 9 (8.7%) at least one grade 3/4 immune‐related AE (IRAE). Respective 1‐ and 2‐year OS rates were 48.8% and 29.1%, while 1‐ and 2‐year progression‐free survival (PFS) rates were 20.9% and 10.1%. PFS was significantly better for patients with IRAE(s) (P = 0.038) than those without and a trend toward better OS (P = 0.06). Delivering radiation before or during/after nivolumab administration was not associated with better OS or PFS. Conclusion: Radiotherapy delivered during the 6 months before, during, or the three months following nivolumab for NSCLCs was not associated with an increased risk of severe or unexpected toxicities. The largest series reporting the safety of nivolumab and radiotherapy combination. The combination of nivolumab and radiotherapy for NSCLC is safe, and the therapeutic sequence has no impact on toxicity rate. PFS is significantly better for patients with immune‐related adverse events. [ABSTRACT FROM AUTHOR]

Abstract: Immune checkpoint blockade‐related pneumonitis is a rare but potentially life‐threatening adverse effect, but its risk factors are not completely understood. This case‐control study was conducted to identify pneumonitis risk factors in patients treated with anti‐PD1 monoclonal antibodies (mAbs), including all the patients who developed pneumonitis after anti‐PD‐1 mAbs treatment in the Cancer Center of the Chinese People's Liberation Army from September 2015 to September 2017. Two controls per case were matched according to a propensity‐score matching algorithm to account for confounding effects caused by individual baseline variables. Demographic and clinical information was obtained from medical records. In total, 55 cases and 110 controls were included in the study. No association was observed between smoking status or primary lung cancer and risk of pneumonitis. Significant risk factors for pneumonitis related to anti‐PD‐1 mAbs were prior thoracic radiotherapy, prior lung disease and combination therapy with odds ratios of 3.34 (1.51‐7.39), 2.86 (1.45‐5.64) and 2.73 (1.40‐5.31), respectively. The associations remained significant in the multivariable logistic regression model. The risk of pneumonitis induced by anti‐PD‐1 mAbs is associated with prior thoracic radiotherapy, prior lung disease, and combination therapy. Clinicians should monitor these features in patients receiving anti‐PD‐1 therapy to optimize clinical safety and efficacy. [ABSTRACT FROM AUTHOR]

Immunotherapies targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death 1 (PD-1) receptor and its ligand (PD-L1) have showed substantial therapeutic benefit in patients with clinically advanced solid malignancies. However, autoimmune toxicities are common and often significant adverse events with these agents. While rash and pruritus remain the most common cutaneous complications in treated patients, novel dermatologic toxicities related to immune checkpoint blockade continue to emerge as the number of patients exposed to immunotherapy increases. Here, we describe 2 patients treated with combination immunotherapy with ipilimumab and nivolumab who developed painful subcutaneous nodules. Although the findings were clinically concerning for disease recurrence, histopathologic examination of biopsies from the lesions revealed a subcutaneous mixed septal and lobular erythema nodosum-like panniculitis. Notably, neither patient received immunosuppressive therapy for these lesions, which subsequently remained stable, and both patients' cancer remained controlled. These cases show that the dermatologic toxicity profile of immune checkpoint blockade is diverse and continues to expand, and illustrates that recognition of such toxicities is critical to optimal patient management. [ABSTRACT FROM AUTHOR]

Chronic hepatitits B virus remains a public health challenge, infecting more than 240 million people globally and causing 600,000 deaths per year from end-stage liver disease and/or hepatocellular carcinoma. Current antiviral therapeutic agents are highly effective at blocking viral replication, but discontinuation of therapy prior to loss of hepatitis B surface antigen generally leads to relapse. New modalities that target host factors of viral persistence such as immune response pathway inhibition hold promise. Other experimental approaches may target virally related persistence factors, including covalently closed circular DNA. All these approaches will require creative new means of assessing proof of biology and proof of mechanism, particularly in the relevant compartment of liver tissue. Furthermore, it is likely to require combinations of modalities in defined patient populations to achieve optimal response. A precompetitive consortium approach may enable companies, regulators, and academic researchers to share best practices and evaluate preclinical and clinical pathways for these novel approaches. [ABSTRACT FROM AUTHOR]

Immunomodulatory drugs that leverages host immune mechanisms to destroy tumor cells have been met with great promise in the treatment of cancer. Immunotherapy, targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death 1 (PD-1) receptor and its ligand (PD-L1) have shown tremendous improvements in the survival of patients with advanced solid tumors. However, the development of dermatologic toxicity (DT) is a consequence to immunotherapy. Review of published reports of the DT to immunotherapy revealed patients receiving anti-CTCLA-4 antibody or anti-PD-1/PD-L1 antibody often develop a DT of any type and grade. In this article, of the 3825 patients who were treated with anti-PD-1 and of 556 patients receiving anti-PD-L1, DT of any type and grade were reported in 1474 (∼39%) and 95 (∼17%) of patients, respectively. The emergence of specific types of DT to immunotherapy is beginning to be recognized can be categorized into four groups: (a) inflammatory, (b) immunobullous, (c) alteration of keratinocytes and (d) alteration of melanocytes. Lichenoid dermatitis and bullous pemphigoid appear to be DT more associated with anti-PD-1/PD-L1 antibody. The DT profile in patients receiving immunotherapy is diverse, and early recognition of specific types of DT that clinicians may encounter is critical for optimal patient care [ABSTRACT FROM AUTHOR]

Glioblastoma is the most aggressive primary central nervous system malignancy with a poor prognosis in patients. Despite the need for better treatments against glioblastoma, very little progress has been made in discovering new therapies that exhibit superior survival benefit than the standard of care. Immunotherapy has been shown to be a promising treatment modality that could help improve clinical outcomes of glioblastoma patients by assisting the immune system to overcome the immunosuppressive tumor environment. Interleukin-15 (IL-15), a cytokine shown to activate several effector components of the immune system, may serve as an excellent immunotherapeutic candidate for the treatment of glioblastoma. Thus, we evaluated the efficacy of an IL-15 superagonist complex (IL-15N72D:IL-15RαSu-Fc; also known as ALT-803) in a murine GL261-luc glioblastoma model. We show that ALT-803, as a single treatment as well as in combination with anti-PD-1 antibody or stereotactic radiosurgery, exhibits a robust antitumor immune response resulting in a prolonged survival including complete remission in tumor bearing mice. In addition, ALT-803 treatment results in long-term immune memory against glioblastoma tumor rechallenge. Flow cytometric analysis of tumor infiltrating immune cells shows that ALT-803 leads to increased percentage of CD8+-cell infiltration, but not the NK cells, and IFN-γ production into the tumor microenvironment. Cell depletion studies, in accordance with the flow cytometric results, show that the ALT-803 therapeutic effect is dependent on CD4+ and CD8+ cells. These results provide a rationale for evaluating the therapeutic activity of ALT-803 against glioblastoma in the clinical setting. [ABSTRACT FROM AUTHOR]

Anti-PD-1 therapy provides high response rates in Hodgkin lymphoma (HL) patients who have relapsed or are refractory (R/R) to autologous stem cell transplantation (ASCT) and brentuximab vedotin (BV), but median progression free survival (PFS) is only one year. The efficacy of treatment following anti-PD-1 is not well known. We retrospectively investigated the efficacy of salvage therapies for unsatisfactory response to anti-PD-1 therapy, assessed by PET-CT according to the Lugano criteria, in 30 R/R HL patients. Patients were highly pre-treated before anti-PD-1 (70% received ASCT and 93% BV). Unsatisfactory responses to anti-PD1 therapy were progressive disease (PD) (n=24) and partial response (PR) (n=6). For the 24 PD patients, median anti-PD-1 related PFS was 7.5 months (95%CI, 5.7-11.6); 17 received subsequent CT alone (Group 1) and 7 received CT in addition to anti-PD-1 (Group 2). 16/24 patients (67%) obtained an objective response. In the 15 patients treated with the same CT, twelve obtained PR or complete response (CR). In Group 1, there were 7 CR (41%), 3 PR (18%), and 7 PD (41%). In Group 2, there were 4 CR (57%), 2 PR (29%), and 1 SD (14%). No unexpected toxicity was observed. Six patients who achieved response proceeded to allogeneic SCT. With a median follow-up of 12.1 months (7-14.7), the median PFS following the initiation of CT was 11 months (95%CI, 6.3; not reached) and the median of overall survival was not reached. These observations in highly pre-treated HL patients suggest that anti-PD-1 therapy might re-sensitize tumor cells to CT. This article is protected by copyright. All rights reserved., (© 2018 Wiley Periodicals, Inc.)