Renal cell carcinoma (RCC) is the most common solid tumour of the kidney and accounts for 3% of all cancers. While immune checkpoint inhibitor (ICI)-based combination therapies have emerged as the first-line treatment for metastatic renal cell carcinoma (mRCC), the role of surgery has become more controversial. This review summarizes the evidence, current role and future directions for surgery in mRCC management. The survival benefits of cytoreductive nephrectomy (CN) shown in the interferon era have encountered increasing disputes in the tyrosine-kinase inhibitor (TKI) and ICI eras. Undoubtedly, several systematic reviews based on retrospective data have supported the survival benefits of CN. Nevertheless, 2 prospective trials, CARMENA and SURTIME, proved that sunitinib as the upfront therapy resulted in noninferior survival outcomes compared with immediate CN. The safety of CN does have solid ground in the current literature. Several studies suggested that preoperative systemic therapy did not seem to aggravate perioperative complications or mortality rates, in experienced centres. Meticulous patient selection is the rule of thumb in the modern management of mRCC patients. The limitations of the existing prognostication models, however, must be acknowledged. Clinicians should adopt a multidisciplinary and holistic approach and contemplate all patient, disease, surgeon and socio-economical factors, before deciding who should go for surgery. The advent of metastasis-directed therapy (MDT) and survival benefits of adjuvant pembrolizumab shown in the oligometastatic subgroup, where complete metastasectomy could be achieved (M1 NED), calls for more comparative studies against upfront ICI combinations. In summary, CN brings survival benefits to well-selected good-to-intermediate-risk mRCC patients. Individualized and multidisciplinary care is pivotal.

Aim: We investigate combining Prussian Blue nanoparticles (PBNPs), as photothermal therapy (PTT) agents, with agonistic CD137 antibodies (αCD137) on a single nanoparticle platform to deliver non-toxic, anti-tumor efficacy in SM1 murine melanoma.Methods: We electrostatically coated PBNPs with αCD137 (αCD137-PBNPs) and quantified their physicochemical characteristics, photothermal and co-stimulatory capabilities. Next, we tested the efficacy and hepatotoxicity of PTT using αCD137-PBNPs (αCD137-PBNP-PTT) in SM1 tumor-bearing mice.Results: The αCD137-PBNPs retained both the photothermal and agonistic properties of the PBNPs and αCD137, respectively. In vivo, SM1 tumor-bearing mice treated with αCD137-PBNP-PTT exhibited a significantly higher survival rate (50%) without hepatotoxicity, compared with control treatments.Conclusion: These data suggest the potential utility of co-localizing PBNP-PTT with αCD137-based agonism as a novel combination nanomedicine.
Photothermal therapy is a strategy to kill cancer cells that uses nanoparticles and lasers to generate heat. Here, we combine photothermal therapy with an immunotherapy that activates the body\'s T cells, a type of white blood cell, on a single platform, to treat melanoma, a type of skin cancer in a mouse. We find that this novel nanoparticle-based platform significantly improves the survival of mice bearing melanoma, without increasing liver toxicity.

Protein arginine methylation is a common post-translational modification (PTM) catalyzed by nine protein arginine methyltransferases (PRMTs). As the major symmetric arginine methyltransferase that methylates both histone and non-histone substrates, PRMT5 plays key roles in a number of biological processes critical for development and tumorigenesis. PRMT5 overexpression has been reported in multiple cancer types including prostate cancer (PCa), but the exact biological and mechanistic understanding of PRMT5 in aggressive PCa remains ill-defined. Here, we show that PRMT5 is upregulated in PCa, correlates with worse patient survival, promotes corrupted RNA splicing, and functionally cooperates with an array of pro-tumorigenic pathways to enhance oncogenesis. PRMT5 inhibition via either genetic knockdown or pharmacological inhibition reduces stemness with paralleled differentiation and arrests cell cycle progression without causing appreciable apoptosis. Strikingly, the severity of antitumor effect of PRMT5 inhibition correlates with disease aggressiveness, with AR+ PCa being less affected. Molecular characterization pinpoints MYC, but not (or at least to a lesser degree) AR, as the main partner of PRMT5 to form a positive feedback loop to exacerbate malignancy in both AR+ and AR- PCa cells. Inspired by the surprising finding that PRMT5 negatively correlates with tumor immune infiltration and transcriptionally suppresses an immune-gene program, we further show that although PRMT5 inhibitor (PRMT5i) EPZ015666 or anti-PD-1 immunotherapy alone exhibits limited antitumor effects, combination of PRMT5i with anti-PD-1 displays superior efficacy in inhibiting castration-resistant PCa (CRPC) in vivo. Finally, to expand the potential use of PRMT5i through a synthetic lethality concept, we also perform a global CRISPR/Cas9 knockout screen to unravel that many clinical-grade drugs of known oncogenic pathways can be repurposed to target CRPC when used in combination with PRMT5i at low doses. Collectively, our findings establish a rationale to exploit PRMT5i in combination with immunotherapy or other targeted therapies to treat aggressive PCa.

Combining bevacizumab with atezolizumab enhances the antitumor effects of the treatment by activating an immune response. This combination is approved for the treatment of unresectable hepatocellular carcinoma (HCC). An abscopal effect is associated with an immune response triggered by radiation-induced immunogenic cell death, based on experimental models. Thus, combining radiotherapy and immunotherapy is expected to induce an abscopal effect. However, the clinical significance of immunotherapy in the abscopal effect remains unknown due to the rarity of clinical cases. Herein, we report a case of advanced HCC with lung and adrenal metastases. The antitumor efficacy of atezolizumab and bevacizumab (atezo/bev) was enhanced following stereotactic body radiotherapy (SBRT), although atezo/bev did not yield a sufficient therapeutic response pre-SBRT. Furthermore, an abscopal effect following SBRT was not observed during atezolizumab alone but was evoked after resuming bevacizumab in combination with atezolizumab, culminating in the patient achieving a complete response status. These findings suggest that immune activation following radiotherapy may be related to the induction of an abscopal effect in clinical practice as well as in experimental settings, and combining immunotherapy with bevacizumab post-radiotherapy could evoke an abscopal effect in a case of HCC, even though immune checkpoint inhibitor use alone may be insufficient.

Relatlimab (rela; anti-LAG-3) plus nivolumab (nivo; anti-PD-1) is safe and effective for treatment of advanced melanoma. We designed a trial (NCT03743766) where advanced melanoma patients received rela, nivo, or rela+nivo to interrogate the immunologic mechanisms of rela+nivo. Analysis of biospecimens from this ongoing trial demonstrated that rela+nivo led to enhanced capacity for CD8+ T cell receptor signaling and altered CD8+ T cell differentiation, leading to heightened cytotoxicity despite the retention of an exhaustion profile. Co-expression of cytotoxic and exhaustion signatures was driven by PRDM1, BATF, ETV7, and TOX. Effector function was upregulated in clonally expanded CD8+ T cells that emerged after rela+nivo. A rela+nivo intratumoral CD8+ T cell signature was associated with a favorable prognosis. This intratumoral rela+nivo signature was validated in peripheral blood as an elevated frequency of CD38+TIM3+CD8+ T cells. Overall, we demonstrated that cytotoxicity can be enhanced despite the retention of exhaustion signatures, which will inform future therapeutic strategies.

Inflammatory myofibroblastic tumor (IMT) is a rare pathological entity first described in 1939. This lesion is most commonly found in the lungs, but cases involving other systems, such as the central nervous system known as intracranial IMT (IIMT), have also been reported. Diagnosis currently relies on pathological results due to the lack of characteristic imaging changes. Surgical resection is an effective treatment, though the disease is invasive and may recur. Previous literature has reported a high level of programmed death 1 (PD-1) expression in IMT tissues, suggesting that immunotherapy may be effective for this condition. In this case report, we present a middle-aged male who received PD-1 inhibitor and oncolytic adenovirus (Ad-TD-nsIL12) treatment after IIMT resection surgery. This successful approach provides a new direction for the treatment of IIMT.

BACKGROUND: Pembrolizumab is a first-line therapy for certain patients with advanced/metastatic non-small cell lung cancer (NSCLC). Combining pembrolizumab with other immunotherapies may enhance tumor cell killing and clinical outcomes. Epacadostat is a selective inhibitor of indoleamine 2,3-dioxygenase 1, an immuno-regulatory enzyme involved in tryptophan to kynurenine metabolism that inhibits T cell-mediated immune responses.
METHODS: In this randomized phase II study, patients with metastatic NSCLC expressing high (≥ 50%) programmed death-ligand 1 (PD-L1) levels received pembrolizumab 200 mg every 21 days plus oral epacadostat 100 mg twice daily (combination) or matching placebo (control). The primary objective was objective response rate (ORR); secondary objectives were progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety/tolerability.
RESULTS: 154 patients were randomized (77 per group). Median (range) follow-up was 6.8 months (0.1-11.4) and 7.0 months (0.2-11.9) in the combination and control groups, respectively Confirmed ORR was similar between groups (combination: 32.5%, 95% CI 22.2-44.1; control: 39.0%, 95% CI 28.0-50.8; difference: - 6.5, 95% CI - 21.5 to 8.7; 1-sided P = 0.8000). Median (range) DOR was 6.2 months (1.9 + to 6.5 +) and not reached (1.9 + to 8.6 +) in the combination and control groups, respectively. Although not formally tested, median PFS was 6.7 and 6.2 months for the combination and control groups, respectively, and median OS was not reached in either group. Circulating kynurenine levels increased from C1D1 to C2D1 (P < 0.01) in the control group and decreased from C1D1 to C2D1 (P < 0.01) in the combination group but were not normalized in most patients. The most frequent serious adverse events (AEs) (≥ 2%) were pneumonia (4.0%), anemia (2.7%), atelectasis (2.7%) and pneumonitis (2.7%) in the combination group and pneumonia (3.9%), pneumonitis (2.6%) and hypotension (2.6%) in the control group. Two deaths due to drug-related AEs were reported, both in the control group.
CONCLUSIONS: Addition of epacadostat to pembrolizumab therapy for PD-L1-high metastatic NSCLC was generally well tolerated but did not demonstrate an improved therapeutic effect. Evaluating higher doses of epacadostat that normalize kynurenine levels when given in combination with checkpoint inhibitors may be warranted.
BACKGROUND: ClinicalTrials.gov, NCT03322540. Registered 10/26/2017.

BACKGROUND: The combination of the checkpoint inhibitor (CPI) pembrolizumab and platinum-based chemotherapy is effective frontline therapy for advanced non-small cell lung cancer (NSCLC) lacking targetable mutations. Indoleamine 2,3- dioxygenase 1 (IDO1), an enzyme involved in kynurenine production, inhibits immune responses. Inhibition of IDO1 may restore antitumor immunity and augment CPI activity. This trial evaluated addition of epacadostat, a potent and highly selective IDO1 inhibitor, to pembrolizumab and chemotherapy for metastatic NSCLC.
METHODS: ECHO-306/KEYNOTE-715 was a partial double-blind, randomized phase II study of adults with treatment-naïve stage IV NSCLC not indicated for EGFR-, ALK-, or ROS1-directed therapy. Patients were randomized to one of three treatment arms: epacadostat-pembrolizumab-chemotherapy (E + P + C; blinded), epacadostat-pembrolizumab (E + P; open-label) or placebo-pembrolizumab-chemotherapy (PBO + P + C; blinded). Stratification was by PD-L1 tumor proportion score (< 50% vs. ≥ 50%) and tumor histology (non-squamous vs. squamous). A protocol amendment closed enrollment in the open-label E + P group, excluding it from efficacy analyses. Intravenous pembrolizumab (200 mg) was administered every 21 days and epacadostat 100 mg or matching placebo (oral) twice daily (BID) for ≤ 35 3-week cycles. The primary objective was objective response rate (ORR) for E + P + C vs. PBO + P + C.
RESULTS: 178 patients were randomized to E + P + C (n = 91) or PBO + P + C (n = 87); 55 were enrolled in the E + P group. The E + P + C group had a lower confirmed ORR (26.4%; 95% CI 17.7-36.7) than the PBO + P + C group (44.8%; 95% CI 34.1-55.9), with a difference of - 18.5% (95% CI - 32.0 - (- 4.3); one-sided P = 0.9948). The E + P + C group had a numerically higher percentage of confirmed responders with extended response ≥ 6 months (29.2% vs. 15.4%). Circulating kynurenine levels at C1D1 were similar to those at C2D1 in all treatment groups and were not reduced to normal levels with epacadostat 100 mg BID plus P + C. The safety profile of E + P + C was consistent with that for PBO + P + C.
CONCLUSIONS: Addition of epacadostat 100 mg BID to pembrolizumab and platinum-based chemotherapy was generally well tolerated but did not improve ORR in patients with treatment-naïve metastatic NSCLC. Evaluating epacadostat doses that normalize circulating kynurenine in combination with CPIs may help determine the clinical potential of this combination.
BACKGROUND: NCT03322566. Registered October 26, 2017.

OBJECTIVE: Atezolizumab and bevacizumab (Atezo/Bev) combination immunotherapy regimens and direct oral anticoagulants (DOACs) are both associated with bleeding. Therefore, combining Atezo/Bev regimens with DOACs may exacerbate the bleeding risk. This study investigated the feasibility of the Atezo/Bev regimen in patients taking DOACs.
METHODS: This retrospective study included 141 patients with unresectable hepatocellular carcinoma (HCC) or advanced lung cancer (LC) treated with Atezo/Bev regimens. Patients who used antithrombotic agents other than DOACs were excluded. Bleeding events during the Atezo/Bev regimen were analyzed.
RESULTS: The incidence rates of bleeding of any grade in the DOAC (n = 11) and no antithrombotic agent (NAA) (n = 130) groups were 9.1% and 10.8%, respectively, with no significant differences. Moreover, no significant difference was found in the frequency of bleeding of grade ≥3 between the DOAC and NAA groups. No patients in the DOAC group discontinued the Atezo/Bev regimen because of severe bleeding. Although serum albumin levels, with a hazard ratio (HR) of 0.298 (95% confidence interval [CI]: 0.105-0.847), independently contributed to bleeding events (p = 0.023), DOAC administration did not (HR: 1.357; 95% CI: 0.157-10.54; p = 0.770). Among only patients with HCC (n = 59), none of the five patients taking DOACs experienced bleeding events. A high albumin-bilirubin score (HR: 9.083, 95% CI: 1.118-73.76) was associated with bleeding events (p = 0.039).
CONCLUSIONS: DOACs did not have a considerable effect on bleeding events in the Atezo/Bev regimens for HCC or LC. Under careful surveillance for bleeding, Atezo/Bev regimens may be feasible in patients receiving DOACs.

BACKGROUND: Programmed death 1 (PD-1)/programmed death 1 ligand 1 (PD-L1)-directed immunotherapy has revolutionized the treatments for advanced non-small cell lung cancer (NSCLC), whereas the optimal therapeutic combinations remain uncertain.
METHODS: Our study encompassed phase Ⅱ/III randomized controlled trials (RCTs) that involved anti-PD-(L)1-based therapies for stage-IV NSCLC. The primary outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and incidences of adverse events (AEs). Subgroup analyses were conducted by treatment lines, PD-L1 expression levels, histological types, and metastatic sites.
RESULTS: Our analysis incorporated 38 publications, covering 14 therapeutic combinations and involving 18,048 participants. PD-(L)1+chemotherapy (CT), PD-(L)1+ cytotoxic T lymphocyte-associated antigen-4 (CTLA4) +CT, and PD-(L)1+ T-cell immunoglobulin and ITIM domain (TIGIT) were notably effective in prolonging OS. Overall, PD-(L)1+CT and PD-(L)1+CT+ vascular endothelial growth factor (VEGF) were significantly beneficial for PFS and ORR. As for the subsequent-line treatments, incorporating radiotherapy can enhance PFS and ORR (ranked fourth among enrolled treatments). For patients with PD-L1 < 1%, PD-(L)1+CT+VEGF and PD-(L)1+CTLA4+CT were favorable approaches. Conversely, in patients with PD-L1 ≥ 50%, PD-(L)1+CT represented an effective treatment. Patients with non-squamous cell carcinoma or liver metastases might benefit from the addition of VEGF. In cases of squamous cell carcinoma or brain metastases, the combination of PD-(L)1+CTLA4+CT yielded superior benefits.
CONCLUSIONS: This study underscores the enhanced efficacy of combination immunotherapies over monotherapy. It highlights the necessity for personalized treatment, considering individual factors. These insights are vital for clinical decision-making in the management of advanced NSCLC.