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Preclinical studies show that locoregional CTLA-4 blockade is equally effective in inducing tumor eradication as systemic delivery, without the added risk of immune-related side effects. This efficacy is related to access of the CTLA-4 blocking antibodies to tumor-draining lymph nodes (TDLNs). Local delivery of anti–CTLA-4 after surgical removal of primary melanoma, before sentinel lymph node biopsy (SLNB), provides a unique setting to clinically assess the role of TDLN in the biological efficacy of locoregional CTLA-4 blockade. Here, we have evaluated the safety, tolerability, and immunomodulatory effects in the SLN and peripheral blood of a single dose of tremelimumab [a fully human immunoglobulin gamma-2 (IgG2) mAb directed against CTLA-4] in a dose range of 2 to 20 mg, injected intradermally at the tumor excision site 1 week before SLNB in 13 patients with early-stage melanoma (phase 1 trial; NCT04274816). Intradermal delivery was safe and well tolerated and induced activation of migratory dendritic cell (DC) subsets in the SLN. It also induced profound and durable decreases in regulatory T cell (Treg) frequencies and activation of effector T cells in both SLN and peripheral blood. Moreover, systemic T cell responses against NY-ESO-1 or MART-1 were primed or boosted (N = 7), in association with T cell activation and central memory T cell differentiation. These findings indicate that local administration of anti–CTLA-4 may offer a safe and promising adjuvant treatment strategy for patients with early-stage melanoma. Moreover, our data demonstrate a central role for TDLN in the biological efficacy of CTLA-4 blockade and support TDLN-targeted delivery methods. Under the skin: Although systemic immune checkpoint blockade (ICB) displays therapeutic efficacy in cancers, it induces immune-related adverse events (irAEs). Avoiding irAEs is crucial for effective ICB. Van Pul et al. performed a phase 1 clinical trial testing the effects of an intradermal injection of anti–CTLA-4 at the site of primary tumor excision in patients with early-stage melanoma. Seven of 13 patients immunologically responded to the treatment, with little to no irAEs. Responders had more tumor antigen–specific T cells in the blood, increased migratory DC activation in the sentinel lymph node (SLN), and decreased Tregs in both the SLN and blood. Thus, intradermal anti–CTLA-4 after primary tumor excision in melanoma induced a favorable immune response and has promise as a treatment option for patients with early-stage melanoma. [ABSTRACT FROM AUTHOR]

Purpose: Treatment efficacy of nivolumab was evaluated in patients with advanced, treatment-refractory solid dMMR/MSI tumors and in-depth biomarker analyses were performed to inform precision immunotherapy approaches., Patients and Methods: Patients with dMMR/MSI tumors who exhausted standard-of-care treatment options were enrolled in the Drug Rediscovery Protocol (DRUP), a pan-cancer clinical trial that treats patients with cancer based on their tumor molecular profile with off-label anticancer drugs (NCT02925234). Patients received nivolumab (four cycles of 240 mg every 2 weeks, thereafter 480 mg every 4 weeks). The primary endpoint was clinical benefit (CB: objective response (OR) or stable disease ≥ 16 weeks). Whole-genome sequencing and RNA-sequencing were performed on pre-treatment tumor biopsies., Results: 130 evaluable patients were enrolled with 16 different cancer types. CB was observed in 62% (95% CI: 53 - 70) with an OR in 45% (95% CI: 36 - 54). After a median follow-up of 14.5 months (95% CI: 13 - 19), median progression-free survival was 18 months (95% CI 9 - not reached) and median overall survival was not reached. While CB was not or only weakly associated with markers of adaptive immune cell infiltration, CB was strongly associated with expression of a broad set of innate immune receptors/ligands. This clearly contrasted findings in melanoma, where markers of adaptive immunity dominated the biomarker landscape., Conclusions: Nivolumab proved highly effective in advanced dMMR/MSI tumors. Expression of key innate immune receptors/ligands was the main predictor of good treatment outcome, contrasting findings in melanoma and strengthening the rationale for tumor-type specific biomarkers for guiding immunotherapy.

Background: Evidence concerning third-line life-prolonging drugs (LPDs) in the treatment of metastatic castration-resistant prostate cancer (mCRPC) patients is incomplete., Objective: To evaluate third-line LPD outcomes in a real-world cohort of mCRPC patients, identify variables associated with overall survival (OS), and establish a prognostic model., Design, Setting, and Participants: Patients with mCRPC who were progressive on second-line LPD before July 1, 2017 were retrospectively identified from the Dutch Castration-resistant Prostate Cancer Registry (CAPRI) and followed until December 31, 2017., Outcome Measurements and Statistical Analysis: Association of potential risk factors with OS was tested by Cox proportional hazard models after multiple imputation of missing baseline characteristics. A predictive score was computed from the regression coefficient and used to classify patients into risk groups., Results and Limitations: Of 1011 mCRPC patients progressive on second-line LPD, 602 (60%) received third-line LPD. Patients receiving third-line LPD had a more favorable prognostic profile at baseline and longer median OS than patients with best supportive care (10.4 vs 2.4 mo, p < 0.001). Eastern Cooperative Oncology Group performance status 1 and ≥2 (hazard ratio [HR] 1.51, p < 0.007 and HR 3.08, p < 0.001, respectively), opioid use (HR 1.55, p = 0.019), visceral metastases (HR 2.09, p < 0.001), hemoglobin <7 mmol/l (HR 1.44, p < 0.002), prostate-specific antigen ≥130 μg/l (HR 1.48, p = 0.001), alkaline phosphatase ≥170 U/l (HR 1.52, p < 0.001), and lactate dehydrogenase ≥250 U/l (HR 1.44; p = 0.015) were associated with shorter survival. Harrell's C-index was 0.74. The median OS values for low-, low-intermediate-, high-intermediate-, and high-risk groups were 14, 7.7, 4.7, and 1.8 mo, respectively. Limitations include the retrospective design., Conclusions: We developed a prognostic model and identified a subgroup of patients in whom third-line LPD treatment has no meaningful benefit. Our results need to be confirmed by prospective clinical trials., Patient Summary: We reported outcomes from third-line life-prolonging drugs in metastatic prostate cancer patients and developed a prognostic model that could be used to guide treatment decisions., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)