Tackling Immunotherapy Resistance: Developing Rational Combinations of Immunotherapy and Targeted Drugs

Mechanisms of resistance to immunotherapies are multiple and complex with components intrinsic to the tumor cell and within the immune microenvironment. We review evidence of the interaction of tumor cell signaling pathways with immune pathways and the role this plays in de novo and acquired resistance. The mitogen-activated protein kinase (MAPK) pathway activation and effects on T-cell function are discussed. Phosphoinositide 3-kinase (PI3K) pathway activation (including PTEN loss of function) correlates with T-cell inhibition and immunotherapy resistance. Wnt signaling has been implicated in T-cell function suppression. Key evidence from preclinical models exists for the role of these signaling pathways and is described. Clinical evidence is less advanced though correlation of mutations in key nodes with immune resistance provides a limited clinical correlation. Serial biomarker analysis in patients receiving targeted drugs has been attempted with notable examples including BRAF inhibition in melanoma patients resulting in dynamic changes in programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes. Drug combinations aim to overcome mechanisms of resistance, and recent years have seen numerous combinations of targeted therapies and immune checkpoint inhibitors proposed. However, clear biological rationale and thoughtful trial designs with a translational focus are required to allow such combinations to achieve their full potential

Response to Paclitaxel in an Adult Patient with Advanced Kaposiform Hemangioendothelioma

Background: Kaposiform hemangioendothelioma (KHE) is a rare neoplasm of vascular origin that typically arises from the skin or soft tissues as a solitary tumor. The optimal therapy for this disease is still unknown. We report the case of an adult patient presenting with metastatic KHE of the spleen, who had a partial response after treatment with paclitaxel. Case Presentation: A 36-year-old man presented in November 2012 with a nontraumatic rupture of the spleen. A splenectomy was performed, and the pathology was consistent with a nonspecific vascular proliferation. Follow-up scans revealed lytic bone lesions and liver metastasis. A biopsy of the liver was performed and confirmed KHE. The decision was made to proceed with treatment with gemcitabine and docetaxel, which was discontinued due to myelotoxicity. The patient was then transferred to our institution, and a pathology review supported the diagnosis of metastatic KHE. His disease remained stable until February 2014, when he developed progression in the liver. Chemotherapy was restarted with paclitaxel, and a partial response was documented after 3 cycles. Unfortunately, disease progression occurred after 24 weeks, and subsequent treatments included prednisone, doxorubicin, interferon-α, gemcitabine, and ifosfamide, without any response. The patient developed Kasabach-Merritt phenomenon and passed away 1 week later due to a major gastrointestinal bleeding. Conclusions: This case report suggests that paclitaxel could be considered as a treatment option for advanced KHE, a rare condition for which no standard treatment exists

Adult soft tissue myoepithelial carcinoma: treatment outcomes and efficacy of chemotherapy.

Soft tissue myoepithelial carcinomas are a rare, malignant subgroup of myoepithelial tumours mostly arising in the extremities with equal predilection for women and men. The mainstay of management of localised disease is complete surgical resection. Despite optimal treatment, 40-45% of tumours recur. Data regarding the efficacy of systemic therapy for advanced and metastatic disease are lacking. The primary aim of this study was to evaluate the outcome of all patients with soft tissue myoepithelial carcinoma treated at a single referral centre. The secondary aim was to establish the efficacy of systemic therapies in patients with advanced disease. A retrospective review of the prospectively maintained Royal Marsden Sarcoma Unit database was performed to identify soft tissue myoepithelial carcinoma patients treated between 1996 and 2019. Patient baseline characteristics and treatment history were recorded. Response to systemic therapy was evaluated using RECIST 1.1. We identified 24 patients treated at our institution between 1996 and 2019,12 males and 12 females. Median age at presentation was 49.6 years [interquartile range (IQR) 40.5-63.3 years]. Twenty-two out of 24 patients (91.7%) underwent primary surgical resection. Nine patients (37.5%) received systemic treatment. A partial response was documented in one patient treated with doxorubicin. The median progression-free survival for first-line chemotherapy was 9.3 months. Myoepithelial carcinoma frequently recurs after complete surgical resection. Conventional chemotherapy demonstrated some activity in myoepithelial carcinoma, however, more effective systemic therapies are required and enrolment in clinical trial should be encouraged

The addition of PD-1/PD-L1 axis blockade to BRAF and MEK inhibition for advanced melanoma patients harboring BRAF mutations: a systematic review and meta-analysis

Objectives: Immune-checkpoint inhibitors (ICI) and targeted-therapies (TT) have become standard options for BRAF-V600 metastatic melanomas (MM). Recently, randomized trials (RCT) addressed the efficacy of combined approaches, with conflicting results. We sought to evaluate efficacy and safety of first-line combination ICI and BRAF/MEK inhibitors (triplets) versus BRAF/MEKi (doublets). Methods: We performed a systematic review and metaanalysis of RCT comparing triplet versus doublet published in MEDLINE and EMBASE from 2016-September/2020. We obtained pooled effect estimates through random-effects model assuming p<0.05 as statistically significant. Results: Among 1,784 studies, 3 RCT were selected. Triplets demonstrated progression-free survival (PFS) (HR 0.79 - CI 0.68-0.91, p=0.001) and overall survival (OS) improvement (HR 0.81 - CI 0.67-0.98, p=0.03), with increased rates of grades 3/4 adverse events (AEs), any grade pyrexia, arthralgia, and aminotransferases elevation. AEdiscontinuation rates of all drugs remained similar. Conclusions: Triplets improved PFS and OS with manageable toxicities. These are preliminary results and mature data are expected